Upton C, Jaffar M
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, UK.
J Pharm Pharmacol. 1998 Aug;50(8):829-35. doi: 10.1111/j.2042-7158.1998.tb03996.x.
The published synthetic route to the antihistaminic tetrahydroindeno[2,1-c]pyridines (phenindamines) relies on catalytic reduction of the precursor dihydroindenopyridines. This reduction gives mixtures of 9,9a- and 4a,9a-enes and the clinically active 4a,9a isomer has to be isolated by recrystallization of an appropriate salt. The structure of the product recovered depends on the anion used to isolate the proton salt and appears to be arbitrary. To rationalize this outcome a series of novel N-2 alkylated tetrahydroindeno[2,1-c]pyridines and their diene precursors has been synthesized from accessible piperidines. The structures and geometry of the piperidines and the dihydro- and tetrahydroindenopyridines have been determined by 1H and 13C NMR. An unusual feature of the proton spectra of the piperidines is the resonance of the axial protons at lower field than their equatorial counterparts. By controlling the reaction conditions for the reduction of the dihydroindenopyridines to their tetrahydro derivatives the kinetic or thermodynamic product can be selected as required. A predictable outcome for the reductions investigated was achieved and is generally applicable.
已发表的合成抗组胺四氢茚并[2,1-c]吡啶（非尼拉敏）的路线依赖于前体二氢茚并吡啶的催化还原。这种还原会产生9,9a-烯和4a,9a-烯的混合物，并且必须通过适当盐的重结晶来分离具有临床活性的4a,9a异构体。回收产物的结构取决于用于分离质子盐的阴离子，而且似乎具有随意性。为了合理解释这一结果，已从易得的哌啶合成了一系列新型的N-2烷基化四氢茚并[2,1-c]吡啶及其二烯前体。哌啶以及二氢茚并吡啶和四氢茚并吡啶的结构和几何形状已通过1H和13C核磁共振确定。哌啶质子光谱的一个不寻常特征是轴向质子的共振峰出现在比其赤道对应物更低的场强处。通过控制二氢茚并吡啶还原为其四氢衍生物的反应条件，可以根据需要选择动力学或热力学产物。所研究的还原反应取得了可预测的结果，并且通常适用。
