Hydrochloric Acid → (3S)-1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-phenylpiperidin-2-one

HRID 1667225Notes

Reaction equation

HRID 1667225 reaction equation
[O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]1=[O:1])[CH2:23]2

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 179862865-fluoro-2,3-dihydro-1H-isoindole hydrochlorideHCID 673587022-(2-Oxo-3-phenylpiperidin-1-yl)acetic acid

Product 1

HCID 67446405(3S)-1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-phenylpiperidin-2-one

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (4.43 g, 18.99 mmol; Example 91D) and 5-fluoroisoindoline hydrochloride (3.63 g, 20.89 mmol) in dichloromethane (30 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (5.04 mL, 28.5 mmol). After a few minutes, a dark brown solution resulted. The reaction was stirred overnight then poured into 1 N HCl (100 mL). The product was extracted into dichloromethane (3×100 mL). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in minimal dichloromethane and was loaded onto a GraceResolv™ 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes to provide the racemic title compound. Supercritical fluid chromatography using a ChiralPak® OD-H 21×250 mm column eluting using 10% to 50% methanol/CO2 over 20 minutes gave the title compound as the first eluting enantiomer. 1H NMR (300 MHz, CDCl3) δ 7.40-7.11 (m, 6H), 6.97 (dd, J=8.6, 18.0, 2H), 4.84 (dd, J=8.7, 19.3, 4H), 4.44 (dd, J=1.6, 15.7, 1H), 4.05 (d, J=15.7, 1H), 3.81-3.47 (m, 3H), 2.34-1.83 (m, 4H); MS (ESI+) m/z 353.0 (M+H)+.

Workup

  1. waitAfter a few minutes
  2. customa dark brown solution resulted
  3. extractionThe product was extracted into dichloromethane (3×100 mL)
  4. washThe combined extracts were washed with brine (100 mL)
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in minimal dichloromethane
  8. washthe product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes

Sources & evidence

ORD record
ord-0033db08fe24490e80977354ca1cfc65
Source dataset
uspto-grants-2011_10
Patent number
US08044069B2

Reaction notes

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