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

HRID 402120Notes

Reaction equation

HRID 402120 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-9c15547efd334be6acae99589ae3570b
Source dataset
uspto-grants-2014_06
Patent number
US08741901B2

Reaction notes

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