Formic Acid → 1-(3,4-Dichlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane

HRID 332122Notes

Reaction equation

Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH:16](O)=O>C=O.O.[OH-].[Na+]>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH3:16])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]

Participants

Conditions

Temperature: 90 °C

Procedure

To a stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (30.0 g, 132 mmol) in 37% aqueous formaldehyde (25.8 mL) was added formic acid (32.4 mL). The resulting solution was stirred at 90° C. for 6 h. The reaction was then diluted with water (100 mL) and 2N aqueous sodium hydroxide added until the pH was greater than 9. The resulting mixture was extracted with CH2Cl2 (2×200 mL) and the combined organic extracts were washed with brine (200 mL), dried (MgSO4) and concentrated under vacuum to provide the title compound (25.0 g, 79% yield) as an orange oil: LC (ELS)/MS: >99%, m/z 242.1 [C12H13Cl2N+H]+; 1H NMR (300 MHz, CDCl3): δ 0.94 (dd, 1H, J=5.3 Hz, J=7.9 Hz), 1.73 (t, 1H, J=4.7 Hz), 1.80 (m, 1H), 2.55 (s, 3H), 2.78 (d, 2H, J=9.2 Hz), 3.35 (d, 1H, J=9.6 Hz), 3.54 (d, 1H, J=9.3 Hz), 6.99 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 7.24 (d, 1H, J=2.1 Hz), 7.35 (d, 1H, J=8.3 Hz).

Workup

additionadded until the pH was greater than 9
extractionThe resulting mixture was extracted with CH2Cl2 (2×200 mL)
washthe combined organic extracts were washed with brine (200 mL)
dry with materialdried (MgSO4)
concentrationconcentrated under vacuum

Sources & evidence

ORD record: ord-bfc3746cde7c486cb4581725cd0c656c
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08877798B2

Reaction notes

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