Potassium Carbonate → HCID 10642490, compound

HRID 481336Notes

Reaction equation

HRID 481336 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]([C:18]([O:20]C)=[O:19])=[C:5]2[OH:22].Br[CH2:24][C:25]([O:27]C)=[O:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[C:4]([C:5]=1[O:22][CH2:24][C:25]([OH:27])=[O:26])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)([OH:20])=[O:19]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 60984Methyl bromoacetateHCID 54731653HCID 54731653, compound

Product 1

HCID 10642490HCID 10642490, compoundYield 106.4%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Procedure

A mixture of methyl 5-chloro-1-(4-fluorophenyl)-3-hydroxy-1H-indol-2-carboxylate (200 g, 0.62 mol), methyl 2-bromoacetate (125 g, 0.81 mol), K2CO3 (112 g, 0.81 mol) and acetone (2.0 L) was refluxed for 18 h. The mixture was cooled to room temperature and filtered, and the solvents were evaporated in vacuo. To the remaining oil (270 g) methanol (1.5 L) and 3N aqueous KOH (0.6 L) was added. After reflux for 1 h, the solution was cooled to room temperature and acidified by concentrated hydrochloric acid. The product thus precipitated was filtered off and dissolved in ethyl acetate and dried (Na2SO4). Evaporation of the solvents afforded 2-[2-carboxy-5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]acetic acid (240 g) as an oil which was decarboxylated without further purification. A mixture of the crude dicarboxylic acid, copper (15 g) and N-methyl-2-pyrrolidone was refluxed for 1.5 h. The mixture was cooled to room temperature and water (2.0 L) was added. The product thus precipitated was filtered off and dissolved in ethyl acetate (1.5 L). The solution was washed with brine (3×1 L) and dried (Na2 SO4). Evaporation of the solvents afforded the crude 2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]acetic acid (223 g) which was dissolved in dry diethyl ether (1.5 L). The thus formed solution was added to a suspension of lithium aluminum hydride (70 g, 1.9 mol) in dry diethyl ether (1.0 L) over 45 min. After reflux for additional 0.5 h, the reaction mixture was cooled to 0° C. and carefully treated with water (70 ml), 4N aqueous NaOH and then water (300 mL). The reaction mixture was filtered and dried (Na2SO4). Evaporation of the solvents afforded crystalline title compound (110 g, 55%). An analytical sample was recrystallized from diethyl ether: mp 118°-120° C.; 1H NMR (CDCl3) δ 2.35 (broad s, 1 H),4.0 (t, 2 H), 4.15 (t, 2 H), 6.85 (s, 1 H), 7.10 (broad d, 1 H), 7.15 (t, 2 H), 7.40 (dd, 2 H), 7.65 (broad s, 1 H). Anal. (C16H13ClF--NO2) C, H, N.

Workup

  1. temperaturewas refluxed for 18 h
  2. filtrationfiltered
  3. customthe solvents were evaporated in vacuo
  4. additionTo the remaining oil (270 g) methanol (1.5 L) and 3N aqueous KOH (0.6 L) was added
  5. temperatureAfter reflux for 1 h
  6. temperaturethe solution was cooled to room temperature
  7. customThe product thus precipitated
  8. filtrationwas filtered off
  9. dissolutiondissolved in ethyl acetate
  10. dry with materialdried (Na2SO4)
  11. customEvaporation of the solvents

Sources & evidence

ORD record
ord-0539f60552ea4b1bb115358b76518227
Source dataset
uspto-grants-1998_08
Patent number
US05789404

Reaction notes

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