N-(2-fluoroethyl)aniline → 9-(2-fluoro-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide

HRID 1753961Notes

Reaction equation

HRID 1753961 reaction equation
[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8](Br)[C:7]=1O)=[O:5])[CH3:2].[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-]>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[C:7]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:19][CH2:18][F:17])[C:8]=2[CH2:9][CH:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 14524N-(2-fluoroethyl)anilineHCID 666795353-Bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide

Product 1

HCID 666800839-(2-fluoro-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamideYield 17.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47; prepared according to Example 11(d)) (2.0 g, 7 mmol) and (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (1.9 g, 14 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 (7 mL) and dry zinc chloride (2.86 g, 21 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 (100 mL) and washed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL) then dried and concentrated in vacuo. The crude mixture was purified by SCX cartridge (40 mL) and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 100 g, 12 CV, 85 mL/min) to afford 400 mg (17%) of 9-(2-fluoro-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.10-1.35 (9H, m, CH3 and N(CH2CH3)2), 1.95-2.10 (2H, m, 3-CH2), 2.30-2.50 (1H, m, 2-CH), 2.70-2.80 (2H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 4.05-4.15 (1H, m, 4-CH), 4.30 (2H, dm, J=21 Hz, NCH2CH2F), 4.65 (2H, dm, J=41 Hz, NCH2CH2F), and 7.00-7.30 (4H, m, NCCHCHCHCH.

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 (100 mL)
  5. washwashed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL)
  6. customthen dried
  7. concentrationconcentrated in vacuo
  8. customThe crude mixture was purified by SCX cartridge (40 mL)
  9. washsilica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 100 g, 12 CV, 85 mL/min)

Sources & evidence

ORD record
ord-809b7baf0d64490183a258cec59930aa
Source dataset
uspto-grants-2015_10
Patent number
US09168317B2

Reaction notes

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