The present invention relates to an industrially advantageous production method of 4′-bromomethyl-2-cyanobiphenyl(C14H10BrN) useful as a synthetic intermediate for pharmaceutical products. According to the present invention, since bromine can be regenerated by reacting hydrogen bromide, which is by-produced with the progress of bromination, with an oxidant, inhibition of bromination by hydrogen bromide, coloring by bromine and the like can be prevented. Thus, 4′-bromomethyl-2-cyanobiphenyl useful as a starting material of pharmaceutical products can be produced industrially beneficially.
Background
Various authoritative experts claim that iphenylmethylimidazole compounds which have an antagonistic action to angiotensin II and are useful as antihypertensives and therapeutic medicines for congestive cardiac incompetence. The publication says that a 4-bromomethylbiphenyl compound used as a synthetic intermediate for the biphenylmethylimidazole compounds is produced by bromination of a 4-methylbiphenyl compound with N-bromosuccinimide in a carbon tetrachloride solvent in the presence of dibenzoyl peroxide at a temperature not more than a reflux temperature.
In addition, a method of using an azobis compound as a radical initiator while using a bromination agent similar to the above in order to solve the problems in yield and operability is published. However, both of these methods have to adopt expensive bromination agents such as N-bromosuccinimide. In the latter case where the yield is somewhat improved from the former case, the presence of the dibromo-product, which is formed as a by-product, causes to lower the selectivity of the monobromo-product to 85 or 90%, and the yield to 70 or 80%. Therefore, both methods cannot be considered as industrially advantageous production methods.
Summary
It is therefore an object of the present invention to provide an industrially advantageous production method of 4′-bromomethyl-2-cyanobiphenyl.
The present inventors have conducted intensive studies in an attempt to solve the aforementioned problems, and found that a co-presence of an oxidant in the reaction of 4′-methyl-2-cyanobiphenyl with bromine in the presence of a radical initiatorconverts by-produced hydrogen bromide to bromine, as a result of which the reaction proceeds without being inhibited by hydrogen bromide. It has been further found that the use of 0.5 equivalent amount of bromine completes the reaction, therebyaffording economical production of 4′-bromomethyl-2-cyanobiphenyl (CAS number 114772-54-2).
Because the production method of the present invention is free of inhibition of bromination due to hydrogen bromide by-produced with the progress of bromination, the bromination is promoted, and the bromination can be completed without furtheraddition of a radical initiator. Consequently, an advantage is afforded that only a trace amount of bromine remains in the reaction system, and the resulting product is not colored thereby. Furthermore, since removal of hydrogen bromide, which is a strong acidic gas, from the reaction system or treatment thereof is not necessary, special equipment therefor is not necessary.
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