HCID 58194817, compound → HCID 66679732, compound

HRID 1753951Notes

Reaction equation

HRID 1753951 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].[CH2:16]([O:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=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:28]3[C:27](=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[N:26]([CH2:25][CH2:24][O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 58194817HCID 58194817, compoundHCID 62566681HCID 62566681, compound

Product 1

HCID 66679732HCID 66679732, compoundYield 30.8%

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)) (2.3 g, 10 mmol) and (2-benzyloxy-ethyl)-(3-fluoro-phenyl)-amine (40) (4.1 g, 17 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 (10 mL) and dry zinc chloride (4.09 g, 30 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 (200 mL) and washed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (5-100% B, 100 g, 28 CV, 60 mL/min) to afford 1.3 g (30%) of 9-(2-benzyloxy-ethyl)-5-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (41) along with the isomer 9-(2-benzyloxy-ethyl)-7-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide as a mixture which was used in the next step without purification. The structure of 9-(2-benzyloxy-ethyl)-5-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (41) was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.10-1.40 (6H, m, N(CH2CH3)2), 1.60-2.60 (4H, m, 2- and 3-CH2), 2.70-2.85 (2H, m, 1-CH2), 3.10-3.65 (4H, m, N(CH2CH3)2 and CH2CH2OBn), 4.00-4.30 (3H, m, CH2CH2OBn and 4-CH), 4.43 (2H, s, OCH2Ph), 6.55-6.65 (1H, m, NCCHCHCHCF), 6.90-7.05 (1H, m, NCCHCHCHCF), 7.05-7.15 (1H, m, NCCHCHCHCF), and 7.16-7.25 (5H, m, Ph).

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 (200 mL)
  5. washwashed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL)
  6. customthen dried
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by silica gel chromatography
  9. washeluting with petrol (A) and ethyl acetate (B) (5-100% B, 100 g, 28 CV, 60 mL/min)

Sources & evidence

ORD record
ord-5972e97b32ee4b9ab72f4756504843f6
Source dataset
uspto-grants-2015_10
Patent number
US09168317B2

Reaction notes

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