Methanol → (1-{4-[4-(2-Benzyloxycarbamoyl-ethyl)-phenoxy]-benzyl}-2-morpholin-4-yl-2-oxoethyl)-carbamic acid tert-butyl ester

HRID 748992Notes

Reaction equation

HRID 748992 reaction equation
C(N1[CH2:9][CH2:8][N:7]([C:10](=[O:39])[CH:11]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[CH2:6]C1)(=O)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1.[CH3:78][OH:79]>CN(C=O)C.C(Cl)(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:11]([CH2:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26](=[O:28])[NH:77][O:76][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)[C:10]([N:7]1[CH2:6][CH2:78][O:79][CH2:9][CH2:8]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]

Participants

9

Reactant 6

HCID 887MethanolHCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 102312Benzyloxyamine hydrochlorideHCID 597628123-(4-{4-[3-(4-Acetyl-piperazin-1-yl)-2-tert-butoxycarbonylamino-3-oxo-propyl]-phenoxy}-phenyl)-propionic acid

Product 1

HCID 59762810(1-{4-[4-(2-Benzyloxycarbamoyl-ethyl)-phenoxy]-benzyl}-2-morpholin-4-yl-2-oxoethyl)-carbamic acid tert-butyl esterYield 44%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
2.5 °C

Procedure

The compound 19 (1.95 g, 3.61 mmol) was dissolved in dry DMF (30 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.54 g, 4.0 mmol), EDCI (0.7 g, 3.61 mmol), and triethylamine (1.5 mL, 11.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.64 g, 4.0 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (60 mL). The organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×40 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Silica gel flash chromatography (CHCl3:MeOH—49:1) yielded the desired benzyl hydroxamate 15 (1.0 g, 44%). 1H NMR (400 MHz, DMSO-d6): 10.93 (s, 1H), 8.23 (s, 1H), 7.28-7.33 (m, 5H), 7.20 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.84 (d, J=7.2 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 4.69 (s, 2H), 4.02 (m, 1H), 3.07-3.42 (m, 8H), 2.60-2.85 (m, 4H), 2.21 (t, J=7.6 Hz, 2H), 1.97 (s, 3H), 1.28 (s, 9H).

Workup

  1. customto come to room temperature
  2. stirringstirred for 18 h
  3. customThe solvent was evaporated under reduced pressure
  4. extractionThe organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×40 mL)
  5. dry with materialThe resulting EtOAc layer was dried
  6. concentrationconcentrated
  7. customto yield the crude product

Sources & evidence

ORD record
ord-eaaaa610733f4470bb10caca609f6e79
Source dataset
uspto-grants-2008_07
Patent number
US07399786B2

Reaction notes

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