Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1994-12-16
1996-01-30
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 52, C07L 6976
Patent
active
054881340
DESCRIPTION:
BRIEF SUMMARY
This Application is a 371 of PCT/JP94/00612 Apr. 12, 1995.
The present invention relates to a novel method of preparing compounds of lignan series. More particularly, it relates to a method of preparing compounds of lignan series having an aryl ketone chain or an alkyl ketone chain and to a method of preparing said compounds of lignan series utilizing Diels-Alder reaction.
The compounds of lignan series are useful for treating arteriosclerosis, particularly atherosclerosis, and various compounds were disclosed and claimed already by the present inventors (Japanese Patent Publication (Kokai) 5-310634, and WO 93/08155).
The present invention relates to a process for preparing a compound represented by the formula (I) ##STR2## in which R.sup.1 is alkyl, cycloalkyl, cycloalkyl-lower alkyl, aralkyl, or optionally-substituted aryl; combined together to form an alkylenedioxy; the formula (II) ##STR3## in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined above, is allowed to react with a compound of the formula: R.sup.7 Cl, wherein R.sup.7 is tri (lower alkyl)silyl, in the presence of a base, and then the resulting compound is subjected to addition reaction with an acetylenic compound of the formula (III) ##STR4## in which R.sup.1 is as defined above, to give a compound represented by the formula (IV) ##STR5## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined above, which is then reduced.
In the present invention, it is particularly preferred when R.sup.1 is phenyl which is optionally substituted with halogen, trihalomethyl, lower alkoxy or lower alkyl because the aimed compound can be prepared with good regioselectivity. For example, the reaction is expressed by the following scheme (See Example 1 hereinafter). ##STR6## In the above-mentioned reaction formulae, two types of products will be produced in the addition reaction. The selectivity for the aimed compound given in the reaction formulae versus the side product which is a positional isomer is high in terms of regioselectivity such as, for example, 8.4:1 in the case of Example 1, 11:1 in the case of Example 4 and 13:1 in the case of Example 5 as will be described hereinafter. As such, it is now possible to prepare the aimed compound with high selectivity when R.sup.1 is an aryl and the method of the present invention is a practical method for a large scale synthesis of lignan analogues having an aryl ketone chain.
In the specification, the term "lower alkoxy" for R.sup.2, R.sup.3 and R.sup.4 means oxy group substituted with "lower alkyl" which is mentioned later and its preferred example is methoxy. The term "alkylenedioxy" for R.sup.2 and R.sup.3 is C.sub.1 to C.sub.3 alkylenedioxy such as methylenedioxy, ethylenedioxy and propylenedioxy.
The term "tri(lower alkyl)silyl" for R.sup.7 means a silyl group substituted with three groups which may be the same or different, which are selected from the "lower alkyl" mentioned later and, the examples therefor are trimethylsilyl and tert-butyldimethylsilyl.
The term "alkyl" for R.sup.1 means C.sub.1 to C.sub.10 alkyl while "lower alkyl" means linear or branched C.sub.1 to C.sub.6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 1-ethylpropyl and 2-ethylbutyl. The term "lower alkyl" for R.sup.5 and R.sup.6 has the same meaning. The term "cycloalkyl" means C.sub.5 to C.sub.7 cycloalkyl such as cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkyl lower alkyl" means a group in which the above-defined lower alkyl has the above-defined cycloalkyl substituent and its examples are cyclohexylmethyl and cyclopentylethyl. The term "aralkyl" means a group in which a lower alkyl which is substituted with an aryl and its examples are benzyl, p-methoxybenzyl, phenylethyl, phenylpropyl and naphthylmethyl.
The term "optionally-substituted aryl" means , for example, phenyl or naphthyl which may be substituted with halogen, trihalomethyl, lower alkoxy or lower alkyl. Preferred examples are phenyl with one halogen substituent (mor
REFERENCES:
Gokhale et al., "An Efficient Synthesis of Naphthalenic Lignan Lactones", Indian Journal of Chemistry, vol. 26B, Nov. 1987, pp. 1030-1034.
Iwao et al., "Generation and Diels-Alder Reaction of 1-Siloxy-3-Arylisobenzofurans from 3-Arylphthalides", Chemistry Letters, pp. 1263-1266, 1984.
Kida Shiro
Mori Sachio
Takechi Shozo
Killos Paul J.
Shionogi & Co. Ltd.
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