Process for the preparation of benzopyran compounds

Details Process for the preparation of benzopyran compounds Process for the preparation of benzopyran compounds

1999-02-08

2000-04-11

Lambkin, Deborah C.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548252, C07D25700

Patent

active

060489839

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP97/04328 Aug. 5, 1997.
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.
Various procedures for preparing such compounds are known in the art but these suffer from certain disadvantages when considered for large scale commercial application. The present invention therefore provides an improved route to substituted benzopyran compounds 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): ##STR1## in which, R.sup.1 is C.sub.1-20 akyl, 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); --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; A is a single bond or a vinylene, propenyl-1-ene, butenyl-1-ene, 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); with the phenyl ring to which they are attached form a substituted benzopyran structure of formula (i): ##STR3## which comprises reaction of a compound of formula (II): ##STR4## in which R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in formula (I) with a compound of formula (III): ##STR5## in which R.sup.1 and A are as defined in formula (I) and X is a suitable group to allow metal insertion in the presence of a metal catalyst and carbon monoxide, and optionally thereafter, formula (I)
Suitably the reaction is carried out at elevated temperature in the presence of a metal catalyst. Metal catalysts include the carbonyl complexes of Ni, Rh, Fe and Co or palladium complexes. A particularly advantageous aspect of the use of palladium complexes is that they can be used in catalytic quantities, thereby avoiding the use of highly toxic metal carbonyls, and enabling easier separation of the desired products from metal residues. Suitable palladium catalysts include Pd(OAc).sub.2, (Ph.sub.3 P).sub.4 Pd, (Ph.sub.3 P).sub.2 PdX.sub.2 [e.g. X=I,Br,Cl], (bipyr).sub.2 Pd, bis(dibenzilidene acetone)Pd(0). The reaction can be carried out in the presence of a reducing agent such as ammonium formate or hydrazine hydrate. Preferably the reaction can be carried out in the presence of additional ligands such as Ph.sub.3 P, sulphonated-Ph.sub.3 P, tri-tolylphosphine, bis(diisopropylphosphinyl)propane, polymer-bound-Ph.sub.2 P, and 1,1'-bis-(diphenylphosphino)ferrocene.
Preferably the reaction is carried out in the presence of a base. Suitable bases include Hunig's base, tri-n-butylamine, DBU, DABCO, or sodium acetate.
Suitably the reaction is carried out in a dipolar aprotic solvent, for example in amidic solvents such as dimethylformamide, N-methyl-pyrrolidinone or dimethylacetamide, or in dimethyl sulphoxide or pyridine. In the case of catalysts with water solu

REFERENCES:
Chemical Abstract, vol. 115, No. 17, 1991, Columbus Ohio, abstract No. 182817v, p. 874, XP002048521, see abstract.

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