L-Alanine → 2-(S)-{[4-(4-Fluoro-benzyl)-1-hydroxy-3-oxo-6-trifluoromethyl-3,4-dihydro-4,4a-diaza-fluorene-2-carbonyl]-amino}-propionic acid

HRID 1512009Notes

Reaction equation

HRID 1512009 reaction equation
CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][C:12]([C:27]([F:30])([F:29])[F:28])=[CH:11][CH:10]=3)[C:6]=1[OH:31])=[O:4].[NH2:32][C@H:33]([C:35]([OH:37])=[O:36])[CH3:34].C[O-].[Na+]>COCCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][C:12]([C:27]([F:30])([F:28])[F:29])=[CH:11][CH:10]=4)[C:6]([OH:31])=[C:5]([C:3]([NH:32][C@@H:33]([CH3:34])[C:35]([OH:37])=[O:36])=[O:4])[C:17]2=[O:18])=[CH:25][CH:24]=1

Participants

5

Reactant 3

HCID 5950L-AlanineHCID 10942334Sodium MethoxideHCID 687624054-(4-Fluoro-benzyl)-1-hydroxy-3-oxo-6-trifluoromethyl-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester

Product 1

HCID 547511742-(S)-{[4-(4-Fluoro-benzyl)-1-hydroxy-3-oxo-6-trifluoromethyl-3,4-dihydro-4,4a-diaza-fluorene-2-carbonyl]-amino}-propionic acidYield 30.1%

Reagents, catalysts & solvents 1

HCID 80192-MethoxyethanolSolvent

Procedure

A mixture of 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-6-trifluoromethyl-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (compound 43 d) (100 mg, 0.23 mmol), L-alanine (205 mg, 2.3 mmol) and sodium methoxide (99 mg, 1.84 mmol) in 2-methoxyethanol (3.5 mL) was microwaved at 150° C. for 2 h and concentrated. Residue was dissolved in water (80 mL), acidified to pH=3-4 using 1 N HCl solution and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography (15%-70% EtOAc (with 0.075% HOAc)/hexanes (with 0.1% HOAc)) to provide the title compound 34 mg. ESI (m/z): 490.03 (M−H)−.

Workup

  1. customwas microwaved at 150° C. for 2 h
  2. concentrationconcentrated
  3. dissolutionResidue was dissolved in water (80 mL)
  4. extractionextracted with EtOAc
  5. washOrganic layer was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customCrude product was purified by silica gel chromatography (15%-70% EtOAc (with 0.075% HOAc)/hexanes (with 0.1% HOAc))

Sources & evidence

ORD record
ord-5a68a2a83e324bd8aa7f1d6fa10981e7
Source dataset
uspto-grants-2012_07
Patent number
US08217043B2

Reaction notes

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