VITAMIN D3 DERIVATIVE AND PROCESS FOR PRODUCING THE SAME

Abstract: A vitamin D₃ derivative represented by the following formula: wherein, R is, independently, a hydrogen atom, tri(C₁ to C₇ hydrocarbon)silyl group, C₂ to C₈ acyl group, or group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is where, R¹ is a methyl group or methylene group, and when R¹ is a methylene group, the bond between the R¹ and the 3-position of the lactone ring is a double bond, R² is a hydrogen atom or C₁ to C₃ alkyl group, R³ is a hydrogen atom, or R² and R³ together indicate a substitutable single methylene group.

Description: TECHNICAL FIELD The present invention relates to a vitamin D 3 derivative useful as a pharmaceutical. More specifically, it relates to a 1α-hydroxy vitamin D 3 derivative useful as a pharmaceutical such as an agent for promoting bone formation, an agent for suppressing proliferation of tumor cells, an agent for high calcium blood diseases, and an immunosuppression agent, a production process thereof, and a production intermediate. BACKGROUND ART It is fully recognized through disclosures in patent publications and a large number of general references that vitamin D 3 metabolites play an extremely important role as substances controlling the metabolism of calcium and phosphates in the body. Recently, further, an increase has been seen in clinical application as drugs for the treatment of various diseases such as with the numerous vitamin D 3 metabolites found to have the function of inducing differentiation of tumorous bone marrow cells. On the other hand, recently, a novel vitamin D 3 active metabolite having an α-hydroxylactone ring at the steroid side chain has been found. [Arch. Bio-chem. Biophys., 204, 387-391 (1980); FEBS LETTERS, 134, 207-211 (1981)]. This compound is 1α,25-dihydroxy-vitamin D 3 -26,23-lactone and is represented by the following structural formula: This compound has been reported to have an action for reducing the concentration of calcium in blood serum (Japanese Unexamined Patent Publication (Kokai) No. 58-118516), an action for suppressing the proliferation of tumor cells (Japanese Unexamined Patent Publication (Kokai) No. 58-210011), an action for promoting bone formation (Japanese Unexamined Patent Publication (Kokai) No. 60-185715), etc. DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel vitamin D 3 derivative having activity to promote bone formation, a production process therefor, and production intermediates. In accordance with the present invention, there is provided a vitamin D 3 derivative having the following formula (I): wherein, R is, independently, a hydrogen atom, a tri(C 1 to C 7 hydrocarbon)silyl group, a C 2 to C 8 acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is where R 1 is a methyl group or methylene group, and when R 1 is a methylene group, the bond between R 1 and the 3-position of the lactone ring is a double bond. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will now be explained in further detail with reference to the drawings. Figure 1 and Fig. 2 are respectively figures showing the results of synthesis of collagen and synthesis of noncollagen protein in the following Examples. BEST MODE FOR WORKING THE INVENTION According to the present invention, there is provided a vitamin D 3 derivative represented by the following formula (2-1): In the above formula (2-1), R 1 / 2 may be either of a methyl group or methylene group. Note that when R 1 / 2 is a methylene group, the bond between R 1 / 2 and the 3-position of the lactone ring is a double bond (same below). Further, when R 1 / 2 is a methyl group, the configuration of the asymmetric center of the 3-position of the lactone ring is the (S) configuration and the configuration of the asymmetric center of the 5-position may be either of the (S) or (R) configuration. Further, the derivative may be a mixture of any ratio of (S) and (R). Further, when R 1 / 2 is a methylene group, the configuration of the asymmetric center of the 5-position of the lactone ring may be either of the (S) or (R) configuration. Further, the derivative may be a mixture of any of (S) or (R). Among these, those where the asymmetric center of the 5-position is an (S) configuration are preferred. In the above formula [1], R 2 / 2 and R 3 / 2 may be the same or different and represent a hydrogen atom, a tri(C 1 to C 7 hydrocarbon)silyl group, or a C 2 to C 8 acyl group. Here, when R 2 / 2 or R 3 / 2 is a tri(C 1 to C 7 hydrocarbon)silyl group, examples of specific examples are preferably a tri(C 1 to C 4 alkyl)silyl group such as a trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl group, a phenyl(C 1 to C 4 alkyl)silyl group such as a t-butyldiphenylsilyl group, and a tribenzylsilyl group. Further, a dimethyl(2,4,6-tri-t-butylphenoxy)silyl group may be used. Further, when R 2 / 2 or R 3 / 2 is a C 2 to C 8 acyl group, the specific examples are preferably an acetyl, propionyl, n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, caproyl, enanthyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl group, etc. Among these, a C 2 to C 6 acyl group, for example, an n-butyryl, iso-butyryl, methoxycarbonyl, ethoxycarbonyl group, and benzoyl group are preferred. Preferable specific examples of the vitamin D 3 derivative represented by the above formula (2-1) of the second aspect of the present invention are as follows: 1) 1α-hydroxyvitamin D 3 -26,23-lactone 2) 23(S),25(S)-1α-hydroxyvitamin D 3 -26,23-lactone 3) 23(R),25(S)-1α-hydroxyvitamin D 3 -26,23-lactone 4) 1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone 5) 23(S)-1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone 6) 23(R)-1α-hydroxy-25,27-dehydro-vitamin D 3 - 26,23-lactone The present invention further includes a process of production of the vitamin D 3 derivative of the above formula (2-1). That is, it provides a production process of the vitamin D 3 derivative represented by the above formula (2-1), characterized by reacting of a lactone compound represented by the following formula (2-2) wherein X 2 is a bromine atom or iodine atom, R 1 / 2 is a methyl group or methylene group with an enyne compound represented by the following formula (2-10) wherein, R 2 / 2 and R 3 / 2 are the same as defined above in the presence of a palladium catalyst. This vitamin D 3 derivative can be made the vitamin D 3 derivative represented by the following formula (2-11) wherein, R 1 / 2 is the same as defined above optionally by effecting a deprotection reaction. In the production process of the vitamin D 3 derivative according to the present invention, for the configurations of the 3-position and 5-position of the lactone ring of the lactone compound represented by the above formulas (2-2), (2-1), and (2-11), when R 1 / 2 is a methyl group, the 3-position is the (S) configuration, but the 5-position may be either of the (S) or (R) configuration. The derivative may also be any mixture thereof. Further, when R 1 / 2 is a methylene group, the configuration of the 5-position of the lactone ring may be either of the (S) or (R) configuration. The derivative may also be any mixture thereof. For example, when a compound represented by the above formula (2-2) wherein the asymmetric center of the 3-position of the lactone ring is the (S) configuration and the asymmetric center of the 5-position is the (S) configuration is used, the configurations of these positions are preserved during the reaction and a lactone compound represented by the above formula (2-1) where the asymmetric center of the 3-position of the lactone ring is the (S) configuration and the asymmetric center of the 5-position is the (S) configuration is obtained. In the same way, when a compound represented by the above formula (2-2) wherein the asymmetric center of the 3-position of the lactone ring is the (S) configuration and the asymmetric center of the 5-position is the (R) configuration is used, a lactone compound represented by the above formula (2-1) where the asymmetric center of the 3-position of the lactone ring is the (S) configuration and the asymmetric center of the 5-position is the (R) configuration is obtained. The vitamin D 3 derivative represented by the above formula (2-11) is produced by reacting the lactone compound represented by the above formula (2-2) with an enyne compound represented by the above formula (2-10) in the presence of a palladium catalyst. Here, the palladium catalyst means, for example, a zero-valent or bivalent organopalladium. Examples of such a palladium compound are tetrakis(triphenylphosphine)palladium or a mixture of tris(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)palladium chloroform, and palladium acetate with a phosphorus compound such as triphenylphosphine or tributylphosphine (molar ratio of 1:1 to 1:10). Among these, as the palladium catalyst, a combination of tris(dibenzylideneacetone)palladium and triphenylphosphine (1:1 to 1:10) or tris(dibenzylideneacetone)palladium chloroform and triphenylphosphine (1:1 to 1:10) is preferred. Here, the lactone compound represented by the above formula (2-2) and the enyne compound represented by the above formula (2-10) stoichiometrically react equimolarly, but to ensure the reaction is reliably completed, it is usually preferable to use a slightly excess amount of either one of the two reactants, whichever is more readily available. Further, the palladium catalyst is used in a range of 1 to 100 molar %, preferably 5 to 30 molar %, with respect to the lactone compound represented by the above formula (2-2). Examples of the organic solvent used in the process of production, are a hydrocarbon type solvent such as hexane or toluene, an ether type solvent such as tetrahydrofuran or dioxane, a water-soluble solvent such as N,N-dimethylformamide or acetonitrile, and mixed solvents thereof. For all of these, it is important to sufficiently deaerate them before use. As the reaction temperature, in general a range of from room temperature to the boiling point of the solvent is used. The reaction time differs according to the reaction solvent used and the reaction temperature, but usually the reaction is preferably performed until either of the lactone compound represented by the above formula (2-2) or the enyne compound represented by the above formula (2-10) is consumed as determined using an analytical means such as thin layer chromatography. Further, in addition to the palladium catalyst, to trap the hydrogen halide, the reaction is preferably performed in the presence of a base such as, for example, triethylamine or diisopropylethylamine. As the amount of the base, at least one equivalent of the lactone compound of the above formula (2-2) is preferable. The combined use as a solvent is also possible, if necessary. Further, the vitamin D 3 derivative represented by the above formula (2-1) of the present invention may if necessary be made the vitamin D 3 derivative represented by the above formula (2-11) by deblocking. As the deblocking reaction, for example, when deblocking the silyl groups, a known method (for example, Calvely, M. J., Tetrahedoron, 20 , 4609 to 4619, 1987) may be used. Examples of the deblocking agent in this case are tetrabutylammonium fluoride, pyridinium-p-toluene sulfonate, etc. The compound represented by the above formula (2-2) used as a starting material in the process of the present invention may, for example, be synthesized in accordance with the following scheme. When X is an iodine atom, the configuration differs in the same way. That is, the lactone compound represented by the above formula (2-2) is obtained by halomethylation of the lactone compound represented by the above formula (2-3). Further, the compound represented by the above formula (2-3) is obtained by deblocking, if necessary, and then oxidizing the lactone compound represented by the above formula (2-5). Further, the lactone compound represented by the above formula (2-5) may be synthesized from the heptanoic acid derivative represented by the above formula (2-6). On the other hand, the lactone compound represented by the above formula (2-2) may be derived from the heptanoic acid derivative represented by the above formula (2-4). Further, the heptanoic acid derivative represented by the above formula (2-4) may be synthesized from the compound represented by the above formula (2-7). These reactions will be shown more specifically in the Examples: wherein R 1 / 2 is a methyl group or methylene group, when R 1 / 2 is a methylene group, the bond between R 1 / 2 and the 3-position of the lactone ring being a double bond. wherein X is a bromine atom or iodine atom. wherein R 4 / 2 is a hydrogen atom, tri(C 1 to C 7 hydrocarbon)silyl group, C 1 to C 7 acyl group, or group forming an acetal group together with an oxygen atom of a hydroxyl group. wherein R 4 / 2 is the same as defined above. wherein X is a bromine atom or iodine atom, Y is a cyano group, formyl group, tosyl group, mesyl group, phenylsulfonyloxy group, tri(C 1 to C 7 hydrocarbon)silyl group, C 1 to C 7 acyl group, or hydroxyl group which may be blocked by an acetal group together with the oxygen atom of a hydroxyl group. The present invention includes compounds represented by the above formulas (2-2), (2-3), (2-4), (2-5), (2-6), and (2-7) serving as intermediates for the synthesis of the vitamin D 3 derivative represented by the above formula (2-1). Here, when the R 1 of the lactone compound represented by the above formula (2-3) and (2-5) is a methyl group, the asymmetric center of the 3-position of the lactone ring is the (S) configuration and the asymmetric center of the 5-position may be either of the (R) configuration or (S) configuration. The derivative may also be any mixture thereof at any ratio. Further, in the heptanoic acid derivative represented by the above formula (2-4) or (2-6), the asymmetric center of the 4-position may be either of the (R) configuration or (S) configuration. The derivative may also be a mixture of any ratio of the two. Preferable specific examples of the compound represented by the above formula (2-2) according to the present invention are as follows: 1) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 2) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 3) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methyldehydro-2(3H)-furanon 4) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methyldehydro-2(3H)-furanon 5) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 6) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 7) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methyldehydro-2(3H)-furanon 8) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methyldehydro-2(3H)-furanon Preferable specific examples of the compound represented by the above formula (2-3) according to the present invention are as follows: 1) (5S)-5-{(2R)-2-[(lR,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 2) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 3) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon 4) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon Preferable specific examples of the compound represented by the above formula (2-4) according to the present invention are as follows: 1) (4S,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 2) (4R,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 3) (4S,6R)-6-[(lR,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 4) (4R,6R)-6-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene Preferable specific examples of the compound represented by the above formula (2-5) according to the present invention are as follows: 1) (5S)-5-{(2R)-2-[(lR,7aR)-octahydro-4-hydroxy-7a-methyl-lH-inden-1-yl]propyl}-3-methylenedehydro-2(3H)-furanon 2) (5R)-5-{(2R)-2-[(lR,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 3) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon 4) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyI-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon 5) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 6) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 7) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4--rimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon 8) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon 9) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 10) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon 11) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon 12) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon Preferable specific examples of the compound represented by the above formula (2-6) according to the present invention are as follows: 1) (4S,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yI]-2-methoxycarbonyl-4-hydroxy-1-heptene 2) (4R,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 3) (4S,6R)-6-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 4) (4R,6R)-6-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 5) (4S,6R)-6-[(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene 6) (4R,6R)-6-[(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene Preferable specific examples of the compound represented by the above formula (2-7) according to the present invention are as follows: 1) (2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propylparatoluenes ulfonate 2) (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile 3) (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanal 4) (2R)-2-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]propylparatoluene-sulfonate 5) (3R)-3-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]butyronitrile 6) (3R)-3-[(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl]butanal The vitamin D 3 derivative represented by the above formula (2-1) may be used as an agent for promoting bone growth. Further, the compounds represented by the above formulas (2-2), (2-3), (2-4), (2-5), (2-6), and (2-7) may be used as intermediates for the synthesis thereof. EXAMPLES The present invention will now be explained in further detail by way of Examples, which, however, do not restrict the present invention in any way. Example 1-1 Production of (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl-p-toluenesulfonate A 2.0 g amount of the compound (1-7), (2R)-2-[(1R, 7aR)(4E)-octahydro-4-hydroxy-7a-methyI-1-H-inden-1-yl] -propanol, and 2.3 g of p-toluenesulfonyl chloride were placed into a 100 ml eggplant-shaped flask. These were dissolved in 10 ml of dried dichloromethane, then the solution was stirred under ice-cooling. A 4 ml amount of pyridine was added thereto, then the solution was stirred under ice cooling for 6 hours. The reaction solution was poured into 100 ml of ethyl acetate and 20 ml of water and extracted. The organic layer was washed 2 times with a saturated aqueous solution of potassium hydrogensulfate, a saturated aqueous solution of sodium bicarbonate, and saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 4.2 g. This was placed in a 100 ml eggplant-shaped flask, then 2.04 g of imidazole was added. Thereto 20 ml of dried dichloromethane was added. The solution was then stirred under ice-cooling. Next, 1.91 ml of trimethylsilyl chloride was added thereto and the solution was stirred at room temperature over night. The reaction solution was poured into 100 ml of ethyl acetate and 20 ml of water and extracted. The organic layer was then washed 2 times with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 4.07 g. This was purified by a silica gel column (IR-60, 200 g, hexane/ethyl acetate = 9/1) to obtain the desired product (1-8), (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl-p-toluenesulfonate in an amount of 3.27 g (yield 87%). 1 H-NMR (CDCl 3 , δ ppm) 7.78 (d, 2H, J=18Hz), 7.34 (d, 2H, J=18Hz), 3.9 to 4.0 (m, 1H), 3.95 (dd, 1H, J=3 & 9.2Hz), 3.79 (dd, 1H, J=4.3 & 9.2Hz), 2.45(s, 3H), 1.00 to 2.00 (m, 13H), 0.89 (d, 3H J=18Hz), 0.83 (s, 3H), 0.03 (s, 9H) Example 1-2 Process of production of (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-iodopropane A 3.27 g amount of the compound (1-8), (2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl-p-toluenesulfonate, was dissolved in 200 ml of acetone in a 500 ml eggplant-shaped flask. To this was added 5 g of sodium iodide. The solution was then heated and refluxed over night. The reaction solution was allowed to cool, then the precipitate was filtered out and the solvent was distilled off under reduced pressure. A 300 ml amount of ether and 200 ml of water were added to the residue and separation performed. Extraction was performed from the aqueous layer by 200 ml of ether, then the organic layer was washed 2 times with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. The result was dried over anhydrous magnesium sulfate, the desiccant was filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 4.5 g. This was purified by a silica gel column (IR-60, 80 g, hexane) to obtain the desired product (1-9), (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-iodopropane, in an amount of 2.72 g (yield 94%). 1 H-NMR (CDCl 3 , δ ppm) 3.99 (m, 1H), 3.33 (dd, lH J=2 & 5Hz), 3.17 (dd, 1H J=5 & 9Hz), 1.00 to 2.00 (m, 13H), 0.99 (d, 3H, J=5.6Hz), 0.92 (s, 3H), 0.05 (s, 9H) Production of (4S,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene and (4R,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene A 3.0 g amount of (3R)-3-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]butanal was placed in a 500 ml eggplant-shaped flask, 100 ml of tetrahydrofuran was added, and the solution was stirred and cooled by an ice-cooled bath. A 3.2 ml amount of methyl-2-bromomethylacrylate was added dropwise to this. Next, 1.37 g of zinc powder and 390 ml of a saturated aqueous solution of ammonium chloride were added and the solution was stirred at the same temperature for 45 minutes. A 150 ml amount of ethyl acetate was added to the reaction solution for extraction. The organic layer was washed 2 times with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 5.0 g. This was purified by a silica gel column (Merck gel, 250 g, hexane/ethyl acetate = 9/1 to 3/1) to obtain (4S,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene (more polar) in an amount of 2.03 g and (4R,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene (less polar) in an amount of 1.522 g (yield 81%). 1 H-NMR (CDCl 3 , δ ppm) 6.25 (d, lH, J=2Hz), 5.66 (d, 1H, J=2Hz), 4.07 (br, 1H), 3.82 to 3.88 (br, 1H), 3 .77 (s, 3H), 2.51 (dd, 1H, J1=1Hz, J2=9Hz), 2.36 (dd, 1H, J1=8Hz, J2=14Hz), 0.96 (s, 1H), 0.94 (d, 3H, J=6Hz), 6.27 (d, 1H, J=1Hz), 5.69 (d, 1H, J=1Hz), 4.07 (br, 1H), 3.80 to 3.86 (br, 1H), 3.77 (s, 3H), 2.69 (dd, 1H, J1=1Hz, J2=10Hz), 2.18 (dd, 1H, J1=9Hz, J2=14Hz), 0.98 (d, 3H, J=7Hz), 0.95 (s, 3H). Example 2-2 Production of (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon A 1.00 g amount of (4S,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene was taken in a 100 ml eggplant-shaped flask, then 15 ml of tetrahydrofuran was added to dissolve it. Further, 15 ml of water was added and the solution was stirred and cooled by an ice-cooled bath. To this was added 6 ml of a 4N aqueous solution of lithium hydroxide, then the solution was stirred at the same temperature for 1 hour. Next, at the same temperature, concentrated hydrochloric acid was dropwise added to adjust the pH to 2, then the solution was stirred at room temperature for 3 hours. To the reaction solution were added 50 ml of water and 200 ml of ethyl acetate for extraction. The organic layer was further washed 3 times with water and was washed 2 times with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 880 mg. 1 H-NMR (CDCl 3 , δ ppm) 6.22 (t, 1H, J=3Hz), 5.62 (t, 1H, J=2Hz), 4.58 (dd, 1H, J1=7Hz, J2=14Hz), 4.08 (d, 1H, J=3Hz), 3.01 to 3.10 (m, 1H), 2.56 to 2.6 (m, 1H), 1.00 (d, 3H, J=7Hz), 0.95 (s, 3H). Example 2-3 Production of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon A 570 mg amount of (4R,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene was taken in a 100 ml eggplant-shaped flask, then 5 ml of tetrahydrofuran was added to dissolve it. Further, 5 ml of water was added and the solution stirred and cooled by an ice-cooled bath. To this was added 3 ml of a 4N aqueous solution of lithium hydroxide. The solution was stirred at the same temperature for 1 hour. Next, under the same temperature, concentrated hydrochloric acid was added dropwise to adjust the pH to 2, then the solution was stirred at room temperature for 3 hours. To the reaction solution were added 50 ml of water and 200 ml of ethyl acetate for extraction. The organic layer was further washed 3 times with water and 2 times with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 451 mg. Example 2-4 Production of (5S)-5-{(2R)-2-[(1R,7R)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon A 2.38 g amount of pyridinium bichromate was taken in a 200 ml eggplant-shaped flask, 50 ml of dimethyl formamide was added, then the solution was cooled by an ice-cooled bath. Thereafter, a solution of 880 mg of (5S)-5-{(2R)-2-[(1R,7R)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon dissolved in 20 ml of dimethyl formamide was dropwise added and the solution was stirred at room temperature for 3 hours. A 200 ml amount of ether was added to the reaction solution, the insolubles were filtered out, then the result was washed with water and then saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 1.02 g. This was purified by a silica gel column (Daiso gel IR-60, 150 g, hexane/ethyl acetate = 3/1 to 2/1) to obtain (5S)-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2 (3H)-furanon in an amount of 700 mg (yield 69%). 1 H-NMR (CDCl 3 , δ ppm) 6.23 (t, 1H, J=3Hz), 5.63 (t, 1H, J=2Hz), 4.6 to 4.7 (m, 1H), 3.0 to 3.13 (m,1H), 2.4 to 2.6 (m,1H), 1.05 (d, 3H, J=7Hz), 0.67 (s, 3H). Example 2-5 Production of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2 (3H)-furanon A 648 mg amount of pyridinium bichromate was taken in a 200 ml eggplant-shaped flask, 10 ml of dimethyl formamide was added, and the solution was cooled by an ice-cooled bath. Thereafter a solution of 240 mg of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon dissolved in 10 ml of dimethyl formamide was dropwise added and the solution was stirred at room temperature for 3 hours. A 100 ml amount of ether was added to the reaction solution, the insolubles were filtered out, then the result was washed with water and saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 600 mg. This was purified by a silica gel column (Daiso gel IR-60, 100 g, hexane/ethyl acetate = 3/1 to 2/1) to obtain (5R)-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 327 mg. 1 H-NMR (CDCl 3 , δ ppm) 6.23 (t, 1H, J=3Hz), 5.63 (t, 1H, J=2Hz), 4.59 (t, 1H, J=7Hz), 3.0 to 3.10 (m, 1H), 2.4 to 2.6 (m, 1H), 1.07 (d, 3H, J=6Hz), 0.66 (s, 3H). Example 2-6 Production of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon A 200 mg amount of (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon was taken in a 100 ml eggplant-shaped flask, 50 ml of ethanol was added, and the solution was stirred for dissolution. A 50 mg amount of 10% Pd/carbon was added under a nitrogen atmosphere, the atmosphere was replaced with hydrogen (balloon), then the solution was stirred at room temperature for 3 hours. The atmosphere was replaced with nitrogen, then the catalyst was filtered out and the solvent was distilled off under reduced pressure to obtain (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon in an amount of 185 mg. 1 H-NMR (CDCl 3 , δ ppm) 4.40 to 4.51 (m, 1H), 2.62 to 2.72 (m, 1H), 2.41 to 2.51 (m, 2H), 2.27 (d, 3H, J=7Hz), 1.03 (d, 3H, J=7Hz), 0.66 (s, 3H). Example 2-7 Production of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon A 1.79 g amount of bromomethylenetriphenylphosphonium bromide was taken in a 100 ml eggplant-shaped flask, 20 ml of dried tetrahydrofuran was added, and the solution was stirred and cooled by a -70°C cooling bath. Thereafter 3.9 ml of a 1M [(CH 3 ) 3 Si] 2 NNA/tetrahydrofuran solution was dropwise added, then the solution was stirred at the same temperature for 1 hour. Next, a solution of 120 mg of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon dissolved in 5 ml of dried tetrahydrofuran was dropwise added to this. The cooling bath was removed, then the solution was stirred for 2 hours. Next, hexane was added and the insolubles filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 1.2 g. This was purified by a silica gel column (Daiso gel IR-60, 80 g, hexane/ethyl acetate = 15/1) to obtain (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a -methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon in an amount of 69 mg (yield 46%). 1 H-NMR (CDCl 3 , δ ppm) 5.65 (d,1H, J=2Hz), 4.40 to 4.50 (m, 1H), 2.85 to 2.90 (m, 1H), 2.62 to 2.72 (m, 1H), 2.41 to 2.50 (m, 1H), 2.67 (d, 3H, J=7Hz), 1.00 (d, 3H, J=7Hz), 0.58 (s, 3H). Example 2-8 Production of (2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propylparatoluene sulfonate A 2.39 g amount of bromomethylenetriphenylphosphonium bromide was taken in a 100 ml eggplant-shaped flask, 40 ml of dried tetrahydrofuran was added, and the solution was stirred and cooled by a -70°C cooling bath. Thereafter 5.28 ml of a 1M [(CH 3 ) 3 Si] 2 NNa/tetrahydrofuran solution was dropwise added, then the solution was stirred at the same temperature for 1 hour. Next, a solution of 300 mg of (2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]propylparatoluene sulfonate dissolved in 10 ml of dried tetrahydrofuran was added dropwise. The cooling bath was removed and then the solution was stirred for 1 hour. Next, hexane was added and the insolubles were filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 2.5 g. This was purified by a silica gel column (Merck gel, 100 g, hexane/ethyl acetate = 14/1, 9/1) to obtain {(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propylparatoluene sulfonate in an amount of 178 mg (yield 48%). 1 H-NMR (CDCl 3 , δ ppm) 7.78 (d, 2H, J=8Hz), 7.35 (d, 2H, J=8Hz), 5.64 (s,1H), 3.96 (dd, 1H, J1=3Hz, J2=9Hz), 3.82 (dd, 1H, J1=6Hz, J2=9Hz), 2.45 (s, 3Hz), 0.99 (d, 3H, J=7Hz), 0.53 (s, 3H). Example 2-9 Production of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile A 178 mg amount of (2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propylparatoluenes ulfonate was taken in a 50 ml eggplant-shaped flask, then 6 ml of dimethyl formamide was added for dissolution. To this was then charged 215 mg of KCN, then the solution was stirred in a 50°C bath for 24 hours. To the reaction solution was added 50 ml of water, then extraction was performed with ether. The organic layer was washed with water and saturated saline, then was dried over anhydrous magnesium sulfate and the desiccant was filtered out. The solvent was distilled off under reduced pressure to obtain a crude product in an amount of 110 mg. This was purified by a silica gel column (Daiso gel, hexane/ethyl acetate = 14/1) to obtain (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile in an amount of 84 mg (yield 69%). 1 H-NMR (CDCl 3 , δ ppm) 5.67 (s, 1H), 2.86 to 2.91 (m, 1H), 2.21 to 2.35 (m, 2H), 1.18 (d, 3H, J=6Hz), 0.59 (s, 3H). Example 2-10 Production of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanal A 84 mg amount of (3R)-3-[(lR,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile was taken in a 25 ml eggplant-shaped flask, then 5 ml of dried dichloromethane was then added to dissolve the same. The solution was cooled by a -70°C bath, then 660 µl of a 1.5M [(CH 3 ) 2 CHCH 2 ] 2 AlH/toluene /toluene solution was added dropwise. The solution was stirred at the same temperature for 1 hour, then 0.5 ml of a saturated aqueous solution of sodium sulfate, 0.3 ml of methanol, 0.5 ml of 2N hydrochloric acid, and 15 ml of ethyl acetate were added and the solution stirred for 30 minutes. The reaction solution was filtered by Celite, then was washed by a saturated solution of ammonium chloride and saturated saline, then was dried over anhydrous magnesium sulfate and the desiccant filtered out. The solvent was distilled off under reduced pressure to obtain (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanal in an amount of 85 mg. Example 2-11 Production of (4S,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl -4-hydroxy-1-heptene and (4R,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene A 105 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanal was taken in a 50 ml eggplant-shaped flask, then 8 ml of dried tetrahydrofuran was then added to dissolve the same. The solution was cooled by an ice cooled bath, then 84 µl of methyl-2-bromomethylacrylate was added dropwise. Further, 35 mg of zinc powder and 10 ml of a saturated aqueous solution of ammonium chloride were added, then the solution was stirred at the same temperature for 1 hour. The reaction solution was extracted by ethyl acetate, the organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 166 mg. This was purified by a silica gel column (Merck gel, hexane/ethyl acetate = 9/1) to obtain (4S,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene in an amount of 43 mg and (4R,6R)-6-[(lR,7aR)-octahydro-4-bromomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl -4-hydroxy-1-heptene in an amount of 55 mg. 1 H-NMR (CDCl 3 , δ ppm) 6.269 (d, 1H, J=1Hz), 5.66 (d, 2H, J=10Hz), 3.77 (s, 3H), 2.84 to 2.93 (m, 1H), 2.65 to 2.72 (m, 1H), 2.13 to 2.27 (m, 1H), 1.02 (d, 3H, J=7Hz), 0.58 (s, 3H), 6.249 (d, 1H, J=1Hz), 5.65 (d, 2H, J=5Hz), 3.77 (s, 3H), 2.84 to 2.90 (m, 1H), 2.53 to 2.55 (m, 1H), 2.31 to 2.39 (m, 1H), 0.97 (d, 3H, J=7Hz), 0.59 (s, 3H) Example 2-12 Production of (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon A 55 mg amount of (4S,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl -4-hydroxy-1-heptene was taken in a 50 ml eggplant-shaped flask, then 6 ml of tetrahydrofuran was added to dissolve the same. Further, 6 ml of water was added, the solution was cooled by an ice-cooled bath, 0.25 ml of 4N lithium hydroxide was added dropwise, and the solution was stirred at the same temperature for 1 hour. Next, concentrated hydrochloric acid was added dropwise under the same temperature to adjust the pH to 2 and the solution was stirred at room temperature for 3 hours. To the reaction solution were added 10 ml of water and 100 ml of ethyl acetate for extraction. The organic layer was washed 3 times with water and 2 times with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 51 mg. 1 H-NMR (CDCl 3 , δ ppm) 6.23 (t, 1H, J=3Hz), 5.62 (t, 1H, J=2Hz), 5.65 (d, 1H, J=2Hz), 4.12 (dd, 1H, J1=7Hz, J2=14Hz), 3.00 to 3.11 (m, 1H), 2.85 to 2.9 (m, 1H), 2.47 to 2.57 (m, 1H), 1.03 (d, 3H, J=7Hz), 0.58 (s, 3H). Example 2-13 Production of (5R)-5-{(2R)-2-[(lR,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon A 70 mg amount of (4R,6R)-6-[(lR,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-1-heptene was taken in a 50 ml eggplant-shaped flask, then 6 ml of tetrahydrofuran was added for dissolution. Further, 6 ml of water was added, the solution was cooled by an ice-cooled bath, 0.35 ml of 4N lithium hydroxide was added dropwise, and the solution was stirred at the same temperature for 1 hour. Next, concentrated hydrochloric acid was added dropwise under the same temperature to adjust the pH to 2 and the solution was stirred at room temperature for 3 hours. To the reaction solution were added 10 ml of water and 100 ml of ethyl acetate for extraction. The organic layer was washed 3 times with water and 2 times with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 60 mg. 1 H-NMR (CDCl 3 , δ ppm) 6.23 (t, 1H, J=3Hz), 5.62 (t, 1H, J=2Hz), 5.65 (d, 1H, J=2Hz), 4.59 to 4.69 (m, 1H), 3.01 to 3.12 (m, 1H), 2.85 to 2.9 (m, 1H), 2.47 to 2.57 (m, 1H), 1.02 (d, 3H, J=7Hz), 0.59 (s, 3H). Example 2-14 Production of 23(S),25(S)-1α-hydroxyvitamin D 3 -26,23-lactone A 28 mg amount of triphenylphosphine was taken in a dried eggplant-shaped flask and deaerated. Thereafter, 19 mg of tris(dibenzylideneacetone)dipalladium chloroform was added, followed by further deaeration, then 6 ml of a mixed solvent of distilled toluene/diisopropylethylamine = 1/1 was added under nitrogen and the solution was stirred at 50°C for 20 minutes. Next, a solution of 65 mg of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-furanon and 60 mg of (3S),(5R)-3,5-bis(trimethylsilyloxy)-1-octen-7-yne dissolved in 3 ml of a mixed solvent of distilled toluene/diisopropylethylamine = 1/1 was added dropwise. This reaction solution was stirred at 100°C for 1.5 hours. This was returned to room temperature, then the reaction solution was poured into 50 ml of ethyl acetate and 10 ml of a saturated aqueous solution of potassium hydrogensulfate for extraction. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, then was dried over anhydrous sodium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 120 mg. This was purified by a silica gel column (Merck gel, hexane/ethyl acetate = 14/1 to 9/1) to obtain 23(S),25(S)-1α-hydroxy-vitamin D 3 -26,23-lactone-1α,3-bistrimethylsilylether in an amount of 52 mg (yield 50%). This was placed in a 25 ml eggplant-shaped flask, then 5 ml of methanol was added to dissolve it. The solution was cooled by an ice-cooled bath, then 100 mg of polymer-bonded pyridinium toluene-4-sulfonate was added and the solution stirred for 15 hours. The reaction solution was filtered by Celite, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 110 mg. This was purified by a silica gel column (Merck gel, hexane/ethyl acetate = 2/1 to 1/1) to obtain 23(S),25(S)-1α-hydroxyvitamin D 3 -26,23-lactone in an amount of 28 mg (yield 72%). 1 H-NMR (CDCl 3 , δ ppm) 6.37 (d, 1H, J=11Hz), 6.00 (d, 1H, J=11Hz), 5.33 (s, 1H), 5.01 (s, 1H), 4.44 (br, 2H), 4.24 (br, 1H), 1.265 (d, 3H, J=8Hz), 0.99 (d, 3H, J=6Hz), 0.56 (s, 3H) Example 2-15 Production of 23(S)-1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone A 22 mg amount of triphenylphosphine was taken in a dried eggplant-shaped flask and then deaearated. Thereafter, 14 mg of tris(dibenzylideneacetone) dipalladium chloroform was added, followed by further deaeration, then 3 ml of a mixed solvent of distilled toluene/diisopropylethylamine = 1/1 was added under nitrogen and the solution was stirred at 50°C for 20 minutes. Next, a solution of 51 mg of (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon and 61 mg of (3S),(5R)-3,5-bis(trimethylsilyloxy)-1-octene-7-in dissolved in 4 ml of a mixed solvent of distilled toluene/diisopropylethylamine = 1/1 was added dropwise. This reaction solution was stirred at 100°C for 1.5 hours, then was returned to room temperature. The reaction solution was poured into 50 ml of ethyl acetate and 10 ml of a saturated aqueous solution of potassium hydrogensulfate for extraction. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, then was dried over anhydrous sodium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 120 mg. This was purified by a silica seppack (Waters, hexane/ethyl acetate = 19/1 to 9/1) to obtain 23(S)-1α-hydroxy-25,27-dehydro-vitamin D 3 -23,26-lactone-1α,3-bistrimethylsilylether in an amount of 46 mg (yield 50%). This was placed in a 25 ml eggplant-shaped flask, then 5 ml of methanol was added for dissolution. The solution was cooled by an ice-cooled bath, 50 mg of polymer-bonded pyridinium toluene-4-sulfonate was added, then the solution was stirred for 15 hours. The reaction solution was filtered by Celite, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 110 mg. This was purified by a silica seppack (Waters, hexane/ethyl acetate = 3/1 to 1/1) to obtain 23(S)-1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone in an amount of 12 mg (yield 40%). 1 H-NMR (CDCl 3 , δ ppm) 6.37 (d, 1H, J=12Hz), 6.22 (t, 1H, J=3Hz), 6.00 (d, 1H, J=11Hz), 5.62 (t, 1H, J=3Hz), 5.323 (d, 1H, J=1Hz), 5.00 (s, 1H), 4.59 (t, 1H, J=7Hz), 4.43 to 4.54 (br, 1H), 4.22 to 4.24 (br, 1H), 2.99 to 3.11 (m, 1H), 2.79 to 2.85 (m, 1H), 2.48 to 2.61 (m, 2H), 2.28 to 2.35 (m, 1H), 1.03 (d, 3H, J=6Hz), 0.56 (s, 3H) Example 2-16 Production of 23(R)-1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone A 26 mg amount of triphenylphosphine was taken in a dried eggplant-shaped flask and deaerated. To this was further added 20 mg of tris(dibenzylideneacetone) dipalladium chloroform followed by further deaeration, then 3 ml of a mixed solvent of distilled toluene/diisopropylethylamine = 1/1 was added under nitrogen and the solution was stirred at 50°C for 20 minutes. Next, a solution of 70 mg of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1 -yl]propyl}-3-methylene-dehydro-2(3H)-furanon and 84 mg of (3S),(5R)-3,5-bis(trimethylsilyloxy)-1-octen-7-yne dissolved in 4 ml of a mixed solvent of distilled toluene/diisopropylethylamine = 1/1 was added dropwise. This reaction solution was stirred at 100°C for 1.5 hours, then was returned to room temperature. The reaction solution was poured into 50 ml of ethyl acetate and 10 ml of a saturated aqueous solution of potassium hydrogensulfate for extraction. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, then was dried over anhydrous sodium sulfate. The desiccant was filtered out and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 190 mg. This was purified by a silica gel seppack (Waters, hexane/ethyl acetate = 19/1 to 9/1) to obtain 23(R)-1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone -1α,3-bistrimethylsilylether in an amount of 50 mg (yield 40%). This was placed in a 25 ml eggplant-shaped flask, then 5 ml of methanol was added to dissolve it. The solution was cooled by an ice-cooled bath, then 100 mg of pyridinium toluene-4-sulfonate bonded to a polymer was added, then the solution was stirred for 15 hours. The reaction solution was filtered by Celite, then the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 110 mg. This was purified by silica seppack (Waters, hexane/ethyl acetate = 3/1 to 1/1) to obtain 23(R)-1α-hydroxy-25,27-dehydro-vitamin D 3 -26,23-lactone in an amount of 14 mg (yield 43%). 1 H-NMR (CDCl 3 , δ ppm) 6.37 (d, 1H, J=11Hz), 6.225 (t, 1H, J=3Hz), 6.00 (d, 1H, J=11Hz), 5.62 (t, 1H, J=2Hz), 5.33 (t, 1H, J=2Hz), 5.00 (s, 1H), 4.59 to 4.69 (m, 1H), 4.41 to 4.45 (m, 1H), 4.21 to 4.25 (m, 1H), 3.01 to 3.10 (m, 1H), 2.79 to 2.85 (m, 1H), 2.47 to 2.58 (m, 2H), 2.28 to 2.35 (m, 1H), 1.02 (d, 3H, J=6Hz), 0.58 (s, 3H) Example 5-1 Measurement of Action of Suppression of Formation of Osteoclasts Induced by 1α,25(OH) 2 D 3 Marrow cells were separated from the femur and tibia of mice (C57/Black 6, 5 weeks old, male) and incubated for 7 days in α-MEM containing 10% fetal calf serum in the presence of 1α,25(OH) 2 D 3 (10 -8 M) with the addition of certain concentrations of compounds. The cells were dyed by tartaric acid resistant acid phosphase (TRAP), and the nuclei were dyed by Methyl Green. Next, the cells with at least 3 nuclei dyed by TRAP (osteoclasts) were counted under a microscope. The results are shown in the following Table 5-1. Compound TRAP-positive MNC cell/well 1α,25(OH) 2 D 3 (VD 3 ) 10 -8 M 61.3±16.0 VD 3 (10 -8 M + Example 2-15 compound 10 -9 M 47.7±9.2 10 -8 M 34.5±9.9 VD 3 (10 -8 M)+ Example 2-16 compound 10 -9 M 23.2±10.4 10 -8 M 24.0±6.9 10 -7 M 17.5±6.6 Example 5-2 Affinity of compound to 1α,25-dihydroxyvitamin D 3 receptor (VDR) in chicken intestinal membrane cells The 1α,25-dihydroxyvitamin D 3 receptor in chicken intestinal membrane cells was isolated and evaluated in receptor affinity by a known method (Steroids, 37, 33-43 (1981). That is, 20 pg of [26,27-methyl- 3 H]1α,25-dihydroxyvitamin D 3 (158 Ci/mmol, 16,800 dpm) and the test compound dissolved in 50 µl of ethanol were added to 12 x 75 mm polypropylene tubes. To these were added 0.2 mg amounts of 1α,25-dihydroxyvitamin D 3 receptor protein in chicken intestinal membrane cells and 1 mg of gelatin dissolved in 1 ml of a phosphate buffer (pH 7.4), then the solutions were reacted at 25°C for one hour. After the reaction, 1 ml portions of a 40% solution of polyethylene glycol 6,000 were added to the tubes which were then shaken vigorously, then were centrifugally separated at 4°C and 2,260 x g for 60 minutes. The tubes of the sediment portions were cut off by a cutter knife and placed in liquid scintillation vials, a dioxane scintillator was added in amounts of 10 ml, and the radioactivity was measured by a liquid scintillation counter. The results are shown in the later given Table 5-2. Example 5-3 Affinity of compounds to vitamin D bonded proteins in fetal calf serum The affinity of 25-hydroxyvitamin D 3 and a test compound to the vitamin D bonded proteins in fetal calf serum was determined by the method of J. Steroid Biochem. Molec. Biol. 41, 109-112 (1992). That is, 200 pg amounts of [26,27-methyl- 3 H]25-hydroxyvitamin D 3 (28 Ci/mmol, 31,000 dpm) dissolved in a 0.01% Triton X-100 solution and the test compound dissolved in 10 µl of ethanol were added to 12 x 105 mm gas tubes. To these were added 0.2 ml amounts of a solution of fetal calf serum diluted 2500-fold by a 0.9% sodium chloride-containing phosphate buffer (pH 7.0), the solutions were reacted at 4°C for 24 hours, then 0.5 ml of 0.5% charcoal, 0.075% dextrin and 0.5% bovine serum albumin solution were added, the solutions reacted at 4°C for 15 minutes, then centrifugally separated at 2,260 x g for 10 minutes. 0.5 ml amounts of the supernatent were taken in liquid scintillation vials and the radioactivity of the [26,27-methyl- 3 H]25-hydroxyvitamin D 3 bonded to the vitamin D bonded protein was measured by a liquid scintillation counter. The results are shown in the following Table 5-2. Compound 1α,25-(OH) 2 D 3 receptor (molar ratio) Vitamin D-bonded protein (molar ratio) 1α,25-(OH) 2 D 3 1 1 Example 2-14 compound 207 41.8 Example 2-15 compound 9.8 10.7 Example 2-16 compound 13.8 39.4 Example 5-4 Synthesis of Collagen and Noncollagen Protein by osteoblasts A murine osteoblast cell strain (MCJT cells) was dispersed in an α-MEM medium containing 10% fetal calf serum (FCS) (1 x 10 4 cells/ml medium). This was sown in 2 ml amounts in 35 mm incubation dishes, then incubated at 37°C under 5% CO 2 . After 4 days, after confluent was reached, the incubation solution was replaced by the same solution, then an ethanol solution of the test compound (1 x 10 -4 M and 1 x 10 -5 M) was added in 2 µl amounts. The control group had only ethanol added in an amount of 2 µl. The specimens were incubated at 37°C under 5% CO 2 . After 45 hours incubation, the medium was replaced by an α-MEM medium containing 0.1% bovine serum albumin (BSA), 0.1 mM ascorbic acid, and 0.5 mM fumaric acid-β-aminopropionitrile, the same amount of the ethanol solution of the test compound or ethanol as the previous time was added again, then incubation performed for 30 minutes, then 4 µCi of [ 3 H] proline were added to petri dishes and were allowed to be taken up by the osteoblasts for 3 hours. The amounts of the synthesized collagen and noncollagen protein were measured by the method of Perterkofsky et al. (Biochemistry, 10, 988-994 (1971)). The results are shown in Fig. 1 and Fig. 2. INDUSTRIAL APPLICABILITY As explained above, the vitamin D 3 derivative according to the present invention is useful as an agent for the promotion of bone formation.

Claims: A vitamin D 3 derivative represented by the following formula (I): wherein R is, independently, a hydrogen atom, a tri(C 1 to C 7 hydrocarbon)silyl group, a C 2 to C 8 acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is where R 1 is a methyl group or methylene group and when R 1 is a methylene group, the bond between the R 1 and the 3-position of the lactone ring is a double bond. A vitamin D 3 derivative as claimed in claim 1 represented by the following formula (2-1): wherein R 1 / 2 is a methyl group or methylene group, provided that when R 1 / 2 is a methylene group, the bond between R 1 / 2 and the 3-position of the lactone ring is a double bond, R 2 / 2 and R 3 / 2 are the same or different and represent a hydrogen atom, a tri(C 1 to C 7 hydrocarbon)silyl group, or a C 2 to C 8 acyl group. A vitamin D 3 derivative as claimed in claim 2, wherein the R 1 / 2of the above formula (2-1) is a methyl group, the asymmetric center of the 3-position of the lactone ring is the (S) configuration, and the asymmetric center of the 5-position is an (S) configuration. A vitamin D 3 derivative as claimed in claim 2, wherein the R 1 / 2 of the above formula (2-1) is a methyl group, the asymmetric center of the 3-position of the lactone ring is the (S) configuration, and the asymmetric center of the 5-position is an (R) configuration. A vitamin D 3 derivative as claimed in claim 2, wherein the R 1 / 2 of the above formula (2-1) is a methylene group, and the asymmetric center of the 5-position of the lactone ring is the (S) configuration. A vitamin D 3 derivative as claimed in claim 2, wherein the R 1 / 2 of the above formula (2-1) is the methylene group, and the asymmetric center of the 5-position of the lactone ring is the (R) configuration. A lactone compound represented by the following formula (2-2): wherein R 1 / 2 is the same as defined above, and X 2 is a bromine atom or iodine atom. A lactone compound represented by the following formula (2-3): wherein, R 1 / 2 is the same as defined above. A heptanoic acid derivative represented by the following formula (2-4): wherein X 2 is a bromine atom or iodine atom. A process for producing a vitamin D 3 derivative according to claim 2 represented by the following formula (2-1): wherein R 1 / 2, R 2 / 2, and R 3 / 2 are the same as defined above, characterized by reacting a lactone compound represented by the following formula (2-2): wherein R 1 / 2 and X 2 are the same as defined above with an enyne compound represented by the following formula (2-10): wherein R 2 / 2 and R 3 / 2 are the same as defined above in the presence of a palladium catalyst.

Inventors: GAO QINGZHI, HAZATO ATSUO, MANABE KENJI, TABE MASAYASU, TANAKA HIROKO, GAO, QINGZHI, HAZATO, ATSUO, MANABE, KENJI, TABE, MASAYASU, TANAKA, HIROKO, GAO, Qingzhi, Teijin Limited, HAZATO, Atsuo, Teijin Limited, MANABE, Kenji, Teijin Limited, TABE, Masayasu, Teijin Limited, TANAKA, Hiroko, Teijin Limited
Applicants: TEIJIN LTD, TEIJIN LIMITED
Application year: 1995
Main classification: C07C401
IPC codes: C07D317, C07C69, C07C401, C07F7, C07D307