Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-14
2001-04-10
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S425000, C560S102000, C564S184000
Reexamination Certificate
active
06214999
ABSTRACT:
The present invention relates generally to the preparation of bromomethylbiphenyl derivatives.
More specifically, the invention relates to a process for preparing 4′-bromomethyl-biphenyl derivatives of general formula:
in which R represents:
a cyano group
a group:
—CO
2
R
1
or —CONR
2
R
3
in which R
1
, R
2
and R
3
, which may be identical or different, represent hydrogen or a linear or branched C
1
-C
6
alkyl group which can be optionally substituted with a halogen atom, a hydroxyl, amino, C
1
-C
4
alkoxy group or with 1 to 3 phenyl groups optionally substituted with 1 to 3 groups chosen from halogen atoms and hydroxyl, nitro, C
1
-C
4
alkyl and C
1
-C
4
alkoxy groups,
a tetrazolyl group of general formula:
in which R
4
, in position 1 or preferably in position 2 of the tetrazolyl group, represents hydrogen or a protecting group, in particular a linear or branched C
1
-C
6
alkyl group optionally substituted with 1 to 3 phenyl groups which are themselves optionally substituted with 1 to 3 groups chosen from halogen atoms and hydroxyl, nitro, C
1
-C
4
alkyl and C
1
-C
4
alkoxy groups.
In particular, R can represent a cyano, tetrazolyl or triphenylmethyltetrazolyl group or a group —CO
2
R
1
in which R
1
represents hydrogen or a methyl, ethyl or propyl group.
Among the compounds of formula I which can be prepared by the process of the invention, mention may be made of:
4′-bromomethyl-2-cyanobiphenyl
4′-bromomethyl-2-tetrazolylbiphenyl
4′-bromomethyl-2-carboxybiphenyl
4′-bromomethyl-2-methoxycarbonylbiphenyl
4′-bromomethyl-2-N-triphenylmethyltetrazolylbiphenyl
However, according to one preferred aspect, the invention relates to the preparation of the compound of formula I in which R represents a cyano group, i.e. 4′-bromomethyl-2-cyanobiphenyl.
The 4′-bromomethylbiphenyl derivatives of formula I are known compounds which have been described in particular in patent applications EP 324 377 and 553 879 or which can be prepared by the processes described therein.
These compounds of formula I constitute intermediates that are particularly useful in the synthesis of many active principles of medicinal products acting in particular against hypertension by a mechanism of inhibition of angiotensin II.
Various methods have recently been proposed for the synthesis of 4′-bromomethyl-2-cyanobiphenyl, these methods being based on a chemically-initiated radical reaction.
For example, mention may be made of patent applications JP 63-23868, 61-92170 and 62-98683 as well as patent applications EP 553 879, 595 150 and 709 369, which all describe, to varying degrees, the bromination of o-tolylbenzonitrile (referred to hereinbelow as OTBN) by means of brominating agents such as N-bromosuccinimide (referred to hereinbelow as NBS), dibromodimethylhydantoin (referred to hereinbelow as DBDMH), N-bromophthalimide or bromine, in the presence of a chemical initiator, generally benzoyl peroxide, t-butyl peroxide, t-butyl perbenzoate or an azobis derivative such as 2,2′-azobis(isobutyronitrile) (referred to hereinbelow as AIBN) or 2,2′-azobis(2,4-dimethylvaleronitrile), the solvent being a C
5
-C
7
alkane, a halogenated C
1
-C
4
aliphatic hydrocarbon such as dichloromethane or carbon tetrachloride, a C
1
-C
4
alkyl ester of acetic acid such as ethyl acetate, or a halogenated aromatic hydrocarbon such as chlorobenzene.
However, these methods comprise both drawbacks and disadvantages, which are occasionally sufficient to exclude them from any industrial-scale use.
For example, the use of peroxide derivatives is found to be very difficult or even dangerous given the explosive nature of this type of product.
Moreover, these processes make use of relatively expensive compounds such as chemical initiators derived from the family of azobis derivatives, or alternatively of products that are sources of pollution since they give rise to unexpected reaction by-products or by-products that are difficult to recycle.
Consequently, the preparation of 4′-bromomethyl-2-cyanobiphenyl via a radical reaction which is not likely to entail pollution, from a minimum amount of compounds, which furthermore is inexpensive and non-hazardous, and according to a method whose industrial implementation is free of major difficulties, remains of unquestionable interest.
To this end, photochemical initiation of a radical-mediated reaction to replace a chemical initiation can, on account of the advantages afforded thereby, represent an approach that is particularly advantageous for offering a solution to the problems previously posed.
Specifically, it is known that chemical initiation:
a) can be inhibited by the presence of impurities in the starting materials, as can a chemical reaction
b) is dependent on the temperature; for example, chemical initiators such as benzoyl peroxide or AIBN require a certain working temperature, preferably a temperature greater than 60° C., in particular for the bromination of OTBN
c) generates decomposition products and, consequently, entails risks of environmental pollution.
A radical-mediated reaction for the preparation of 4′-bromomethyl-2-cyanobiphenyl which involves a photochemical initiation has been suggested in patent applications JP 62-98683 and EP 709 369.
Thus, patent application JP 62-98683 mentions the possibility of photochemical reaction of OTBN with a brominating agent at a temperature of from 0 to 80° C., preferably from 10 to 40° C. and in a fatty acid ester as solvent, ethyl acetate being mentioned more particularly.
In addition, NBS and DBDMH are noted therein as preferred brominating agents and are given therein as examples. Although bromine is also mentioned therein as a brominating agent, no example illustrates its use.
Orientation tests carried out in the context of the development of the present invention have revealed certain drawbacks inherent to this method on account of the nature of the solvent used. Specifically, it has been noted that interfering reactions take place, involving the solvent, i.e. ethyl acetate, giving rise to an increased consumption of the brominating agent, in particular bromine.
Similarly, patent application EP 709 369 reports a process for brominating OTBN, according to which this compound is reacted with bromine at a temperature of from 0 to 100° C., preferably 20 to 80° C. and in the presence of a chemical initiator, i.e. an azobis derivative or benzoyl peroxide and in a halogenated hydrocarbon or a C
5
-C
7
alkane as solvent.
It is also reported therein that the formation of radicals can be ensured by a simple photo-irradiation without the use of a radical initiator.
However, no details whatsoever are given in particular as regards the operating conditions for carrying out this process, which is not exemplified in any way.
In the context of the present invention, an attempt has been made to carry out this radical-mediated photochemical reaction.
It has thus been observed that the bromination of OTBN by bromine with photo-irradiation is slow at temperatures below 50° C. in the conventional organic solvents used for this type of reaction. For example, at 40° C. in dichloromethane, the reaction requires at least 3 hours while at 0° C., the reaction time is greater than 6 hours.
Given that the selectivity of this radical-mediated bromination into monobromo derivative at the expense of the corresponding dibromo derivative increases as the temperature decreases, it appears to be of paramount importance to be able to work at temperatures of less than or equal to 45° C.
Mention will also be made of patent EP 336 567, relating to a process for the photochemical bromination of an alkylarene by means of hydrobromic acid/hydrogen peroxide in a two-phase medium formed from an aqueous phase and an organic phase and at a temperature of from 20 to 80° C., preferably from 60 to 70° C.
The process of this patent can be applied in particular to the bromination of the carbon &agr; to an alkyl group attached to a benzene ring which itself bears a deactivating group such as
Biard Michel
Castro Bertrand
Alexander Michael D.
McKane Joseph K.
Murray Joseph
Sanofi-Synthelabo
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