Hydrochloric Acid → 2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acid

HRID 1471655Notes

Reaction equation

HRID 1471655 reaction equation
[CH2:1]([C:4]1[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].O[Li].O.Cl>C1COCC1.CO.O>[CH2:1]([C:4]1[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 168937Lithium hydroxide, monohydrateHCID 90289981tert-Butyl 2-allyl-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate

Product 1

HCID 902812522-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acidYield 94.8%

Reagents, catalysts & solvents 1

HCID 21892291Methanol tetrahydrofuran waterSolvent

Procedure

tert-Butyl 2-allyl-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (300 ma, 0.87 mmol) was dissolved in 6 mL of THF/MeOH/H2O (3/2/1) and to it was added LiOH.H2O (110 mg, 2.6 mmol). The reaction mixture was allowed to stir at ambient temperature for 20 minutes. The reaction mixture was cooled to 0° C. and acidified with 1N (aq) HCl. The reaction mixture was extracted with ethyl acetate and the organic layer was separated and dried over MgSO4. The mixture was filtered and concentrated to afford 260 mg of 2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl) acetic acid. The acid from the step above (260 mg, 0.82 mmol) was dissolved in 4 mL of DMF, and to it were added 1-(3-bromo-5-fluorobenzyl)-N-(4-chlorophenyl)-N-methylhydrazinecarboxamide hydrochloride (0.74 mmol) and N,N-diisopropylethylamine (427 μL, 2.5 mmol). The reaction mixture was cooled to 0° C. and HATU (343 mg, 0.9 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for two hours and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl, saturated aqueous NaHCO3 and brine. The organic layer was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 418 mg of tert-butyl 2-allyl-3-(2-(2-(3-bromo-5-fluorobenzyl)-2-(4-chlorophenyl)(methyl)carbamoyl)hydrazinyl)-2-oxoethyl)-1H-indole-1-carboxylate as a white solid. MS (m/z): 685.1 [M+H]+; HPLC retention time 5.14 min (5-99% acetonitrile:water with 0.05% formic acid).

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. extractionThe reaction mixture was extracted with ethyl acetate
  3. customthe organic layer was separated
  4. dry with materialdried over MgSO4
  5. filtrationThe mixture was filtered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-cb9ac13a4d694cb9a48e572c91370b6a
Source dataset
uspto-grants-2015_04
Patent number
US09012441B2

Reaction notes

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