Sodium Hydroxide → HCID 89572991, compound

HRID 74766Notes

Reaction equation

HRID 74766 reaction equation
[C:1]([NH:4][C:5]([CH:13]1[CH2:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(C#N)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][CH:5]([CH:13]1[CH2:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 86685739Ethyl (acetylamino)(bicyclo[4.2.0]octa-1,3,5-trien-7-yl)cyanoacetate

Product 1

HCID 89572991HCID 89572991, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

To a mixture of #99 (4.38 mg, <16.1 mmol, 1 eq.) in methanol (30 mL, 0.53 M) was added a 1 N aqueous solution of sodium hydroxide (38 mL, 38 mmol, 2.4 eq.). The reaction mixture was heated at reflux overnight, then concentrated in vacuo, diluted with water (40 mL), and acidified with a 1 N aqueous solution of hydrochloric acid (40 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (Solvent A: dichloromethane; Solvent B: 20% methanol in dichloromethane containing 0.02% trifluoroacetic acid; Gradient: 0% to 40% B) then by supercritical fluid chromatography (Column: Chiralpak AD-H, 250×21 mm; Eluent: 85:15 carbon dioxide/methanol; Flow Rate: 65 g/min; Detection: 210 nm; Instrument: Berger minigram preparative SFC system). The second eluting peak was isolated to give #100 (600 mg, 17% over two steps) as a single enantiomer (retention time=3.37 minutes, purity >99%). LC-MS: m/z 220.3 [M+H+], retention time=2.10 minutes; 1H NMR (400 MHz, CD3OD) δ 7.14-7.24 (m, 2H), 7.03-7.09 (m, 2H), 4.59 (d, J=8.6 Hz, 1H), 3.87 (ddd, J=8.5, 5.3, 2.4 Hz, 1H), 3.35 (dd, J=14.5, 5.4 Hz, 1H, assumed; partially obscured by solvent peak), 3.10 (dd, J=14.4, 2.4 Hz, 1H), 2.00 (s, 3H). Optical rotation: [α]D25+70.9° (c 0.67, methanol)

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux overnight
  3. concentrationconcentrated in vacuo
  4. additiondiluted with water (40 mL)
  5. extractionThe aqueous layer was extracted with dichloromethane (3×30 mL)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe resulting oil was purified by silica gel chromatography (Solvent A: dichloromethane; Solvent B: 20% methanol in dichloromethane containing 0.02% trifluoroacetic acid; Gradient: 0% to 40% B)
  10. customThe second eluting peak was isolated
  11. customto give #100 (600 mg, 17% over two steps) as a single enantiomer (retention time=3.37 minutes, purity >99%)

Sources & evidence

ORD record
ord-f05fc181f3194fb5b3d0a4fc0da7496e
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Reaction notes

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