Hydrochloric Acid → HCID 526946, compound

Temperature

-75 °C

A solution of 3-ethyl-thiophene (12.14 g, 54.4 mmol) in acetonitrile (60 mL) is cooled to 10° C. before a solution of N-bromo-succinimide (9.31 g, 52.3 mmol) in acetonitrile (90 mL) is added dropwise. The reaction is slightly exothermic. The mixture is stirred and warmed to rt. Another portion of N-bromo-succinimide (2.0 g, 11.2 mmol) dissolved in acetonitrile (40 mL) is added dropwise. Stirring is continued for 2 h before a third portion of N-bromo-succinimide (0.5 g, 2.81 mmol) dissolved in acetonitrile (10 mL) is added. After additional 1 and 2 h, a further portion of N-bromo-succinimide (0.75 g, 4.21 mmol, and 500 mg, 2.81 mmol, respectively) is added. Stirring is continued for another hour before the solvent is evaporated. The residue is dissolved in DCM, washed twice with 2 M aq. NaOH followed by brine, dried over MgSO4, filtered and concentrated. The crude product is purified by distillation at 180° C./50 mbar to give 2-bromo-3-ethyl-thiophene (11.0 g) as a colourless liquid; LC-MS*: tR=0.92 min. 1H NMR (CDCl3): δ 1.22 (t, J=7.5 Hz, 3H), 2.62 (q, J=7.8 Hz, 2H), 6.85 (d, J=5.5 Hz, 1H), 7.22 (d, J=5.8 Hz, 1H) b) A solution of 2-bromo-3-ethyl-thiophene (1.00 g, 5.23 mmol) in THF (25 mL) is cooled to −75° C. before n-butyl lithium (3.6 mL of a 1.6 M solution in THF) is added. The mixture is stirred at −75° C. for 1 h. DMF (765 mg, 10.5 mmol) is added and stirring is continued at −75° C. for 2 h. The mixture is warmed to 10° C., treated with 1 N aq. HCl (5 mL), diluted with water and extracted with EA (3×50 mL). The organic extracts are washed with water (30 mL) followed by brine (30 mL), combined, dried over MgSO4, filtered and concentrated to give crude 3-ethyl-thiophene-2-carbaldehyde (650 mg) as a yellow oil; LC-MS*: tR=0.78 min, 1H NMR (CDCl3): δ 1.34 (t, J=7.5 Hz, 3H), 3.03 (q, J=7.5 Hz, 2H), 7.06 (d, J=5.0 Hz, 1H), 7.67 (d, J=5.0 Hz, 1H), 10.08 (s, 1H). c) The title compound is prepared in analogy to the procedures described in the literature (G. Constantino et al., II Farmaco 59 (2004), 93-99; A. J. Carpenter et al., Tetrahedron 41 (1985) 3803-3812) starting from the above 3-ethyl-thiophene-2-carbaldehyde; LC-MS*: tR=0.15 min, [M−1]−=183.16; 1H NMR (D6-DMSO): δ1.24 (t, J=7.5 Hz, 3H), 3.00 (q, J=7.5 Hz, 2H), 7.72 (s, 1H), 10.11 (s, 1H).

1. additionis added
2. stirringstirring
3. waitis continued at −75° C. for 2 h
4. temperatureThe mixture is warmed to 10° C.
5. extractionextracted with EA (3×50 mL)
6. washThe organic extracts are washed with water (30 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated

ORD record

ord-fd1992ff99444491bc0c197d92854f5f

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08148410B2