HCID 58194817, compound → HCID 57399616, compound

HRID 1753954Notes

Reaction equation

HRID 1753954 reaction equation
[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[F:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2].[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:21]3[C:20](=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]

Participants

6

Reactant 2

HCID 58194817HCID 58194817, compoundHCID 80700116HCID 80700116, compound

Product 2

HCID 57399616HCID 57399616, compoundYield 6%HCID 57403127HCID 57403127, compoundYield 3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35; prepared according to Example 7(c)) (161 mg, 0.6 mmol) and (2-fluoro-ethyl)-(3-fluoro-phenyl)-amine (43) (184 mg, 1.2 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 (1 mL) and dry zinc chloride (245 mg, 1.8 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 (10 mL) and washed with 2 N HCl (5 mL), water (2×5 mL) and aqueous potassium carbonate solution (2×5 mL) then dried and concentrated in vacuo. The crude material was purified by semi preparative HPLC eluting with water (A) and methanol (B) (Gemini 5 u, C18, 110 A, 150×21 mm, 50-95% B over 20 Min, 21 mL/min) to afford 20 mg (6%) of 7-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide as a white solid and 10 mg (3%) of 5-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 10) as a white solid. The structure of 7-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.14 (3H, t, J=7 Hz, N(CH2CH3)2), 1.33 (3H, t, J=7 Hz, N(CH2CH3)2), 1.80-2.15 (4H, m, 2- and 3-CH2), 2.70-2.80 (2H, m, 1-CH2), 3.50-3.80 (4H, m, N(CH2CH3)2), 4.20-4.35 (1H, m, 4-CH), 4.40 (2H, dm, J=21 Hz, NCH2CH2F), 4.60 (2H, dm, J=41 Hz, NCH2CH2F), 6.70-6.80 (1H, m, NCCHCFCHCH), and 7.00-7.10 (2H, m, NCCHCFCHCH).

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 (10 mL)
  5. washwashed with 2 N HCl (5 mL), water (2×5 mL) and aqueous potassium carbonate solution (2×5 mL)
  6. customthen dried
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by semi preparative HPLC
  9. washeluting with water (A) and methanol (B) (Gemini 5 u, C18, 110 A, 150×21 mm, 50-95% B over 20 Min, 21 mL/min)

Sources & evidence

ORD record
ord-71fa958732564507ab2d500fcae76973
Source dataset
uspto-grants-2015_10
Patent number
US09168317B2

Reaction notes

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