Diethyl Ether → Azepane-1-carboxylic acid {1-[2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylcarbamoyl]-3-methyl-butyl}-amide

HRID 278886Notes

Reaction equation

HRID 278886 reaction equation
[N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH2:49])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([NH:49][C:12]([CH:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 79724-MethylmorpholineHCID 7530182(2S)-2-(azepane-1-carbonylamino)-4-methylpentanoic acidHCID 70090603(S)-2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine

Product 1

HCID 18711789Azepane-1-carboxylic acid {1-[2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylcarbamoyl]-3-methyl-butyl}-amideYield 24%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 87 mg (0.34 mmol) of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.131 mL (1.2 mmol) 4-methylmorpholine was stirred at 25° C. for 30 minutes, after which 136 mg (0.36 mmol) 0-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was added. The resulting solution was cooled in an ice-bath and 150 mg (0.34 mmol) 2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine (Example 3, Step D) was added. The resulting solution was warmed to 25° C. and stirred for 30 minutes. The mixture was then poured into 35 mL diethyl ether, and washed sequentially with 25 mL each of 2.5% aqueous HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an amber oil that was purified by preparative thin-layer chromatography on a 1000 μm silica gel plate with 50:50:1 ethyl acetate:hexane:methanol as eluant to give 46 mg (24%) of the title compound as a pale amber glass.

Workup

  1. temperatureThe resulting solution was cooled in an ice-bath
  2. washwashed sequentially with 25 mL each of 2.5% aqueous HCl solution, brine, saturated aqueous sodium bicarbonate solution
  3. dry with materialThe mixture was then dried over anhydrous sodium sulfate
  4. concentrationconcentrated at reduced pressure
  5. customto give an amber oil that
  6. customwas purified by preparative thin-layer chromatography on a 1000 μm silica gel plate with 50:50:1 ethyl acetate

Sources & evidence

ORD record
ord-87331e3db36346b9808635bd6250a2d6
Source dataset
uspto-grants-2002_03
Patent number
US06362174B1

Reaction notes

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