3-Bromo-5-chloro-1-methylpyridin-2(1H)-one → 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,l-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester

HRID 895886Notes

Reaction equation

HRID 895886 reaction equation
Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][CH:25]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=2)=[CH:28][CH:29]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]

Participants

6

Reactant 2

HCID 223820353-Bromo-5-chloro-1-methylpyridin-2(1H)-oneHCID 59912887N-Boc-4-(Tributylstannyl)-L-phenylalanine Methyl Ester

Product 1

HCID 599128884-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,l-dimethylethoxy)carbonyl]-L-phenylalanine methyl esterYield 54%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 3-bromo-5-chloro-1-methyl-2-pyridone (660 mg, 2.97 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (1.7 g, 2.99 mmol) in DMF (30 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). Tetrakis(triphenylphosphine)palladium (140 mg, 0.20 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 140 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in 1:1 ether:ethyl acetate (60 mL). The solution was washed with water (3×10 mL) and brine (1×10 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 150 g of silica gel eluting with 7:3 ethyl acetate:hexane to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (670 mg, 54%). LRMS-Electrospray: m/z 863 (2M+Na), 858 (2M+NH4), 443 (M+Na), 438 (M+NH4), 421(M+H).

Workup

  1. additionan additional 140 mg portion of the catalyst was added
  2. temperatureheating
  3. temperatureto cool
  4. filtrationwas filtered through a pad of celite
  5. customThe filtrate was evaporated to dryness
  6. dissolutionthe residue was dissolved in 1:1 ether
  7. washThe solution was washed with water (3×10 mL) and brine (1×10 mL)
  8. dry with materialwas dried (MgSO4)
  9. customThe residue obtained upon concentration
  10. customwas chromatographed over 150 g of silica gel eluting with 7:3 ethyl acetate

Sources & evidence

ORD record
ord-6ffa7d2b48c94d98b982339c51443fa3
Source dataset
uspto-grants-2005_07
Patent number
US06916933B2

Reaction notes

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