Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1996-11-29
1999-02-23
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
552510, 540 50, 540 51, 540 60, C07J 900, C07J 5300, C07J 7100
Patent
active
058745980
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for synthesizing provitamin D compounds or provitamin D compounds in which the 5,7-diene structure is protected which are intermediates for synthesis of vitamin D derivatives having a substituent at the 2.beta.-position which have various physiological activities such as a calcium controlling activity in vivo and a differentiation deriving activity of tumor cells, etc.
More specifically, the present invention relates to a process for introducing a substituent into the 2.beta.-position by reacting a 1.alpha.,2.alpha.-epoxy compound with an alcohol under basic conditions.
1. Background Art
Hitherto, in introducing a substituted lower alkoxy group at the 2.beta.-position of vitamin D derivatives, a process in which the addition reaction of an alcohol to 1.alpha.,2.alpha.-epoxy compound is carried out under an acidic conditions has been known (Japanese Patent Application (Kokai) No. 61-267549), but this process is not satisfactory due to its low yield, etc.
2. Disclosure of Invention
As a result of extensive studies, the present inventors found that, in introducing a substituent at the 2.beta.-position by reacting a 1.alpha.,2.alpha.-epoxy compound (1) represented by the formula (I): ##STR2## (wherein R.sub.1 represents a hydrogen atom or a protective group, R.sub.2 are such a hydrogen atom or a hydroxyl group, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are such that each of R.sub.3 and R.sub.4, and R.sub.5 and R.sub.6 forms a double bond, or R.sub.4 and R.sub.5 form a double bond, and R.sub.3 and R.sub.6 bond to dienophile which is capable of protecting a conjugated double bond), with an alcohol, the reaction proceeds even under basic conditions whereby a ring-cleaved product represented by the following formula (II) can be obtained in a high yield: ##STR3## (wherein R.sub.1 represents a hydrogen atom or a protective group, R.sub.2 represents a hydrogen atom or a hydroxyl group, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are such that each of R.sub.3 and R.sub.4, and R.sub.5 and R.sub.6 forms a double bond, or R.sub.4 and R.sub.5 form a double bond, and R.sub.3 and R.sub.6 bond to dienophile which is capable of protecting a conjugated double bond, and R.sub.7 represents a lower alkyl group, a cycloalkyl group or a lower hydroxyalkyl group wherein the hydroxyl group may be protected.)
In the above reaction, protection of some functional groups which has been considered necessary in a conventional ring-cleaving reaction under an acidic condition becomes unnecessary, but the reaction may be carried out while protected. Further, in the process of this invention, the ring-cleaved product can be obtained in a high yield as compared with the reaction under acidic conditions.
The provitamin D.sub.3 derivatives prepared according to the process of this invention can be converted into the corresponding vitamin D.sub.3 derivatives by subjecting the provitamin D.sub.3 derivatives to conventional thermal isomerization after irradiation with U.V. light.
In the present invention, examples of the protective groups in the formula include an acyl group such as an acetyl group, a pivaloyl group, a methoxycarbonyl group, a benzyloxycarbonyl group and a p-toluenesulfonyl group, an alkyl group which may be substituted such as a methyl group and a methoxymethyl group, and a substituted silyl group such as a trimethylsilyl group, a triethylsilyl group and a t-butyldimethylsilyl group, and, preferably, a trimethylsilyl group, a triethylsilyl group and a t-butyldimethylsilyl group.
The alcohol compound means an aliphatic monohydric or polyhydric alcohol having from 1 to 7 carbon atoms, and some of the hydroxyl groups thereof other than any one hydroxyl group thereof may be protected. Examples of the alcohol compound include propanol, butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.
The lower alkyl group means a straight chain or a branched alkyl group having from 1 to 6 carbon a
REFERENCES:
patent: 4046760 (1977-09-01), Jones et al.
patent: 4666634 (1987-05-01), Miyamoto et al.
Weissenberg et al., "Cleavage of the epoxide ring in trans-epoxy-alcohols by sodium borohydride in methanol". J. Chem. Soc. Perkin I, (6) pp. 565-568, 1978.
Weissenberg et al., "Studies on epoxides-VI: Opening reactions of alpha-substituted epoxysteroids". Tetrahedron, vol. 29, p. 353-358, 1973.
Ochi et al., "Synthetic studies of vitamin D3 analogues from bile acids. Part 3 . . . ". J. Chem. Soc. Perkin I, vol. 1979(1), pp. 165-169, 1979.
Weissenberg, et al, J. Chem. Soc., Perkin Trans. I (6), pp. 565-568 (1978).
Weissenberg, et al, Tetrahedron, 29(2), pp. 353-358 (1973).
Ikekawa, Nobuo, `Structures and Biological Acivities of Vitamin D Metabolites and their Analogs`, Medicinal Research Reviews, vol. 7, No. 3, pp. 333-366, 1987.
Badio Barbara
Chugai Seiyaku Kabushiki Kaisha
Dees Jos,e G.
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