Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-08-01
1996-06-11
Springer, David B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D25704
Patent
active
055257330
DESCRIPTION:
BRIEF SUMMARY
This application is A 371 of PCT/EP94/00 305 filed Feb. 1, 1994.
The present invention relates to a novel process for preparing certain tetrazole compounds which are of use in the preparation of therapeutically active substances, in particular certain benzopyran compounds useful as inhibitors of 5-.alpha.-reductase and as leukotriene antagonists. The invention further relates to novel salt forms of the tetrazole compounds and to a process for preparing them.
Benzopyran compounds substituted by a tetrazole ring are described in the art, for example in EP 0173156-A. In addition, unpublished British Patent Application No. 9224922.6, filed 27 Nov. 1992, discloses a new process for preparing certain of the compounds of EP 0173156-A, in particular compounds of structure (A): ##STR1## in which
R.sup.1 is, inter alia, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl or a carboxylic group, X is oxygen or sulphur and R.sup.2 and R.sup.3 are, for example, hydrogen, by cyclisation of the corresponding intermediate compounds of structure (B): ##STR2## Compounds of structure (B) are described as being prepared by reaction of compounds of structure (C): ##STR3## with a tetrazole derivative of structure (D): ##STR4## or salts thereof, in which Z is a leaving group. The compounds (D), for example where Z is an i-butoxy group, are described as being prepared from the corresponding tetrazole-5-carboxylic disodium salt by reaction with i-butyl chloroformate, followed by workup under acidic conditions. Preparation of salts of compounds (D) is not specifically described in GB 9224922.6 although, for example, the preparation of the sodium salt of ethyl-5-tetrazole carboxylate, in solution only, is described in the literature (Australian Journal of Chemistry (1984) 37, 2453-2468). In particular, the process described in GB 9224922.6 is used to prepare the compounds of structure (A1): ##STR5##
It has now been found that, by using novel methods described herein, the tetrazole compounds (D) and the salts thereof can be prepared in high yield and in high purity, avoiding the undesirable azide by-products associated with known methods.
The present invention therefore produces, in a first aspect, a process for preparing a compound of structure (I): ##STR6## or a hydrate or solvate thereof in which R.sup.1 is C.sub.1-6 alkyl, optionally substituted phenyl or optionally substituted phenylC.sub.1-6 alkyl, which comprises combining an azide of structure (II) M.sup..sym. N.sub.3.sup..crclbar. in which M is an alkali metal atom, with a compound of structure (III) NC.CO.sub.2 R.sup.1 in which R.sup.1 is as described for structure (I), to form an intermediate compound of structure (IV): ##STR7## in which R.sup.1 is as described for structure (I) and M is as described for structure (II), followed by conversion of the salt (IV) to the free tetrazole (I) or to a hydrate or solvate thereof.
Suitably, R.sup.1 is C.sub.1-6 alkyl, optionally substituted phenyl or optionally substituted phenylC.sub.1-6 alkyl Preferably, R.sup.1 is C.sub.1-6 alkyl, for example, methyl, ethyl, i-butyl or t-butyl.
Suitably, alkali metal atoms M include lithium, sodium and potassium. Preferably M is sodium or potassium.
Suitably, the reaction between the compounds of structures (II) and (III) is carried out in a suitable solvent in the presence of an acid, at a temperature of between ambient and reflux temperature of the solvent used, for as long as is required to take the reaction to completion. Suitable solvents include 2,6-lutidine and suitable acids include trifluoroacetic acid.
This process for preparing the tetrazole derivatives of structure (I) proceeding via the intermediate salts (IV) provides a more efficient and safer method of preparing compounds (I) than has been known before. Preparation of the tetrazole derivatives as described in EP 0323885 is a low yielding method and that described in Chem. Ber. (1975) 108, 887 is a very cumbersome method involving potential hazardous steps such as evaporation to dryness which makes them unsuitable for large scal
REFERENCES:
patent: 4316037 (1982-02-01), Sellstedt et al.
Hanson John C.
Novack Vance
Ward Neal
Kanagy James M.
Lentz Edward T.
SmithKline Beecham Plc
Springer David B.
Suter Stuart R.
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