Hydrochloric Acid → 1H-Indole-3-acetic acid, 1-[(1,1-dimethylethoxy)carbonyl]-2,3-dihydro-

HRID 1983998Notes

Reaction equation

HRID 1983998 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@@H:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

3

Reactant 2

HCID 313Hydrochloric AcidHCID 68855231HCID 68855231, compound

Product 1

HCID 185458151H-Indole-3-acetic acid, 1-[(1,1-dimethylethoxy)carbonyl]-2,3-dihydro-

Procedure

Methyl (RS)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (50 g, 0.17 mol) was mixed with Candida Antarctica Lipase (CAL, SP-435, Novo Nordisk, Denmark) (2.5 g) and subsequently added 0.1 M phosphate buffer (pH=7.0) (3 L) under vigorous stirring. The resulting mixture was stirred vigorously at 25° C. for 120 h, and the pH was maintained at 7 by the addition of 0.5 N NaOH. After addition of about 0.45 equivalent of base, filtering off the enzyme stopped the reaction. The enzyme was washed with diethyl ether (1 L), and the pH of the aqueous phase was adjusted to 8. The aqueous phase was extracted with diethyl ether (2×1 L), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give crude methyl (R)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid, which was used for the synthesis of (−)-(R)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (see below). The aqueous phase was cooled by addition of ice, and the pH adjusted to 1.5 with 37% HCl (aq). The aqueous phase was extracted with diethyl ether (3×1 L), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give crude title compound (enantiomeric excess was about 80-85%). A number of precipitations from diisopropyl ether gave the title compound: mp 137-138° C.; enantiomeric excess 96.5%; [α]D=+12.8° (c=0.45, methanol). The chiral analysis was performed on a Ultron ES OVM 150×4.6 mm, flow 1.0 ml/min, eluent 25 mM phosphate buffer (pH≅4.6)/methanol/2-propanol/tetrahydrofuran 90/5/5/0.5, T=30° C. Enantiomeric purities expressed as enantiomeric excess (ee) were calculated from peak areas.

Workup

  1. temperatureThe aqueous phase was cooled by addition of ice
  2. extractionThe aqueous phase was extracted with diethyl ether (3×1 L)
  3. dry with materialthe combined organic extracts were dried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customto give crude title compound (enantiomeric excess was about 80-85%)
  6. customA number of precipitations from diisopropyl ether

Sources & evidence

ORD record
ord-b82c2e1d819b4e388f828279548a0f64
Source dataset
uspto-grants-2009_06
Patent number
US07544685B2

Reaction notes

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