Diisopropylethylamine → (s)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-amide

HRID 990365Notes

Reaction equation

HRID 990365 reaction equation
Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:39]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]([NH:22][C:46]([N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:15]2)=[CH:5][CH:4]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 119722Hexahydro-1H-azepine-1-carbonyl chlorideHCID 70157127(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride

Product 1

HCID 53782609(s)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-amideYield 20%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 241BenzeneSolvent

Procedure

To a solution of (S)-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride (189 mg, 0.46 mmol) in benzene (2 mL) were added sequentially N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), 4-dimethylaminopyridine (20 mg), and azepane-1-carbonyl chloride (0.13 mL, 0.78 mmol) under nitrogen atmosphere. The resulting reaction mixture was refluxed for 16 hours, then cooled to ambient temperature. The reaction mixture was filtered to remove the white solid formed during the reaction; the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a slightly amber colored oil. The crude product was purified first by flash chromatography (50% EtOAc in hexanes), then by preparative plate (50% EtOAc in hexanes) affording 46.6 mg (20%) of the pure titled compound as a clear oil. APCI-MS m/z 513.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. temperaturewas refluxed for 16 hours
  3. filtrationThe reaction mixture was filtered
  4. customto remove the white solid
  5. customformed during the reaction
  6. concentrationthe filtrate was concentrated in vacuo
  7. dissolutionThe residue was dissolved in EtOAc (25 mL)
  8. washwashed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationThe solution was concentrated in vacuo
  11. customaffording a slightly amber colored oil
  12. customThe crude product was purified first by flash chromatography (50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-293f0ba10f044612b5070fc3348ef8a1
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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