Ishihama H, Kabuto S, Tamaki T
Radioisotopes. 1978 May;27(5):235-40. doi: 10.3769/radioisotopes.27.5_235.
In order to study the metabolic fate of prazepam (PZ), a new synthetic method of [5-14C]PZ(I) and [sidechain-14C]PZ (II) was investigated. The synthesis of these labelled compounds has already been described by E. J. Merrill, et al., but their method requires many synthetic steps and the yield is unfavorably poor. We have recently found much more convenient and efficient method, which is summarized below. 2-Iodo-4-chloroaniline was cyanized with Cu14CN obtained from K14CN, then reacted with phenylmagnesium bromide, hydrolyzed with conc. HCl to give [carbonyl-14C]2-amino-5-chloro-benzophenone(ACB). ACB was bromoacetylated, aminated with NH3 in MeOH, then heated and cyclized to [5-14C]desalkylprazepam(DPZ) according to the usual procedure. DPZ was converted to its Na salt with MeONa, then reacted with cyclopropylmethyl bromide in DMF to give I (2.61 mCi/mmol) with the overall yield of 41.9% from K14CN. [5-14C] Diazepam was also obtained by using MeI instead of cyclopropylmethyl bromide. On the other hand, 14CO2 generated from Na214CO3 and H2SO4 was reacted with cyclopropylmagnesium bromide to give [carboxyl-14C]cyclopropanecarboxylic acid, which was reduced with LiAlH4, then naphthalenesulfonylated to [alpha-14C]cyclopropylmethyl 2-naphthalenesulfonate. Na salt of DPZ was treated with the naphthalenesulfonate in DMF to give II (3.45mCi/mmol) with the overall yield of 36.9% from Na214CO3.
为研究普拉西泮（PZ）的代谢命运，对[5-¹⁴C]PZ（I）和[侧链-¹⁴C]PZ（II）的一种新合成方法进行了研究。E. J. 梅里尔等人已描述了这些标记化合物的合成方法，但他们的方法需要许多合成步骤且产率低得不利。我们最近发现了一种更方便高效的方法，总结如下。2-碘-4-氯苯胺用由K¹⁴CN制得的Cu¹⁴CN氰化，然后与苯基溴化镁反应，用浓盐酸水解得到[羰基-¹⁴C]2-氨基-5-氯二苯甲酮（ACB）。ACB进行溴乙酰化，在甲醇中用氨胺化，然后按常规方法加热环化得到[5-¹⁴C]去烷基普拉西泮（DPZ）。DPZ用甲醇钠转化为其钠盐，然后在N,N-二甲基甲酰胺中与环丙基甲基溴反应得到I（2.61 mCi/mmol），从K¹⁴CN的总产率为41.9%。用碘甲烷代替环丙基甲基溴也得到了[5-¹⁴C]地西泮。另一方面，由Na₂¹⁴CO₃和硫酸产生的¹⁴CO₂与环丙基溴化镁反应得到[羧基-¹⁴C]环丙烷羧酸，用氢化铝锂还原，然后萘磺酰化得到[α-¹⁴C]环丙基甲基2-萘磺酸酯。DPZ的钠盐在N,N-二甲基甲酰胺中用萘磺酸酯处理得到II（3.45 mCi/mmol），从Na₂¹⁴CO₃的总产率为36.9%。
