N-(2-fluoroethyl)aniline → [9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone

HRID 1753932Notes

Reaction equation

HRID 1753932 reaction equation
Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=O.[F:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[F:17][CH2:18][CH2:19][N:20]1[C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[C:3]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2

Participants

5

Reactant 2

HCID 14524N-(2-fluoroethyl)anilineHCID 666798302-Bromo-6-(piperidine-1-carbonyl)-cyclohexanone

Product 1

HCID 57392689[9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanoneYield 27%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20; prepared according to example 3(b)) (500 mg, 1.7 mmol) and (2-fluoro-ethyl)-phenyl-amine (24) (890 mg, 3.5 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (2 mL) and dry zinc chloride (682 mg, 5 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with 2 N HCl (20 mL), water (2×20 mL) and aqueous potassium carbonate solution (2×20 mL) then dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 151 mg (27%) of [9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (non-radioactive imaging agent 6) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC21.6, 21.8, 24.7, 26.5, 26.9, 27.4, 37.3, 43.1 (d, JCF=45 Hz), 47.0, 82.1 (d, JCF=173 Hz), 108.5, 108.9, 118.6, 119.4, 121.0, 126.8, 136.2, 172.7.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux under N2 for 16 h
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue was dissolved in ethyl acetate (50 mL)
  5. washwashed with 2 N HCl (20 mL), water (2×20 mL) and aqueous potassium carbonate solution (2×20 mL)
  6. customthen dried
  7. concentrationconcentrated in vacuo
  8. customThe crude material was triturated with diethyl ether

Sources & evidence

ORD record
ord-ef0651d3ac1249379a2e3f3e8375e6aa
Source dataset
uspto-grants-2015_10
Patent number
US09168317B2

Reaction notes

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