Process for the production of 2H-1-benzopyrans

Details Process for the production of 2H-1-benzopyrans Process for the production of 2H-1-benzopyrans

1998-08-11

1999-07-06

Dentz, Bernard

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D31158, C07D31170

Patent

active

059199539

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the production of 2H-1-benzopyrans by converting aliphatic aldehydes with aliphatic alcohols in the presence of a dehydrating compound and an aluminium oxide/silicium oxide catalyst in a first stage into aliphatic acetals and their further reaction in a second stage with phenols in the presence of a base in an inert organic solvent. 2H-1-benzopyrans are important intermediate or final products in the production of pharmaceuticals (North et al., J.O.C., 60.3397, 1995; Bell et al., Synthesis, 707, 1995) for example in the production of pyranylcyanoguanidines, used in the treatment of epilepsy and migraine (EP-A 0 629 619).
The 2H-1-benzopyrans which can be produced according to the invention have the general formula ##STR1## where R.sup.1 is hydrogen, a (C.sub.1 -C.sub.4) alkyl group, R.sup.2 is hydrogen, a (C.sub.1 -C.sub.6) alkyl group and R.sup.3 is hydrogen, a (C.sub.1 -C.sub.4) alkyl group, a (C.sub.1 -C.sub.4) haloalkyl group, a (C.sub.2 -C.sub.4) alkenyl group, a (C.sub.1 -C.sub.4) alkoxycarbonyl group, a (C.sub.1 -C.sub.4) alkoxymethyl group, a (C.sub.1 -C.sub.4) alkanoyl group, a (C.sub.1 -C.sub.4) alkoxy group, a (C.sub.1 -C.sub.4) alkylsulphonyl group, halogen, amino, alkylamino, dialkylamino, nitril, nitro or hydroxy.
The production of acetals using aluminium oxide/silicium oxide catalysts has been described in the literature on the basis of ketones (Thuy et Maite, Bull. Soc. Chim. Fr. 11. 2558; 1975) and on the basis of paraformaldehyde (Deshmukh et al., Synth. Commun. 25, 3939; 1995). The disadvantage of these methods of synthesis known from the literature is the high proportion of catalyst in relation to the starting products which is used in the synthesis.
Compounds with the general formula I and processes to produce such compounds are listed in the European Patent Application EP-A 0 629 619. For example this application describes a process where 3-methyl-crotonaldehyde is reacted with an aliphatic alcohol, a dehydrating agent and alternatively sodium hydrogen sulphate, potassium hydrogen sulphate or quarternary ammonium hydrogen sulphate as the catalyst, and the purified acetal obtained is then condensed with a phenol in the presence of a tertiary amine in an inert organic solvent. The disadvantage of this process is that large quantities of potassium carbonate are needed for the processing of the acetal, and in the second stage large quantities of the catalytic tertiary amine are used, in relation to the educts.
The task of the present invention was therefore to provide an improved process whereby compounds with the general formula I can be produced economically.
According to the invention this problem is solved by the process according to patent claim 1. In this in a first stage aliphatic aldehydes with the general formula ##STR2## where R.sup.1 and R.sup.2 have the meaning stated above, are converted with an aliphatic alcohol with the formula R.sup.4 OH or HOR.sup.4 OH, where R.sup.4 is a (C.sub.1 -C.sub.4) alkyl group or a (C.sub.2 -C.sub.4) alkyldiyl group, in the presence of a dehydrating compound with the formula HC(OR.sup.5).sub.3, where R.sup.5 is a (C.sub.1 -C.sub.4) alkyl group, and of an aluminium oxide/silicium oxide catalyst, into an aliphatic acetal with the general formula ##STR3## where R.sup.1 and R.sup.2 have the above-mentioned meaning and R.sup.4, as stated above, is a (C.sub.1 -C.sub.4) alkyl group or both R.sup.4 together mean a cyclical (C.sub.2 -C.sub.4) alkyldiyl group.
R.sup.1 means hydrogen or a straight-chain or branched alkyl group with 1-4 C atoms. Methyl, ethyl, n-propyl, i-propyl, n-, i-, t-butyl are possibilities. It is particularly preferred for R.sup.1 to mean hydrogen and methyl. R.sup.2 means hydrogen or a straight-chain or branched alkyl group with 1-6 C atoms. Methyl, ethyl, n-propyl, i-propyl, n-, i-, t-butyl, pentyl and its isomers as well as hexyl and its isomers are possibilities. It is particularly preferred if R.sup.2 means hydrogen and methyl. R.sup.4 means a straight-chain or branched alkyl group w

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