Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1994-06-13
1995-07-25
Niebling, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
552611, 568665, 20415715, 20415767, 2041579, 20415792, C07J 300, C07J 7500
Patent
active
054364019
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a 22-oxacholecalciferol derivative expected useful as a drug, an intermediate for the same, and a process for preparing the 22-oxacholecalciferol derivative using the intermediate.
BACKGROUND OF THE INVENTION 22-Oxacholecalciferol derivatives have hitherto
been prepared by, for example, the process starting with a compound represented by formula (II): ##STR2## wherein R.sub.4 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group; R.sub.5 represents a hydroxyl group or a protected hydroxyl group; and R.sub.6 and R.sub.7 represent a hydrogen atom respectively or they are taken together to form a double bond, process, as illustrated by the following reaction scheme (1), comprises reacting the compound of formula (II) with 1-bromo-3-propene in the presence of a basic catalyst to form a 20S-(3-butenyloxy) compound, oxidizing the 20S-(3-butenyloxy) compound with oxygen in the presence of a catalyst to obtain a 20S-(3-oxobutyloxy) compound, and reacting the 208-(3-oxobutyloxy) compound with a Grignard reagent to obtain a 20S-(3-hydroxy-3-methylbutyloxy) compound. ##STR3##
However, the above process requires complicated operation. In addition, since the reaction between the compound (II) and 1-bromo-3-propene is attended by by-production of a 20S-(2-butenyloxy) compound in a considerable proportion, resulting in a low yield of the desired compound, and separation and purification of the desired compound involves difficulty.
DISCLOSURE OF THE INVENTION
As a result of extensive investigations, the inventors have found a technique for constructing the side chain by O-alkylating the 20-hydroxyl group with a compound represented by formula (III): atoms, formula (II): ##STR4## wherein R.sub.4 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group; R.sub.5 represents a hydroxyl group or a protected hydroxyl group; and R.sub.6 and R.sub.7 represent a hydrogen atom respectively or they are taken together to form a double bond.
The compound of formula (II) can be synthesized by, for example, the process disclosed in Japanese Patent Public Disclosure No. 267550/86.
Where starting with the compound of formula (II) in which the hydroxyl group(s) are protected, the protecting groups for a hydroxyl group include those which are not released under a basic condition, such as lower alkylsilyl groups, e.g., a trimethylsilyl group, a triethylsilyl group, and a t-butyldimethylsilyl group, with a t-butyldimethylsilyl group being preferred.
The compound of formula (II) is reacted with a compound represented by formula (III): atoms, in the presence of a basic catalyst.
Examples of the compound of formula (III) include acrylamide compounds, such as dimethylacrylamide and diethylacrylamide.
Examples of suitable bases which can be used in the reaction include metal hydroxides, such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; and metal hydrides, such as sodium hydride, potassium hydride, and calcium hydride.
Where a metal hydroxide is used as a base, an organic solvent which increases solubility of the reactant reagents and is easily miscible with water and stable to an alkali is used. Such solvents preferably include ethers, e.g., tetrahydrofuran (hereinafter abbreviated as THF), dioxane, and diglyme. A water-immiscible organic solvent may also be used if stable to an alkali. Such solvents include aromatic hydrocarbons, e.g., toluene, xylene, and benzene. In the latter cases, it is preferable to use a phase transfer catalyst, preferably a tetrabutylammonium salt. Where a metal hydride is used as a base, it is preferable to use the above-mentioned solvents after drying. That is, an ether, such as THF, dioxane or diglyme, or an aromatic hydrocarbon, such as toluene, xylene or benzene but preferably THF, is used, after drying.
While the reaction temperature and time may be selected appropriately, it is recommended to carry out the reaction at room temperature or lower in order to prevent the acrylamide compound (III) from polym
REFERENCES:
"Reactions of Carbonyl Compounds with Grignard Reagents in the Presence of Cerium Chlpride" Journal of the American Chemical Society, vol. III, No. 12, Jun. 7, 1989, 4392-4398.
Kato Masahiro
Kubodera Noboru
Mikami Tetsuhiro
Ochi Kiyoshige
Watanabe Hiroyoshi
Chugai Seiyaku Kabushiki Kaisha
Niebling John
Wong Edna
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