Yield:66504-88-9 87%

Reaction Conditions:

with hydrogenchloride in ethyl acetate;isopropyl alcohol at 20;Product distribution / selectivity;

Steps:

IV.C.2

Method 2 EPO A flask was charged with 2.0 L ethyl acetate. 150.1 g (659.2 mmol) of the HCl salt prouct (described in section B, method 2 in this Example III) were added and the stirred white suspension was externally cooled with an ice/2-propanol-bath. 52.8 ml (725.1 mmol, 1.1 equiv) of thionyl chloride were added dropwise at 0 °C within 20 min. A small exotherm could be detected (the inside temperature rose from 0 to 3 °C). After full addition the mixture was stirred 1.5 h at low temperature (0-3 ⁰C). The initial suspension turned almost completely homogeneous. Then 824 ml (5526.0 mmol, 8.0 equiv) of 12.5% ammonium hydroxide were added within 60 min keeping the inside temperature below 5 °C with external cooling. The now white emulsion was allowed to warm to room temperature and stirred overnight. The aqueous layer was separated and reextracted with 500 ml ethyl acetate. The combined ethyl acetate layer was dried over sodium sulphate and concentrated on rotavap (20 mbar) then in high vacuum to afford 121.0 g (106 % crude yield) of a clear yellowish oil.The crude material was dissolved in 600 ml ethyl acetate. To the filtrate was added 1.0 equiv of HCl/2-propanol under stirring at room temperature. BicifadineHCl crystallized immediately from the mixture with low exotherms. The white crystals were filtered to afford 119.7 g (87% yield) of (-)-Bicifadine HCl. The NMR and HPLC spectra of the crystals show a >98% chemical purity. The material has>98% ee as measured by chiral HPLC. [α]²⁰_D = -60 (c=l, MeOH). ¹H NMR (D₆- DMSO, 300 MHz) δ 10.0 (bs, 2 H, NH₂Cl), 7.15 - 7.07 (m, 4 H, ArH), 3.78 - 3.56(m, 4 H, CH₂NCH₂), 2.33 (s, 3 H), 1.92 (m, 1 H, ArCCH₂CH), 1.54 (dd, J= 6.6, 4.8Hz, 1 H, ArCCH₂CH), 1.20 (m, 1 H, ArCCH₂CH).

References:

WO2006/96810,2006,A2 Location in patent:Page/Page column 66-67