Sodium Carbonate → Ethyl 5-([2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)ethyl]{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate

HRID 875333Notes

Reaction equation

HRID 875333 reaction equation
I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl.[Cl:22][C:23]1[CH:24]=[C:25]([C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)[CH:26]=[CH:27][C:28]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH2:39][NH:40][CH:41]1[CH2:50][CH2:49][CH2:48][C:47]2[N:46]=[C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43][C:42]1=2>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([C:56]2[CH:57]=[CH:58][C:59]([C:62]([F:64])([F:65])[F:63])=[CH:60][CH:61]=2)[CH:26]=[CH:27][C:28]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH:41]1[CH2:50][CH2:49][CH2:48][C:47]2[N:46]=[C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43][C:42]1=2

Participants

5

Reactant 3

HCID 10340Sodium Carbonate2×HCID 22639144Methyl 4-(2-iodoethyl)benzoate4×HCID 86709822Ethyl 5-{[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate dihydrochloride

Product 1

HCID 86709821Ethyl 5-([2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)ethyl]{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

685 mg (2.36 mmol) of methyl 4-(2-iodoethyl)benzoate and 188 mg (1.77 mmol) of anhydrous sodium carbonate were added to a solution of 740 mg (1.18 mmol) of ethyl 5-{[2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate dihydrochloride (Enantiomer 2, Example 116A) in 20 ml of dry acetonitrile, and the mixture was heated under reflux overnight. A further 342 mg of methyl 4-(2-iodoethyl)benzoate were then added, and the mixture was stirred under reflux overnight. This procedure was repeated two more times on the subsequent days. Then, another 342 mg of methyl 4-(2-iodoethyl)benzoate and 188 mg of anhydrous sodium carbonate were added and the mixture was again stirred under reflux overnight. Another 342 mg of methyl 4-(2-iodoethyl)benzoate were then added to the reaction solution, and the mixture was heated under reflux overnight and then cooled to room temperature. The reaction was filtered, the filter cake was washed with acetonitrile and the filtrate was concentrated to dryness. The residue was taken up in ethyl acetate, and water was added. The organic phase was separated, dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 588 mg (0.40 mmol, 63% of theory) of the title compound.

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux overnight
  3. temperatureunder reflux overnight
  4. stirringthe mixture was again stirred
  5. temperatureunder reflux overnight
  6. temperaturethe mixture was heated
  7. temperatureunder reflux overnight
  8. filtrationThe reaction was filtered
  9. washthe filter cake was washed with acetonitrile
  10. concentrationthe filtrate was concentrated to dryness
  11. additionwater was added
  12. customThe organic phase was separated
  13. dry with materialdried over magnesium sulphate
  14. filtrationfiltered
  15. customevaporated to dryness
  16. customThe residue obtained
  17. customwas purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1)

Sources & evidence

ORD record
ord-560327a249204ab8be0e6f9676ab6412
Source dataset
uspto-grants-2015_03
Patent number
US08981104B2

Reaction notes

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