Reaction #1832

Reaction equation

benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

3-t-butoxycarbonylamino-3-methylbutanoic acid

triethylamine

→

product

Yield 94.0%

3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide

Yield 94.0%

Solvents

ethyl acetate

methylene chloride

Conditions

Workup

1. 1
   Otherwas immersed in an ambient temperature
2. 2
   Washwashed three times with 5% aqueous citric acid
3. 3
   OtherThe organic layer was removed
4. 4
   Dryingdried over magnesium sulfate
5. 5
   Filtrationfiltered
6. 6
   Concentrationthe filtrate concentrated under vacuum
7. 7
   OtherThe residue was purified by preparative high pressure liquid chromatography on silica
8. 8
   Washeluting with ethyl acetate/hexane (4:1)

Procedure

A solution of 8.70 g (49.4 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step E) in 100 mL of methylene chloride was treated with 10.73 g (49.4 mmol) of 3-t-butoxycarbonylamino-3-methylbutanoic acid (Step H) and 13.8 mL of triethylamine (10.0 g, 99 mmol, 2 eq.). The reaction flask was immersed in an ambient temperature water bath then 26 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (59 mmol, 1.2 eq) was added all at once and the mixture stirred at room temperature for 2 hours. The reaction mixture was added to 300 mL of ethyl acetate and washed three times with 5% aqueous citric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (4:1), to afford 17.42 g (46.4 mmol, 94%) of the product as a white solid. 1H NMR (200 MHz,CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz,1H), 2.59 (d,15 Hz,1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz,1H), 6.98 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).

Source