Dimethylformamide → 5-Fluoro-3-[2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-pyridazin-4-yl)-butyrylamino]-4-oxo-pentanoic acid tert-butyl ester

HRID 446889Notes

Reaction equation

HRID 446889 reaction equation
[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([NH2:13])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:25]2[CH:26]=[CH:27][CH:28]=N[C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:39]([N:41](CC)CC)C.CC(OI1(OC(C)=O)(OC(C)=O)[O:59][C:57](=O)[C:56]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]1=2)=O.[CH3:68][N:69]([CH:71]=[O:72])C>C(O)(C)C.ClCCl>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([NH:13][C:57](=[O:59])[CH:56]([C:51]1[C:71](=[O:72])[N:69]([C:68]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:41]=[CH:39][C:52]=1[CH3:53])[CH2:55][CH3:54])[C:9](=[O:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 159087TriacetoxyperiodinaneHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 108566723-Amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester

Product 1

HCID 866364985-Fluoro-3-[2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-pyridazin-4-yl)-butyrylamino]-4-oxo-pentanoic acid tert-butyl esterYield 72%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of the carboxylic acid derivative of Preparation 1-5) (271 mg, 1.00 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (see Tetrahedron Letters, 1994, 35(52), 9693-9696, 248 mg, 1.2 eq) and HATU (494 mg, 1.3 eq) was cooled to 0° C., triethylamine (0.56 mL, 4.0 eq) was added thereto in DMF solvent (5 mL), and the mixture was reacted for one day. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (30 mL×2), washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. To this compound and Dess-Martin reagent (848 mg, 2.0 eq) was added anhydrous dichloromethane (4 mL), which was then stirred for 1 h at room temperature. The reaction was stopped by isopropyl alcohol (1 mL). The solid was removed by celite filtration under reduced pressure, and extracted with ethyl acetate (20 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (30-40% ethyl acetate-hexane) to give 330 mg (72%) of the title compound.

Workup

  1. distillationThe solvent was distilled under reduced pressure
  2. extractionThe residue was extracted with ethyl acetate (30 mL×2)
  3. washwashed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution
  4. dry with materialdried (anhydrous Na2SO4)
  5. concentrationconcentrated under reduced pressure
  6. customThe solid was removed by celite filtration under reduced pressure
  7. extractionextracted with ethyl acetate (20 mL×2)
  8. washThe extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution
  9. dry with materialdried (anhydrous Na2SO4)
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was separated by column chromatography (30-40% ethyl acetate-hexane)

Sources & evidence

ORD record
ord-732530e5fc234186853ebc6bfd917788
Source dataset
uspto-grants-2013_07
Patent number
US08481537B2

Reaction notes

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