Methanesulfonic Acid → 4-Benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

HRID 883608Notes

Reaction equation

HRID 883608 reaction equation
C(O)(=O)/C=C/C(O)=O.[S:9]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([CH:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH2:21][N:20]([CH3:30])[CH2:19]3)[CH:16]=[CH:17][C:10]1=2.S(O)(C)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[S:9]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([CH:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH2:21][N:20]([CH3:30])[CH2:19]3)[CH:16]=[CH:17][C:10]1=2

Participants

5

Reactant 3

HCID 6395Methanesulfonic AcidHCID 14798Sodium HydroxideHCID 131727465(+)-4-Benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, fumarate salt

Product 1

HCID 689943124-Benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolineYield 53%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of the product obtained from Step E (25.0 g, 76.5 mmol) in CH2Cl2 (500 mL) was added MsOH (74 g, 770 mmol) slowly at room temperature. The solution was stirred at room temperature for 15 minutes. The mixture was slowly added to an ice-cooled NaOH solution (2 N, 500 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (200 mL) one more time. The organic layers were combined, washed with water (500 mL) and brine 300 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (eluent: MeOH/EtOAc/Hex 1:9:15) to give 4-benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (12.5 g, 53%) as a foam solid. It was then resolved by a CHRIALPAK AD column (eluent: 10 IPA/90Heptane/0.1 DEA). A small amount of (+)-enantiomer [[α]25D +74.3° (c 0.07, methanol)] (65 mg, 0.21 mmol) was dissolved in methanol (5 mL), and to this solution was added fumaric acid (24 mg, 0.21 mmol). The solution was concentrated to less than 1 mL. To this solution was added water (5 mL). The resulting suspension was then lyophilized on a freeze dryer to give (+)-4-benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, fumarate (55 mg, 62%, >99% AUC HPLC) as a white solid: mp 103-105° C.; 1H NMR (500 MHz, CD3OD) δ 7.89 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.34 (d, J=5.5 Hz, 1H), 7.17 (dd, J=8.3, 1.6 Hz, 1H), 6.84-6.80 (m, 3H), 6.72 (s, 4H), 4.60 (dd, J=10.5, 6.0 Hz, 1H), 4.48-4.42 (m, 2H), 3.37-3.74 (m, 4H), 3.44 (t, J=10.5 Hz, 1H), 2.98 (s, 3H); ESI-MS m/z 310 [M+H]+.

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous layer was extracted with dichloromethane (200 mL) one more time
  3. washwashed with water (500 mL) and brine 300 mL),
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. customThe residue was purified by flash column chromatography (eluent: MeOH/EtOAc/Hex 1:9:15)

Sources & evidence

ORD record
ord-7d2530d0fbf44a00abf43158a04a5b96
Source dataset
uspto-grants-2012_08
Patent number
US08236796B2

Reaction notes

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