Process for preparation of 1,4-benzodioxane derivative

Details Process for preparation of 1,4-benzodioxane derivative Process for preparation of 1,4-benzodioxane derivative

1997-09-24

1998-07-14

Owens, Amelia

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549362, 549366, C07D49300, C07D31914

Patent

active

057806500

DESCRIPTION:

BRIEF SUMMARY
FIELD OF ART

The present invention relates to a process for the preparation of a 1,4-benzodioxane derivative useful for the intermediate of circulatory drugs and drugs for psychoneurosis which are alpha and beta-adrenergic antagonists.


BACKGROUND OF ART

A 1,4-benzodioxane derivative is used for an intermediate for the preparation of circulatory drugs and drugs for psychoneurosis having alpha and beta-adrenergic antagonist-activity and its various kind of processes are known. For example, a method of reacting a catechol derivative with glycidyl tosylate in the presence of sodium hydride (Japanese patent publication No.9613/1994) or a method of reacting a catechol derivative with epichlorohydrin in the presence of pyridine (J. Org. Chem. 46,3846 (1981)) is known. A method is also known to make a 1,4-benzodioxane skeleton by reactng a catechol derivative with glycerol 1-tosylate acetonide and, after removing the protective group, the acetonide, by introducing two tosyl groups onto it and then by isolating it, and further by cyclizing it (J. Chem. Soc., Chem. Commun., 921 (1976)).
Among the above methods, besides the method comprising the use of glycidyl tosylate is costly because of expense of that compound, the epoxy group is also reduced on the deprotection by hydrogenolysis and the yield decreases. In the method comprising the use of epichlorohydrin, the excess of epichlorohydrin and dichloropropanediol as a by-product must be eliminated by their evaporation with xylene, and the hydrochloric acid and acetic acid used must be eliminated by evaporation with ethanol, and therefore such procedures are troublesome. Moreover, the reaction is carried out under reflux of piperidine or hydrochloric acid. Therefore a compound having substituents which are unstable to an acid or a base can not be used. When using a optically active epichlorohydrin, racemization occurs and an optically pure product cannot be obtained. In the method which comprises the reaction of a catechol derivative with glycerol 1-tosylate acetonide, the resulting ditosylated product must be separated after tosylation and therefore the yield of the ditosylated product is 55%, or lower. These methods have many disadvantages in application of an industrial scale. An improved method has been desired.


DISCLOSURE OF INVENTION

The present inventors, taking into consideration the above fact, extensively engaged in study to find an improved method for the preparation of a 1,4-benzodioxane derivative, and found the present invention. After sulfonating a phenoxypropanediol compound, by cyclizing the resulting product in the presence of a base, the desired 1,4-benzodioxane derivative is favorably obtained in an industrial scale.
The present invention relates to a process of preparing a 1,4-benzodioxane derivative as shown by the following formula (1) ##STR2## wherein R.sup.1 is a hydrogen atom or RSO.sub.2 in which R is C.sub.1 -C.sub.4 alkyl, or phenyl which may be substituted by C.sub.1 -C.sub.4 alkyl, R.sup.2, R.sup.3 and R.sup.4 are, respectively, hydrogen, halogen, hydroxy, nitro, cyano, formyl, carboxyl, alkoxycarbonyloxy having 1-4 carbon atoms in the alkyl portion, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 haloalkyl, N,N-di C.sub.1 -C.sub.4 alkylamino, alkylcarbonyl having 1-4 carbon atoms in the alkyl portion, alkoxycarbonyl having 1-4 carbon atoms in the alkyl portion or phenyl which may be substituted by C.sub.1 -C.sub.4 alkyl, or two groups among R.sup.2, R.sup.3, and R.sup.4 may be combined together to constitute methylenedioxy on adjacent carbon atoms, or two groups among R.sup.2, R.sup.3 and R.sup.4 may be combined together to constitute phenyl on the adjacent carbon atoms, which is characterized in reacting a diol compound as shown by the following formula (2) ##STR3## wherein R.sup.2, R.sup.3 and R.sup.4 are the same as defined above, R.sup.5 is benzyl, allyl (e.g. 2-propenyl, etc.), o-nitrobenzyl, t-butyldimethylsilyl or benzyloxycarbonyl, or R.sup.5 may be constituted methylenedioxy, isopropylidenedioxy, cyclo

REFERENCES:
Delgado, A. et al `Short and enantioselective synthesis of (R)-and (S)-2-hydroxymethyl-1,4-benzodioxan` Tetrahedron Letters, vol. 29, No. 30 pp. 3671-3674 1988.
JP-6-9613A Benzodioxane Derivative Jan. 1994 Abstract.

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