Benzhydryl Piperazines

Cinnamoyl chloride Benzhydryl piperazine Lithium aluminum hydride... 

This compound can be prepared by the reaction of cinnamoyl chloride with benzhydryl-piperazine. The reaction is carried out in dry benzene under reflux. The benzene is then evaporated, the residue taken up in chloroform, washed with dilute HCI and then made alkaline. 

One-tenth mol (20 g) of benzhydryl chloride was mixed with 0.19 mol (19 g) of N-methyl-piperazine and about 10 cc of benzene and the whole was heated on the steam bath four hours. The contents of the flask was partitioned between ether and water, and the ethereal layer was washed with water until the washings were neutral. The base was then extracted from the ethereal layer by N hydrochloric acid and the extract, made acid to Congo red paper, was evaporated under vacuum, 29.5 g of the pure dihydrochloride of N-methyl-N -benzhydryl piperazine was recovered from the residue by recrystallization from 95% alcohol melting above 250°C with decomposition. 

Benzhydryl-3-carbamyloxymethy -7a-hydroxy-7/3-(2-thienylacetamido)-decephalosporanate Cefoxitin sodium Benzhydryl piperazine Cinnarizine Cyclizine Benzilic acid... 

Another successful approach to replacing the benzhydryl stereocenter has been to synthesize and evaluate diarylamines with pendant basic amines. A simple transposition of the nitrogen and carbon atoms of the benzhydryl-piperazine leads to diarylaminopiperidine delta opioid agonists, as Carroll and coworkers at the Research Triangle Institute (RTI) demonstrated [30]. Scientists at AstraZeneca [31] and the R.W. Johnson Research Institute [32] have also disclosed delta opioid agonists possessing the carbon-nitrogen transposition. Boyd and coworkers at R.W. Johnson were the first to report on compounds where the aminopiperidine was further constrained as an aminotropane. Compound 47 has a K = 0.4 nM at the delta opioid receptor, with 14000-fold selectivity versus the mu opioid receptor (Fig. 8). 

Delorme and coworkers have published a stereoselective route that is effective with a wide range of amines, including those without a stereocenter on the amine (Scheme 8) [43]. Chiral reduction of the appropriate benzophe-none (as a chromium tricarbonyl complex) using Corey s oxazaborolidine approach afforded the benzhydrol with 91% ee. Treatment with tetrafluo-roboric acid followed by the piperazine gave the desired benzhydryl piperazine without any erosion of stereochemical purity after decomplexation. In addition to simplifying analogue synthesis, these two complementary routes provide a useful base for the future development of stereoselective manufacturing routes. 

Benzhydryl piperazine causes orofacial malformations in rat embryos, possibly the result of the oedema induced in the embryo. It has also been suggested that changes in embryonic pH may underlie the teratogenicity of certain compounds. 

Ceterizine should be interpreted as a traditional benzhydryl piperazine H antagonist (see chlorcyclizine, No. 13, Table 13-1), where the N-methyl group has been interchanged for an ethoxycarboxylic acid. 

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