Process for the preparation of 4-bromomethyl diphenyl compounds

Details Process for the preparation of 4-bromomethyl diphenyl compounds Process for the preparation of 4-bromomethyl diphenyl compounds

1999-10-19

2000-08-29

McKane, Joseph

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

558425, 560205, 564161, C07D25704, C07C25500, C07C 6952, C07C23300

Patent

active

061111147

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a novel process for the preparation of compounds of general formula I: ##STR2## in which R represents CN, COOR.sub.1, CONR.sub.2 R.sub.3 (wherein R.sub.1, R.sub.2 and R.sub.3, which are the same or different, are H, straight or branched C.sub.1 -C.sub.6 alkyl, or C.sub.3 -C.sub.6 cycloalkyl) or optionally substituted tetrazolyl.
Said process provides advantageously on an industrial scale compounds which are key intermediates to the synthesis of biologically active substances, in particular in the field of Angiotensin II antagonists.
Various methods for the synthesis of bromomethyl diphenyl derivatives are known in patent literature. Patents EP 253310, EP 291969 and RP 449699 disclose brominations carried out with N-bromosuccinimide in carbon tetrachloride, in the presence of benzoyl peroxide as a radical initiator, but this method involves safety problems as the solvent used is highly toxic, the radical initiator is explosive and the reactions are very rapid and exothermic thus making the control of the developed heat difficult. Patents EP 553879, JP 6298683 and JP 6298684 disclose bromination methods by means of brominating agents such as bromosuccinimide, bromophthalimide or dibromodimethyl hydantoin in halo or ester solvents in the presence of either initiators such as azobisisobutyronitrile and analogues or of light radiation. These methods solve the safety problem, however they make use of brominating agents much more expensive than those of the present invention and involve the use of thermal initiators which affect costs, or of photochemical initiators poorly suitable to the industrial use. Furthermore, the yields obtained with these procedures are generally lower than those obtainable with the procedure described in the present invention.
On the basis of what described above and as a result of the increasing commercial interest in substituted bromomethyl diphenyl derivatives, as intermediates in the preparation of biologically active compounds, an industrial method for the preparation of these compounds in mild, safe and economically more advantageous conditions is highly interesting.
The process of the present invention relates to the preparation of 4-bromomethyl diphenyl derivatives of general formula I by means of radicalic bromination using bromine or HBr aqueous solutions in the presence of H.sub.2 O.sub.2, in optionally halo aliphatic or aromatic hydrocarbon solvents of 4-methyl diphenyl compounds of general formula II: ##STR3## in which R is CN, COOR.sub.1, in which R.sub.1 is hydrogen or a C.sub.1 -C.sub.6 straight, branched or cyclic alkyl group, CONR.sub.2 R.sub.3, in which R.sub.2 and R.sub.3 can be independently hydrogen or a C.sub.1 -C.sub.6 straight, branched or cyclic alkyl group; a tetrazole group, optionally substituted with a tert-butyl, triphenylmethyl group, or another protective group compatible with the reaction conditions, selected for example from those cited in T. Greene P. WUTS "Protective groups in organic chemistry" John Wiley & Sons INC: (1991).
The reaction is carried out using Br.sub.2 as brominating agent, in molar ratios ranging between 0.5 and 1 per mol of the diphenyl derivative, or aqueous HBr in concentrations ranging between 48% and 10%, in molar ratios from 1 to 1.5 and in the presence of H.sub.2 O.sub.2 aqueous solutions in concentrations ranging between 1% and 30%, in molar ratios equivalent to those of the brominating agents.
The solvent used for the reaction consists of a mixture of H.sub.2 O and one or more water-immiscible solvents, selected from hydrocarbons, such as hexane, heptane, cyclohexane; halo solvents such as methylene chloride, dibromoethane, bromochloromethane, 1,1,1-trichloroethane; aromatic solvents such as chlorobenzene, t-butylbenzene and the like. The H.sub.2 O to solvents ratio is usually 1:1. The reaction temperature can range from 10.degree. C. to the boiling temperature of the organic solvent used, and generally does not exceed 80.degree. C. The reaction times can range from 1 to 25 hours, depending o

REFERENCES:
Patent abstracts of Japan, vol. 014, No. 531, Nov. 21, 1990 and JP 02-221233, Sanko Kagaku Kogyo KK, Sep. 4, 1990.

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