HCID 59722694, compound → HCID 59722712, compound

HRID 1664858Notes

Reaction equation

HRID 1664858 reaction equation
[CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=2[F:27])[CH2:16][N:15]2[C:28]([C:31]([O:33]C)=O)=[CH:29][N:30]=[C:14]12)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:27][C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[C@H:17]1[CH2:16][N:15]2[C:28]([C:31]3([OH:33])[CH2:2][CH2:1]3)=[CH:29][N:30]=[C:14]2[C@H:13]([NH:12][C:10](=[O:11])[O:9][C:5]([CH3:7])([CH3:8])[CH3:6])[CH2:19][CH2:18]1

Participants

5

Reactant 2

HCID 59722694HCID 59722694, compoundHCID 178418443HCID 178418443, compound2×

Product 1

HCID 59722712HCID 59722712, compoundYield 42.2%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalyst2×HCID 3283Diethyl EtherSolvent

Procedure

Ethylmagnesium bromide (3 M in ether; 0.17 mL, 0.51 mmol) was added dropwise over 15 min to a solution of titanium(IV) isopropoxide (0.08 mL, 0.26 mmol) and methyl (6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine-3-carboxylate (54 mg, 0.13 mmol) in ether (0.9 mL) at 0° C. After 1.5 h, additional titanium(IV) isopropoxide (0.08 mL, 0.26 mmol) and ethylmagnesium bromide (3 M in ether; 0.17 mL, 0.51 mmol) were added. After 1.5 h, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated. Purification by reverse phase HPLC (C-18, 80% water/acetonitrile→40% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (23 mg). MS 420.2 (M+1).

Workup

  1. waitAfter 1.5 h
  2. customthe mixture was quenched with saturated aqueous sodium bicarbonate
  3. extractionextracted with ethyl acetate (3×)
  4. washThe combined organic layers were washed with saturated brine
  5. dry with materialdried with magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification by reverse phase HPLC (C-18, 80% water/acetonitrile→40% water/acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-e1de8473f4444997a4c7a1a99f649f10
Source dataset
uspto-grants-2011_10
Patent number
US08039460B2

Reaction notes

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