Ethyl Acetate → Ethyl 5-([2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-5-fluorophenyl)ethyl]{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate

HRID 875332Notes

Reaction equation

HRID 875332 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[CH2:23][CH2:24][NH:25][CH:26]4[CH2:35][CH2:34][CH2:33][C:32]5[N:31]=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:28][C:27]4=5)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:43]=1.I[CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[CH2:23][CH2:24][N:25]([CH2:45][CH2:46][C:47]4[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=4)[CH:26]4[CH2:35][CH2:34][CH2:33][C:32]5[N:31]=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:28][C:27]4=5)=[CH:41][CH:42]=3)=[N:7][C:6]=2[CH:43]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium Carbonate3×HCID 22639144Methyl 4-(2-iodoethyl)benzoate3×HCID 86709818Ethyl 5-{[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate

Product 1

HCID 86709820Ethyl 5-([2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-5-fluorophenyl)ethyl]{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
110 °C

Procedure

A suspension of 375 mg (0.63 mmol) of ethyl 5-{[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]-oxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 117A), 272 mg (0.94 mmol) of methyl 4-(2-iodoethyl)benzoate and 99 mg (0.94 mmol) of anhydrous sodium carbonate in 10 ml of dry acetonitrile was stirred overnight at a bath temperature of 110° C. A further 272 mg of methyl 4-(2-iodoethyl)benzoate and 99 mg of sodium carbonate were then added, and the mixture was once more heated under reflux overnight. Another 272 mg of methyl 4-(2-iodoethyl)benzoate and 99 mg of sodium carbonate were then added, and the mixture was again heated under reflux overnight. After cooling of the reaction mixture, ethyl acetate and water were added, the organic phase was separated off and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1→2:1). This gave 324 mg (0.42 mmol, 68% of theory) of the target compound.

Workup

  1. temperaturethe mixture was once more heated
  2. temperatureunder reflux overnight
  3. temperaturethe mixture was again heated
  4. temperatureunder reflux overnight
  5. additionwere added
  6. customthe organic phase was separated off
  7. extractionthe aqueous phase was extracted three more times with ethyl acetate
  8. dry with materialThe combined organic phases were dried over magnesium sulphate
  9. filtrationfiltered
  10. customevaporated to dryness
  11. customThe residue obtained
  12. customwas purified chromatographically on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1→2:1)

Sources & evidence

ORD record
ord-c65e82ee7bda46bfa815e2e47ec81d1b
Source dataset
uspto-grants-2015_03
Patent number
US08981104B2

Reaction notes

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