Process for the production of tetrazolylbenzopyrans

Details Process for the production of tetrazolylbenzopyrans Process for the production of tetrazolylbenzopyrans

1999-07-06

2000-05-30

Stockton, Laura L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548253, C07D40504

Patent

active

06069257&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for preparing substituted benzopyran compounds known in the art as therapeutic agents and the novel preparation of intermediates useful in the process. The invention also relates to novel compounds useful 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-a-reductase inhibitors and useful in therapy in the treatment of diseases caused or exacerbated by leukotrienes or 5-a-reductase activity.
In particular the compound 4-oxo-8-[4-(4'-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyra n which has the INN pranlukast is being developed as an anti-asthma agent. Various procedures for preparing such compounds are known in the art, however some procedures suffer from certain disadvantages when considered for large scale commercial application. In particular the procedures known in the art are multi-step syntheses and there is therefore need for an improved route which gives the desired compounds in good yield with relatively few process steps.
In a first aspect is therefore provided a process for the preparation of a compound of structure (I): ##STR2## 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: ##STR3## 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): --COOR.sup.6 (wherein R.sup.6 represents hydrogen or C.sub.1-6 alkyl), C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkylthio; butadienyl-1-ene or ethynylene group optionally being substituted by one, two or three C.sub.1-10 alkyl and/or phenyl group(s); provided that the group formed by R.sup.1 and A provides a double or triple bond adjacent to the carbonyl group of the compound of formula (I); ##STR4## in which R.sup.1, R.sup.2, R.sup.3 and A are as defined in formula (I) and optionally thereafter forming a pharmaceutically acceptable salt, hydrate or N-oxide.
The reduction of compounds of formula (II) is suitably carried out using a reducing agent such as tributyltin hydride+AIBN (Azodiisobutyl nitrile, 2,2'-azo-bis(2-methylpropionitrile)), DMSO+sulfuric acid, titanium trichloride+CO.sub.2 +HCl, powdered Fe in acetic acid, palladium+acetic acid and acetic anhydride, triphenyl phosphine, triethyl phosphite, 3-sulfolene, di-n-propyl sulfoxylate and titanium (0). Preferably the reducing agent is titanium (0). Preferably the titanium (0) is generated in situ, for example from titanium tetrachloride and lithium aluminium hydride. The reduction is suitably carried out in an inert solvent at ambient or elevated temperature. Preferably the reduction is carried out in THF at elevated temperature, for example at reflux temperature.
In particular, the reactions claimed benefits herein are useful in the preparation of compounds (I) in which R.sup.1 and A form a group of formula (ii): ##STR5##
Preferably R.sup.2 and R.sup.3 are both hydrogen.
Most preferably the process of the invention can be used to prepare the compound pranlukast, that is to say the compound 4-oxo-8-[4-(4'-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyra n or salt, hydrate or N-oxide thereof.
Compounds of formula (II) can be prepared by reaction of a compound of formula (III): ##STR6##


(III)
alkyl or an alkali metal ion with a compound of formula (IV): ##STR7##


(IV)
using chemistry known in the art, for example the procedures disclosed in WO94/12492. Suitably R.sup.7 is hydrogen, C.sub.1-6 alkyl or an alkali metal ion such as sodium or potassium.

REFERENCES:
H. Dziklinska et al., Bull. Soc. Chim. Belg., vol. 98, No. 4, 1989, pp. 227-284, XP002065412, fig. 4, Compound G.

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