Chloroacetonitrile → HCID 131727468, compound

HRID 883613Notes

Reaction equation

HRID 883613 reaction equation
[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][NH:12][CH2:11]3)[CH:8]=[CH:9][C:2]1=2.Cl[CH2:21][C:22]#[N:23].[C:24](=[O:27])([O-:26])[O-].[Cs+].[Cs+].[C:30]([O:33]CC)(=[O:32])C>CN(C=O)C>[C:30]([OH:33])(=[O:32])/[CH:21]=[CH:22]/[C:24]([OH:26])=[O:27].[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][N:12]([CH2:21][C:22]#[N:23])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2

Participants

6

Reactant 4

HCID 7856ChloroacetonitrileHCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 11536296HCID 11536296, compound

Product 1

HCID 131727468HCID 131727468, compoundYield 31%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-benzo[b]thiophen-5-yl-1,2,3,4-tetrahydroisoquinoline (250 mg, 0.94 mmol, the preparation of which was described in Example 20), chloroacetonitrile (285 mg, 3.77 mmol), and cesium carbonate (614 mg, 1.88 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed with 5% LiOH solution, then brine, and the organic layer dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (SiO2, 12 g, 85% to 0% hexane/ethyl acetate) to provide the desired tetrahydroisoquinoline (90 mg, 31%). This material was dissolved in methanol and treated with a solution of fumaric acid in methanol (5 mL) at 0° C. The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether providing (4-benzo[b]thiophen-5-yl-3,4-dihydro-1H-isoquinolin-2-yl)-acetonitrile, fumarate salt (91 mg, 73%, 97.6% AUC HPLC): 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (d, J=8.3 Hz, 1H), 7.74-7.68 (m, 2H), 7.39 (d, J=5.4 Hz, 1H), 7.24-7.06 (m, 4H), 6.83 (d, J=7.6 Hz, 1H), 6.63 (s, 2H), 4.43-4.39 (m, 1H), 3.99-3.76 (m, 4H), 3.12-3.07 (m, 1H), 2.83-2.77 (m, 1H); ESI-MS m/z=306 [M+H].

Workup

  1. customthe preparation of which
  2. washwashed with 5% LiOH solution
  3. dry with materialbrine, and the organic layer dried over magnesium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by column chromatography (SiO2, 12 g, 85% to 0% hexane/ethyl acetate)

Sources & evidence

ORD record
ord-bf0a9145ab794ef695c5c13696cd617f
Source dataset
uspto-grants-2012_08
Patent number
US08236796B2

Reaction notes

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