Hydrochloric Acid → (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid

HRID 1072288Notes

Reaction equation

HRID 1072288 reaction equation
C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([OH:18])(=[O:17])/[CH:14]=[CH:15]/[CH3:16].CN(OC)C(C1CC1)=O.[Na+].[Cl-].Cl.CS(O)(=O)=O.[F:36][C:37]1[CH:51]=[CH:50][C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[NH2:49])=O)=[CH:39][CH:38]=1>C1COCC1.O.C(O)(=O)C>[CH:10]1([C:11]2[C:16](/[CH:15]=[CH:14]/[C:13]([OH:18])=[O:17])=[C:41]([C:40]3[CH:50]=[CH:51][C:37]([F:36])=[CH:38][CH:39]=3)[C:43]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:49]=2)[CH2:8][CH2:9]1

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 5234Sodium ChlorideHCID 7912DiisopropylamineHCID 637090Crotonic AcidHCID 15643267N-Methoxy-N-methylcyclopropanecarboxamideHCID 53446970(2-Aminophenyl)(4-fluorophenyl)methanone methanesulfonateHCID 178418339Butyllithium

Product 1

HCID 22392019(E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
0 °C

Procedure

To a mixture of diisopropylamine (2.42 g, 24.0 mmol) and 8.88 ml (24.0 mmol) butyllithium (2.7M in Heptan) in THF (20 ml) at −70° C. is added a soln. of crotonic acid (1.03 g, 12.0 mmol) in THF (10.0 ml). After stirring at −70° C. and 0° C., a soln. of cyclopropanecarboxylic acid N,O-dimethylhydroxylamide (1.29 g, 10.0 mmol) in THF (10.0 ml) is added. The solution is heated to 48° C. After cooling to −50° C., a solution of glacial acetic acid (5 ml) in THF (10 ml), and 20% aq. NaCl (25 ml) are slowly added. The pH is adjusted to 1.5 with 2M HCl and the mixture is extracted with CH2Cl2 (3×25 ml). Organic phases are washed with 20% aqeous NaCl (2×25 ml) and evaporated to dryness under reduced pressure. The resulting yellow oil is dissolved in toluene (100 ml). 4-Fluoro-2′-aminobenzophenone methansulfonic acid salt (3.23 g, 10.4 mmol) is added and the solution is refluxed in a water separator apparatus for 24 h. Upon cooling, a brown precipitate is formed, which is separated from the mother liquor and purified by chromatography on silica gel (CH2Cl2—MeOH) to afford (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid. MS (ES): [M−H]− 332.

Workup

  1. additionis added a soln
  2. temperatureThe solution is heated to 48° C
  3. temperatureAfter cooling to −50° C.
  4. extractionthe mixture is extracted with CH2Cl2 (3×25 ml)
  5. washOrganic phases are washed with 20% aqeous NaCl (2×25 ml)
  6. customevaporated to dryness under reduced pressure
  7. dissolutionThe resulting yellow oil is dissolved in toluene (100 ml)
  8. temperatureUpon cooling
  9. customa brown precipitate is formed
  10. customwhich is separated from the mother liquor
  11. custompurified by chromatography on silica gel (CH2Cl2—MeOH)

Sources & evidence

ORD record
ord-c6e0b3d880b64d3baddbb954bbe9e263
Source dataset
uspto-grants-2005_06
Patent number
US06909003B2

Reaction notes

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