GAS PHASE PRODUCTION OF
343
boiled under reflux for further 2 h. After cooling to room temperature the
suspension was filtered through celite. The phases were separated and the
organic layer was evaporated in vacuo to give a mixture of 6 and 7. Et2O
(200 ml) and water (200 ml) were added to the residue and the aqueous phase
was acidified with 4 M aqueous HCl. The phases were separated and the
aqueous phase was extracted with Et2O (3 Â 100 ml). The combined organic
phases were dried (MgSO4) and the solvents evaporated in vacuo. The residue
was purified by column chromatography (EtOAc/heptane 1:3) yielding 2.4 g
(11%) of 7 as a colorless oil. The remaining aqueous phase was made alkaline
with 25% aqueous NH3 and extracted with Et2O (3 Â 200 ml). The combined
organic phases were dried (MgSO4) and the solvent was evaporated in vacuo
yielding 15.3 g (70%) of 6 as an yellow oil.
LC/MS (m/z): 311 (M++1), purity >97%.
1H NMR (CDCl3) d 1.35 (m, 1 H), 1.48 (m, 1 H), 2.15 (m, 1 H), 2.23
(m, 1 H), 2.36 (s, 3 H), 2.85 (t, J=7.1 Hz, 2 H), 5.15 (d, JAB=13.0 Hz, 1 H),
5.19 (d, JAB=13.0 Hz, 1 H), 7.00 (t, J=8.5 Hz, 2 H), 7.40 (m, 3 H), 7.50
(s, 1 H), 7.58 (d, J=8.0 Hz, 1 H).
13C NMR (CDCl3) d 24.3, 36.4, 39.0, 51.8, 71.2, 91.1, 111.6, 115.1,
115.3, 118.5, 122.7, 125.1, 126.6, 126.7, 131.7, 139.5, 140.3, 149.3, 162.0
(d, JC–F=239 Hz).
(S)-1-(3-Chloropropyl)-1-(4-fluorophenyl)-1,3-dihyroisobenzofuran-5-carboni-
trile (7). A mixture of S-desmethylcitalopram (6) (15.0 g, 48 mmol) in EtOH
(100 ml), K2CO3 (13.8 g, 100 mmol) and ethyl bromoacetate (6.0 ml, 54 mmol)
was boiled under reflux for 4 h. After cooling to room temperature the mixture
was filtered and the volatile solvents were evaporated in vacuo. The remaining
residue was dissolved in Et2O (200 ml) and washed with brine. The aqueous
phase was extracted with additional Et2O (2 Â 200 ml). The combined organic
phases were dried (MgSO4) and the solvent was evaporated in vacuo yielding
16.3 g of a yellow oil. The residue was dissolved in toluene (100 ml) and
the resulting mixture was added dropwise to a refluxing mixture of
ethyl chloroformate (42.1 ml, 0.44 mol) in toluene (100 ml) and boiled under
refluxed for 2 h. After cooling the low boiling components were removed
in vacuo. Purification by column chromatography (EtOAc/heptane 1:3) gave
8.1 g (52%) of 7 as a colorless oil. The overall yield of 7 from 4 amounts to
10.5 g (47%) taking into account the amount of 7 formed in the dealkylation
of 4.
1H NMR (CDCl3) d 1.66 (m, 1 H), 1.79 (m, 1 H), 2.26 (m, 1 H), 2.34
(m, 1 H), 3.56 (m, 2 H), 5.14 (d, JAB=13.2 Hz, 1 H), 5.19 (d, JAB=13.2 Hz,
1 H), 7.02 (t, J=8.5Hz, 2 H), 7.42 (m, 3 H), 7.52 (s, 1 H), 7.61 (d, J=8.0 Hz, 1 H).
13C NMR (CDCl3) d 27.3, 38.5, 45.0, 71.3, 90.8, 111.9, 115.4, 115.5, 118.6,
122.7, 125.3, 126.7, 126.8, 132.0, 139.1, 140.3, 149.1, 162.1 (d, JC–F=252 Hz).
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 335–348