Process for preparing benzopyran compounds

Details Process for preparing benzopyran compounds Process for preparing benzopyran compounds

1996-11-21

1998-07-07

McKane, Joseph

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548253, C07D25704

Patent

active

057771286

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/01915 filed May 18, 1995.
The present invention relates to a process for preparing certain substituted benzopyran compounds which are useful as intermediates in the preparation of a class of substituted benzopyran compounds known in the art as therapeutic agents.
Substituted benzopyran compounds are known in the art. For example EP 0 173 516-A discloses a class of substituted benzopyran compounds which are described as compounds having activity as leukotriene antagonists and 5-.alpha.-reductase inhibitors and useful in therapy in the treatment of diseases caused or exacerbated by leukotrienes or 5-.alpha.-reductase activity.
The present invention relates to a method for preparing key intermediates used in the preparation of a particular sub-class of the compounds disclosed in EP 0 173 516-A, in particular compounds of the structure (A): ##STR1## in which, R.sup.1 is C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, or a group of structure: ##STR2## each of which may be substituted by one or two substituents selected independently from C.sub.1-20 alkyl, C.sub.2-20 alkenyl or C.sub.2-20 alkynyl, up to 5 carbon atom(s) of which may optionally be replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) and/or nitro group(s); R.sup.2 is hydrogen or C.sub.1-6 alkyl; R.sup.3 is hydrogen, halogen, hydroxy, nitro, a group of general formula --COOR.sup.4 (wherein R.sup.4 represents hydrogen or C.sub.1-6 alkyl), C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkylthio; A is a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group optionally being substituted by one, two or three C.sub.1-10 alkyl and/or phenyl group(s); and X is oxygen or sulphur.
Known procedures for preparing such compounds of structure (A) include a final step reaction in which the intermediate (B) (in which R is tetrazol-5-yl) is reacted with an activated intermediate such as (C) to form the desired compounds (A): ##STR3##
The compounds of structure (B) are prepared via procedures described in EP 0 173 516-A in which the benzopyran ring is formed first and then the tetrazole ring prepared via conversion from the corresponding compound B in which R is a carboxylic acid group, via the amide and nitrile group using standard chemistry techniques.
The present invention provides an improved route to the intermediates of structure (B) (and closely related compounds).
In a first aspect is therefore provided a process for the preparation of a compound of structure (I): ##STR4## in which Y is NO.sub.2, NH.sub.2 or Y is NO.sub.2, NH.sub.2 or NHacetyl, N(Bn).sub.2, CO(Tet) where Tet is a tetrazol-5-yl group, ##STR5## and X is hydrogen or halogen, which process comprises cyclisation of a compound of structure (II): ##STR6## in which X and Y are as described for structure (I).
Suitably, the reaction is carried out at reflux temperature in a C.sub.1-4 alkanol solvent, in the presence of a suitable acid. Preferably, the reaction is carried out at reflux temperature in methanol as a solvent in the presence of concentrated hydrochloric acid or concentrated sulphuric acid.
Suitable amine protecting groups Y will be apparent to those skilled in the art, and include, for example, NHacetyl, N(Bn).sub.2, CO(Tet) where Tet is a tetrazol-5-yl group, ##STR7##
It will be appreciated that compounds of formula (II) can exist as salts, for example as the sodium salt. Compounds of formula (II) can also exist in different tautomeric forms. Salt and tautomeric forms of compounds of formula (II) can be used in the above process and form an aspect of the invention.
The compounds of structure (II) can be prepared by standard techniques or, alternatively, by rearrangement of compounds of structure (III): ##STR8## in which X and Y are as de

REFERENCES:
patent: 4159273 (1979-06-01), Brown et al.
patent: 5597929 (1997-01-01), Ushio et al.
Kakai et al., New Potent Antagonist of Leukotrienes, J. Med. Chem., 31(1), 84-91, 1988.
Chemical Abstracts, vol. 115, No. 17, 1991, p874, col. 2, abstract 182817v.

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