Vitamin D3 derivative and production process thereof

Abstract: A vitamin D 3 derivative represented by the following formula: 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 group forming an acetal bond together with an oxygen atom of a hydroxyl group, and A is where R 2 is a hydrogen atom or a C 1 to C 3 alkyl group, R 3 is a hydrogen atom, or R 2 and R 3 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. 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 (3-1): wherein R 1 / 3 is a hydrogen atom or a C 1 to C 3 alkyl group, R 2 / 3 is a hydrogen atom, or R 1 / 3 and R 2 / 3 together indicate a single optionally substituted methylene group. R 3 / 3 an independently 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. Here, when R 1 / 3 is a C 1 to C 3 alkyl group, specific examples are preferably methyl, ethyl, and propyl. Further, examples of the substituent, when R 1 / 3 and R 2 / 3 together represent a substitutable single methylene group, are preferably a t-butyl group, phenyl group, or methyl group. When R 3 / 3 is a tri(C 1 to C 7 hydrocarbon)silyl group, a tri(C 1 to C4 alkyl)silyl group such as a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group or a phenyl (C 1 -C 4 alkyl)silyl group such as a t-butyldiphenylsilyl group are preferable. Further, when R 3 / 3 is a C 2 to C 8 acyl group, an acetyl, propionyl, N-butyryl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, or benzyloxycarbonyl group are preferable. Further, when R 3 / 3 is a group forming an acetal bond with an oxygen atom of a hydroxyl group, a methoxymethyl, 2-methoxy-ethoxymethyl, 2-methoxy-2-propyl, 2-tetrahydrofuranyl, or 2-tetrahydropyranyl group are preferable. Here, the configuration of the 25-position of the vitamin D 3 derivative of the present invention may be either of the (R) configuration or (S) configuration. The derivative may also be any mixture thereof at any ratio of the two components. Specific examples of the vitamin D 3 derivative according to the third aspect of the present invention are given below: 1) 1α,25(R)-dihydroxyvitamin D 3 -26-carboxylic acid 2) 1α,25(S)-dihydroxyvitamin D 3 -26-carboxylic acid 3) 1α,25(R)-dihydroxyvitamin D 3 -26-carboxylic acid methylester 4) 1α,25(S)-dihydroxyvitamin D 3 -26-carboxylic acid methylester 5) 1α,25(R)-dihydroxyvitamin D 3 -26-carboxylic acid ethylester 6) 1α,25(S)-dihydroxyvitamin D 3 -26-carboxylic acid ethylester 7) 1α,25(R)-dihydroxyvitamin D 3 -26-carboxylic acid methylester-1,3-bistrimethylsilylether 8) 1α,25 (S) -dihydroxyvitamin D 3 -26-carboxylic acid methylester-1,3-bistrimethylsilylether 9) 1α,25(R)-dihydroxyvitamin D 3 -26-carboxylic acid ethylester-1,3-bistrimethylsilylether 10) 1α,25(S)-dihydroxyvitamin D 3 -26-carboxylic acid ethylester-1,3-bistrimethylsilylether 11) 25,26,27-trinor-1α-hydroxy-24-[(2S,5R)-2-t-butyl-5-methyl-1,3-dioxolan-4-one-5-yl]-vitamin D 3 12) 25,26,27-trinor-1α-hydroxy-24-[(2S,5R)-2-t-butyl-5-methyl-1,3-dioxolan-4-one-5-yl]-vitamin D 3 -1,3-bistrimethylsilylether 13) 25,26,27-trinor-1α-hydroxy-24-[(2S, 5R)-2-t-butyl-5-methyl-1,3-dioxolan-4-one-5-yl]-vitamin D 3 -1,3-bis(t-butyldimethylsilylether) Further, the present invention includes a production process of a vitamin D 3 derivative represented by the above formula (3-1). That is, it provides a production process of a vitamin D 3 derivative represented by the above formula (3-1) characterized by reacting a heptanoic acid derivative represented by the following formula (3-2): wherein R 2 / 3 and R 3 / 3 are the same as defined above with an enyne compound represented by the following formula (3-5): wherein R 3 / 3 is the same as defined above in the presence of a palladium catalyst. In the production process of the vitamin D 3 derivative according to the present invention, the configuration of the asymmetric center of the 2-position of the starting material, that is, the heptanoic acid derivative represented by the above formula (3-2), may be either of the (R) configuration or (S) configuration. Further, the derivative may be any mixture of these stereo isomers at any ratio. For example, when a heptanoic acid derivative represented by the above formula (3-2) where the asymmetric center of the 2-position is the (R) configuration is used, the configuration is preserved during the reaction and a vitamin D 3 derivative represented by the above formula (3-1) where the asymmetric center of the 25-position is the (R) configuration is obtained. In the same way, when a heptanoic acid derivative represented by the above formula (3-2) where the asymmetric center of the 2-position is an (S) configuration is used, a vitamin D 3 derivative represented by the above formula (3-1) where the asymmetric center of the 25-position is the (S) isomer configuration is obtained. The vitamin D 3 derivative represented by the above formula (3-1) is produced by reacting the heptanoic acid derivative represented by the above formula (3-2) with the enyne compound represented by above formula (3-5) in the presence of a palladium catalyst. Here, as the palladium catalyst used, mention may be made for example of a zero-valent or bivalent organopalladium compound. Examples of such a palladium compound are tetrakis(triphenyl phosphine)palladium or a mixture of a tris(dibenzylidene-acetone palladium, tris(dibenzylideneacetone)palladium chloroform, palladium acetate, etc. with a phosphorus compound such as triphenylphosphine or tributylphosphine (molar ratio of 1:1 to 1:10). Among these, as the palladium catalyst, the combination of tris(dibenzyli-deneacetone)palladium and triphenylphosphine (1:1 to 1:10) or tris(dibenzylideneacetone)palladium chloroform and triphenylphosphine (1:1 to 1:10) is preferred. Here, the heptanoic acid derivative represented by the above formula (3-2) and the enyne compound represented by the above formula (3-5) stoichiometrically react equimolarly, but it is desirable to use a slight excess of the more readily available compound. Further, the palladium catalyst is used in the range of 0.1 to 100 molar %, preferably 1 to 20 molar %, with respect to the heptanoic acid derivative represented by the above formula (3-2). Examples of the reaction solvent used in this reaction are a hydrocarbon type solvent such as hexane or toluene, an ether type solvent such as ether, tetrahydrofuran, dioxane, or dimethoxyethane, a water soluble solvent such as N,N -dimethylformamide or acetonitrile, or any mixed solvents thereof. All of these are preferably used after sufficient deaeration. As the reaction temperature, a range of from room temperature to the boiling point is used. The reaction time differs according to the reaction temperature, but usually it is preferable that the reaction be performed until one of the heptanoic acid derivative represented by the above formula (3-2) or enyne compound represented by the above formula (3-5) is consumed as determined using an analytical means such as thin layer chromatography. Further, to trap the acids such as the hydrogen halides produced during the reaction, it is preferable to add a base such as, for example, triethylamine or diisopropylethylamine and cause a reaction. As the amount of the base, at least one equivalent of the heptanoic acid derivative represented by the above formula (3-2) is preferably used. It is also possible to use together as a solvent. Therefore, the vitamin D 3 derivative represented by the above formula (3-1) is produced in the reaction system, but it is further possible to effect a deblocking reaction, if necessary. As the method of the deblocking reaction, it is possible to use a known method in the case of deblocking, for example, the silyl groups (for example, Calveley, M.J., Tetrahedron, 20, 4609 to 4619, 1987). Examples of the deblocking agent in this case are tetrabutylammonium fluoride and pyridinium-p-toluene sulfonate. An example of the synthesis method of a heptanoic acid derivative represented by the above formula (3-2) used as a starting material in the process of the present invention is shown in the following scheme. The same applies when R 2 / 3 and R 3 / 3 are other groups. wherein, in the above scheme, R 41 is a hydrogen atom, tri(C 1 to C 7 hydrocarbon)silyl group, or a group forming an acetal bond with an oxygen atom of a hydroxyl group. wherein, R 1 / 3 is a hydrogen atom or C 1 to C 3 alkyl group, R 2 / 3 is a hydrogen atom, or R 1 / 3 and R 2 / 3 together represent a substitutable single methylene group (examples of the substituent at this time are a C 1 to C 6 alkyl group such as methyl, t-butyl, or phenyl). wherein, R 1 / 3 and R 2 / 3 are the same as defined above, and R 4 / 3 is a hydrogen atom, tri(C 1 to C 7 hydrocarbon)silyl group, C 1 to C 7 acyl group, or represent an acetal group together with the oxygen atom of the hydroxyl group. That is, the heptanoic acid derivative represented by the above formula (3-2) is obtained by bromomethylation of the heptanoic acid derivative represented by the above formula (3-3). Further, the heptanoic acid derivative represented by the above formula (3-3) is obtained by deprotecting and subsequently oxidising the heptanoic acid derivative represented by the above (3-4) when necessary. Specific examples of these reactions are shown in the Examples. Here, the configuration of the 2-position of the heptanoic acid derivatives represented by the above formula (3-2), (3-3), or (3-4) may be either of the (R)configuration or (S) configuration. The derivative may also be any mixture thereof at any ratio. The present invention includes intermediates for synthesis of the vitamin D 3 derivative according to the present invention represented by the above formulas (3-2), (3-3), or (3-4). Preferable examples of the heptanoic acid derivative represented by the above formula (3-2) of the present invention are as follows: 1) (2S,5R)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 2) (2R,5S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]pentyl}-2-t-butyl-5-methyl-1, 3-dioxolan-4-one 3) (2S,5R)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 4) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 5) (2S,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 6) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid methylester 7) (2S,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid ethylester 8) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-trimethylsilyloxy-2-methylheptanoic acid methylester 9) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-t-butyldimethylsilyloxy-2-methylheptanoic acid methylester 10) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-acetoxy-2-methylheptanoic acid methylester 11) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl}-2-methoxymethyloxy-2-methylheptanoic acid methylester Further, preferable examples represented by the heptanoic acid derivative of the above (3-3) according to the present invention are as follows: 1) (2R,5S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 2) (2R,5S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 3) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl] pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 4) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 5) (2S,6R)-6-((1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 6) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid methylester 7) (2S,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid ethylester 8) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-trimethylsilyloxy-2-methylheptanoic acid methylester 9) (2R,6R)-6-{(1R, 7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-t-butyldimethylsilyloxy-2-methylheptanoic acid methylester 10) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-acetoxy-2-methylheptanoic acid methylester 11) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-methoxymethyloxy-2-methylheptanoic acid methylester Further, preferable examples of the heptanoic acid derivative represented by the above (3-4) according to the present invention are as follows: 1) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 2) (2R,5S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 3) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 4) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl]pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 5) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-benzyloxy-7a-methyl-1H-inden-1-yl]pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 6) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-methoxymethyloxy-7a-methyl-1H-inden-1-yl] pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 7) (2R,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 8) (2S,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 9) (2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 10) (2S,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 11) (2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid 12) (2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid methylester 13) (2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid methylester 14) (2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid ethylester 15) (2R,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl}-2-trimethylsilyloxy-2-methylheptanoic acid methylester 16) (2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl}-2-trimethylsilyloxy-2-methylheptanoic acid methylester 17) (2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-acetoxy-2-methylheptanoic acid methylester 18) (2R, 6R)-6-{(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-methoxymethyloxy-2-methylheptanoic acid methylester The vitamin D 3 derivative represented by the above formula (3-1) may be used as an agent for promoting bone formation. Further, the heptanoic acid derivatives represented by the above formulas (3-2), (3-3), and (3-4) 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 1-11 (Comparative) Production of 23,24,25,26,27-pentanol-1α-hydroxy-22-[(1R, 4S)-1-hydroxy-1-methyl-2-cyclopenten-4-yl]-vitamin D 3 A 58.8 mg amount of the compound (1-22), 23,24,25,26,27-pentanol-1α-hydroxy-22-[(1R,4S)-1-trimethylsilyloxy-1-methyl-2-cyclopenten-4-yl]-vitamin D 3 -1α,3-bistrimethylsilylether, was taken in a 25 ml eggplant-shaped flask, then 5 ml of dried tetrahydrofuran was added and the solution stirred. A 0.5 ml amount of a 1M solution of tetrabutylammoniumfluoride in tetrahydrofuran was added and the solution stirred under ice cooling for 3 hours. The reaction solution was poured in 50 ml of ethyl acetate and 10 ml of a saturated aqueous solution of potassium hydrogensulfate and extracted. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by a silica gel column (IR-60 Merck gel, 250 g, hexane/ethyl acetate = 1/1 to 1/3) to obtain the desired product (1-23),23,24,25,26,27-pentanol-1α-hydroxy-22-[(1R, 4S)-1-hydroxy-1-methyl-2-cyclopenten-4-yl]-vitamin D 3 in an amount of 22.1 mg (yield 57%). 1 H-NMR (CDCl 3 , δ ppm) 6.38 (d, 1H, J=11.2Hz), 6.01 (d, 1H, J=11.2Hz), 5.64 (s, 2H), 5.33 (s, -1H), 5.00 (s, 1H), 4.40 to 4.50 (m, 1H), 4.15 to 4.30 (m, 1H), 1.20 to 2.90 (m, 25H), 1.32 (s, 3H), 0.96 (d, 3H J=6.3Hz), 0.55 (s, 3H) Example 2-14 (Comparative) 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-methyldehydro-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 (Comparative) 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 or 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 (Comparative) 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) Reference Example 3-1 Production of (2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propanol A 10.78 g amount of (2R)-2-[(1R, 7aR)(4E)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]propanol dissolved in 80 ml of pyridine was added to a 100 ml eggplant-shaped flask and the solution was stirred under ice-cooling. Thereafter, 6.57 ml of pivaloyl chloride was added, then the solution was stirred over night. To this reaction solution was added 150 ml of water. The solution was then extracted 3 times by 200 ml of ether. The organic layer was washed 2 times each by 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 and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 14.7 g. This was placed in a 200 ml eggplant-shaped flask, 10.9 g of imidazole was added, 60 ml of dried dichloromethane was added, and the solution was stirred under ice-cooling. To this was added 10.2 ml of trimethylsilyl chloride, then the solution was stirred over night at room temperature. The reaction solution was poured in 300 ml of ethyl acetate and 100 ml of water for extraction. The organic layer was washed 2 times each by 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 and the solvent was distilled off under reduced pressure to obtain a crude product in an amount of 18.11 g. A 17.2 g amount of t-butoxy potassium was placed in a 1-liter eggplant-shaped flask, then 440 ml of ether was added and the solution was stirred under ice-cooling. A 2.1 ml amount of water was added, then a solution of 18.11 g of the above residue dissolved in 120 ml of ether was added and the solution was stirred over night at room temperature. A 200 ml amount of water was poured into the reaction solution for separation, then extraction was performed with 500 ml of ether. 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 15.2 g. This was purified by a silica gel column (IR-60, 1 kg, hexane/ethyl acetate = 19/1 to 6/1) to obtain (2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propanol in an amount of 12.6 g (yield 87%). 1 H-NMR (CDCl 3 , δ ppm) 3.95 (d, 1H, J=3Hz), 3.58 (m, 1H), 3.31 (m, 1H), 1.00 to 2.00 (m, 14H), 0.96 (d, 3H, J=8Hz), 0.85 (s, 3H), 0.03 (s, 9H) Reference Example 3-2 Production of (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propanal A 427 mg amount of cellite, 37 mg of sodium acetate, and 444 mg of pyridinum chlorochromate were placed in a 50 ml eggplant-shaped flask, then 10 ml of dichloromethane was added and the solution stirred. Thereafter, a dichloromethane solution (3 ml) of 426 mg of (2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propanol was added, then the solution was stirred at room temperature for 3.5 hours. The reaction solution was filtered by Celite, then was concentrated and the obtained residue was purified by a silica gel column to obtain (2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propanal in an amount of 254 mg (yield 60%). 1 H-NMR (CDCl 3 , δ ppm) 9.56 (d, 1H J=3Hz), 3.90 to 4.00 (m, 1H), 2.20 to 2.50 (m, 1H), 1.00 to 2.00 (m, 12H), 0.92 (d, 3H, J=6.3Hz), 0.91 (s, 3H), 0.05 (s, 9H) Reference Example 3-3 Production of methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-pentenoate A 3.27 g amount of (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]propanal and 11.9 g of methyl(triphenylphosphoranilidene)acetate were placed in a 200 ml eggplant-shaped flask, 70 ml of toluene was added, and the solution was stirred at 80°C over night. This was cooled to room temperature, then 100 ml of hexane was added, the precipitated deposit was filtered out, and the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 4.1 g. This was purified by a silica gel column (IR-60, 200 g, hexane/ethyl acetate = 40/1) to obtain methyl(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-pentenoate in an amount of 3.82 g (yield 96%). 1 H-NMR (CDCl 3 , δ ppm) 6.83 (dd, 1H, J=9.9 & 16Hz), 5.73 (d, 1H, 16Hz), 3.99 (brs, 1H), 3.72 (s, 3H), 2.10 to 2.30 (m, 2H), 1.00 to 2.00 (m, 15H), 1.00 (d, 3H, J=6.6Hz), 0.92 (s, 3H), 0.05 (s, 9H) Reference Example 3-4 Production of (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-penten-1-ol A 3.66 g amount of methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -2-pentenoate was placed in a 500 ml eggplant-shaped flask, and 100 ml of hexane and 40 ml of toluene were then added to dissolve it. The solution was cooled to -95°C, then 12.2 ml of diisobutylaluminum hydride was slowly added and the solution stirred at the same temperature for 1 hour. Next, a further 24 ml of diisobutylaluminum hydride was added, followed by stirring for 2 hours. The consumption of the material was confirmed by thin layer chromatography, then the excess reducing agent was broken down by methanol and a saturated aqueous solution of sodium sulfate and then 300 ml of ethyl acetate and 80 ml of a saturated aqueous solution of ammonia chloride were added for separation. Extraction was performed from the aqueous layer by 100 ml of ethyl acetate, then the organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate = 19/1 to 4/1) to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y 1]-2-penten-1-ol in an amount of 3.31 g (98%). 1 H-NMR (CDCl 3 , δ ppm) 5.5 to 5.6 (m, 2H), 4.07 (brd, 2H), 3.99 (brs, 1H), 1.0 to 2.2 (m, 14H), 1.00 (d, J=6.6Hz, 3H), 0.90 (s, 3H), 0.05 (s, 9H) Reference Example 3-5 Production of (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-penten-1-al A 1.34 g amount of (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-penten-1-ol and 760 mg of N-methylmorpholine-N-oxide were placed in a 100 ml eggplant-shaped flask, then were dissolved in 30 ml of acetone. Thereafter, RuCl 2 (PPh 3 ) 3 was added, then the solution was stirred at room temperature for 1.5 hours. To the reaction solution were added 50 ml of hexane and 1.5 g of Celite, the solution was stirred for 15 minutes, then was filtered and the solvent distilled off under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate = 50/1 to 30/1) to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethyl-silyloxy-7a-methyl-1H-inden-1-yl]-2-penten-1-al in an amount of 0.854 g (yield 86%). 1 H-NMR (CDCl 3 , δ ppm) 9.51 (d, J=7.9Hz, 1H), 6.71 (dd, J=8.6 & 16Hz, 1H), 6.04 (dd, J=7.9 & 16Hz, 1H), 4.01 (brs, 1H), 2.3 to 2.4 (m, 1H), 1.1 to 2.2 (m, 12H), 1.11 (d, J=6.6Hz, 3H), 0.94 (s, 3H), 0.05 (s, 9H) Reference Example 3-6 Production of (5R,2S)-5-{(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1, 3-dioxolan-4-one A 15 ml amount of tetrahydrofuran and 910 µl of diisopropylamine were placed in a 100 ml eggplant-shaped flask, then the solution was cooled to -78°C. Thereafter, 2.52 ml of n-BuLi was added, then the solution was stirred at the same temperature for 15 minutes, was stirred at 0°C for 30 minutes, then was again cooled to -78°C and was stirred for 15 minutes. To this was added a tetrahydrofuran solution (6 ml) of 627 mg of (5S,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-one. The solution was stirred at the same temperature for 15 minutes, then a tetrahydrofuran solution (8 ml) of 854 mg of (4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-penten-1-al was added and the solution was reacted at -78°C for 30 minutes. To the reaction solution were added a saturated aqueous solution of ammonium chloride and ether for separation, then extraction was performed from the aqueous layer by ethyl acetate. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate and filtered, then the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate = 15/1 to 4/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 1.24 g (yield 96%). 1 H-NMR (CDCl 3 , δ ppm) 5.0 to 5.7 (m, 3H), 4.1 to 4.2 (m, 1H), 3.99 (brs, 1H), 1.0 to 2.2 (m, 17H), 0.88 to 1.0 (m, 15H), 0.04 (s, 9H) Reference Example 3-7 Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one A 1.24 g amount of (5R,2S)-5-{(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y l]-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1, 3-dioxolan-4-one and 1.0 g of 4-dimethylaminopyridine were dissolved in 15 ml of dichloromethane in a 50 ml eggplant-shaped flask. The solution was stirred under ice-cooling while slowly adding 315 µl of methyl chloroformate, then was stirred at the same temperature for 15 minutes and at room temperature for 1.5 hours. A 100 ml amount of ethyl acetate and 30 ml of water were added for separation, and extraction was performed from the aqueous layer by 50 ml of ethyl acetate. The organic layer was washed by a saturated aqueous solution of potassium hydrogensulfate, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline and was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate = 19/1 to 9/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 1.388 g (98%). 1 H-NMR (CDCl 3 , δ ppm) 5.3 to 5.9 (m, 2H), 5.25 (s, 1H), 5.11 (d, J=7Hz, 1H), 3.99 (brs, 1H), 3.78 & 3.75 (s, 3H), 1.0 to 2.2 (m, 16H), 0.8 to 1.0 (m, 15H), 0.05 (s, 9H) Example 3-1 Production of (5R,2S)-5-{(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one Pd(OAc) 2 was placed in a 100 ml eggplant-shaped flask and dissolved in 50 ml of tetrahydrofuran. Further, 0.54 ml of n-Bu 3 P was added, the solution stirred at room temperature for 15 minutes, 681 mg of ammonium formate was added, a tetrahydrofuran solution (10 ml) of 1.38 g of (5R,2S)-5-((4R)-4-[(1R,7aR)-octahydro-4-trimethyl-silyloxy-7a-methyl-1H-inden-1-yl]-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one was added, and the solution was reacted at 40°C over night. To the reaction solution were added 50 ml of hexane and 50 ml of ether 50 ml, the solution was filtered, then the solvent was distilled off under reduced pressure to obtain 920.8 mg of any oily substance. This was subjected to the following reaction divided into two times without purification. A 398 mg amount of the oily substance was dissolved in ethyl acetate, 10% Pd/C was placed in Microspatel Cup, then this was stirred over night under a flow of hydrogen. The solution was filtered, then concentrated to obtain a crude product in an amount of 0.43 g. A 520 mg amount of the remaining oily substance was treated in the same way to obtain 0.494 g. These were combined and purified to obtain 0.867 mg of (5R,2S)-5-{(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one (yield 73%). 1 H-NMR (CDCl 3 , δ ppm) 5.19 (s, 1H), 3.99 (brs, 1H), 1.41 (s, 3H), 1.0 to 2.0 (m, 19H), 0.96 (s, 9H), 0.88 (d-like, 3H), 0.87 (s, 3H), 0.05 (s, 9H) Example 3-2 Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl] pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one A 913 mg amount of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one was placed in a 100 ml eggplant-shaped flask and dissolved in 10 ml of tetrahydrofuran. A tetrahydrofuran solution (1M, 2.5 ml) of tetrabutylammonium fluoride was added under ice cooling, then the solution was stirred at the same temperature for 15 minutes, was returned to room temperature, then was stirred for 1 hour. Thereafter, 100 ml of ether and 20 ml of water for separation were added, extraction was performed from the aqueous layer by ether, then the organic layer was washed with saline and then was dried over anhydrous magnesium sulfate. Further, this was concentrated, then purified by a silica column (hexane/ethyl acetate = 9/1 to 6/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 764 mg (99%). 1 H-NMR (CDCl 3 , δ ppm) 5.19 (s, 1H), 4.08 (brs, 1H), 1.44 (s, 3H), 1.0 to 2.1 (m, 20H), 0.96 (s, 9H), 0.93 (s, 3H), 0.90 (d, 3H, J=6.6Hz) Example 3-3 Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl] pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one A 384 mg amount of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl] pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one and 74 mg of RuH 2 (PPh 3 ) 4 were placed in a 100 ml two-necked flask and dissolved in 20 ml of toluene. Thereafter, 8 ml of methylallyl carbonate was added, then the solution was stirred at 100°C over night. The reaction solution was allowed to cool, then the precipitate was filtered out, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (hexane/ethyl acetate = 19/1 to 10/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 370 mg (yield 96%). 1 H-NMR (CDCl 3 , δ ppm) 5.19 (s, 1H), 1.44 (s, 3H), 1.0 to 2.0 (m, 19H), 0.96 (brs, 12H), 0.64 (s, 3H) Example 3-4 Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one A 5.19 g amount of PPh 3 CH 2 Br•Br was placed in a 100 ml eggplant-shaped flask, was suspended in 30 ml of tetrahydrofuran, and stirred at -78°C. Thereafter, 11.3 ml of TMS 2 NNa (1M-THF) was added, then the solution was stirred at room temperature for 1 hour and, then, was further added a tetrahydrofuran solution (10 ml) of 449 mg of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one, then the solution was returned to room temperature and stirred for 30 minutes. To the reaction solution was added ether, the solution was stirred at room temperature, then the precipitate was filtered out and the solvent was distilled off under reduced pressure. The result was purified by a silica gel column (hexane/ethyl acetate = 100/0 to 100/1 to 4/1) to obtain (5R, 2S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 242 mg (yield 45%). 1 H-NMR (CDCl 3 , δ ppm) 5.65 (s, 1H), 5.19 (s, 1H), 2.80 to 3.00 (m, 1H), 1.44 (s, 3H), 1.0 to 2.1 (m, 18H), 0.96 (s, 9H), 0.93 (d, 3H J=6Hz), 0.56 (s, 3H) Example 3-5 Production of 25,26,27-trinol-1α-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D 3 -1α, 3-bistrimethylsilylether A 17 mg amount of Pd 2 (dibenzylideneacetone) 3 •CHCl 3 , and 51.7 mg of PPh 3 were placed in a 100 ml two-neck eggplant-shaped flask and dissolved in 9 ml of toluene and 9 ml of diisopropylethylamine. Thereafter, 141.5 mg of (5R,2S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one dissolved in 2 ml of toluene and 2 ml of diisopropylethylamine was added, then the solution was heated and refluxed for 1.5 hours. The solution was allowed to cool, then 20 ml of hexane was added, the precipitate filtered out, and the filtrate was washed with a saturated solution of potassium hydrogensulfate and saturated saline, then was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by a silica gel column (hexane/ethyl acetate = 100/1 to 30/1) to obtain 25,26,27-trinol-1α-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D 3 -1α,3-bistrimethylsilylether in an amount of 118.5 mg (yield 58%). 1 H-NMR (CDCl 3 , δ ppm) 6.27 (d, 1H, J=12Hz), 6.04 (d, 1H, J=12Hz), 5.19 (brs, 2H), 4.90 (brs, 1H), 4.30 to 4.40 (m, 1H), 4.15 to 4.25 (m, 1H), 1.0 to 2.9 (m, 23H), 1.43 (s, 3H), 0.96 (s, 9H), 0.93 (d, 3H, J=6Hz), 0.54 (s, 3H), 0.12 (s, 18H) Example 3-6 Production of 25,26,27-trinol-1α-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl} vitamin D 3 A 112 mg amount of 25,26,27-trinol-1α-hydroxy-24-{(5R, 2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D 3 -1α,3-bistrimethylsilylether was placed in a 50 ml eggplant-shaped flask and dissolved in 30 ml of methanol, then 50 mg of pyridinium-para-toluene sulfonate was added and the solution stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by a silica gel column (hexane/ethyl acetate = 1/1) to obtain 25,26,27-trinol-1α-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D 3 in an amount of 40.2 mg (yield 46%). 1 H-NMR (CDCl 3 , δ ppm) 6.38 (d, 1H, J=11Hz), 6.01 (d, 1H, J=11Hz), 5.32 (s, 1H), 5.19 (s, 1H), 5.00 (s, 1H), 4.40 to 4.50 (m, 1H), 4.20 to 4.30 (m, 1H), 1.0 to 2.9 (m, 25H), 1.44 (s, 3H), 0.96 (s, 9H), 0.93 (d, 3H, J=6Hz), 0.54 (s, 3H) Example 3-7 Production of 1α,25-dihydroxyvitamin D 3 -26-carboxylic acid methylester A 40 mg amount of 25,26,27-trinol-1α-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D 3 was placed in a 50 ml eggplant-shaped flask and dissolved in 5 ml of methanol, then 4N lithium hydroxide was added and the solution was stirred at room temperature for 1 hour. The reaction solution was neutralized, tetrahydrofuran was added, the solution was washed five times by saturated saline, then was dried over anhydrous magnesium sulfate. The solution was filtered and concentrated, the obtained residue was dissolved in benzene/methanol (4/1), 0.8 ml of a hexane solution (about 10%) of trimethylsilyldiazomethane was added, and the solution was stirred at room temperature for 1 hour. The excess reagent was broken down by formic acid, then the solution was concentrated. The obtained residue was purified by a silica gel column (hexane/ethyl acetate = 2/3 to 1/3) to obtain 1α,25-dihydroxyvitamin D 3 -26-carboxylic acid methylester in an amount of 24.4 mg (yield 68%). 1 H-NMR (CDCl 3 , δ ppm) 6.38 (d, 1H, J=11Hz), 6.01 (d, 1H, J=11Hz), 5.33 (s, 1H), 5.00 (s, 1H), 4.35 to 4.45 (m, 1H), 4.20 to 4.30 (m, 1H), 3.79 (s, 3H), 1.0 to 3.1 (m, 26H), 1.40 (s, 3H), 0.90 (d, 3H, J=6Hz), 0.53 (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 (Comparative) 10 -9 M 47.7±9.2 10 -8 M 34.5±9.9 VD 3 (10 -8 M)+ Example 2-16 compound (Comparative) 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 sintillation vials, a dioxane sintillator was added in amounts of 10 ml, and the radioactivity was measured by a liquid sintillation 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. Bioi. 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 sintillation 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 sintillation 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 1-11 compound (23) 104 1.2 Example 2-14 compound 207 41.8 Example 2-15 compound 9.8 10.7 Example 2-16 compound 13.8 39.4 Example 3-17 compound 3.6 >500 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 (3-1): wherein R 1 3 is a hydrogen atom or a C 1 to C 3 alkyl group and R 2 3 is a hydrogen atom or R 1 3 and R 2 3 together are an optionally substituted single methylene group, R 3 3 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 vitamin D 3 derivative as claimed in claim 1, wherein the asymmetric center of the 25-position of the above formula (3-1) is the (R) configuration. A vitamin D 3 derivative as claimed in claim 1, wherein the asymmetric center of the 25-position of the above formula (3-1) is the (S) configuration. A heptanoic acid derivative represented by the following formula (3-2): wherein R 1 3 and R 2 3 are the same as defined above. A heptanoic acid derivative represented by the following formula (3-3): wherein R 1 3 and R 2 3 are the same as defined above. A process for producing a vitamin D 3 derivative according to claim 1 of the following formula (3-1): wherein R 1 3 , R 2 3 , and R 3 3 are the same as defined above characterized by a reacting a heptanoic acid derivative represented by the following formula (3-2): wherein R 1 3 and R 2 3 are the same as defined above, with an enyne compound represented by the following formula (3-5): wherein R 3 3 is the same as defined above in the presence of a palladium catalyst. A heptanoic acid derivative represented by the following formula (3-4): wherein R 1 3 and R 2 3 are as defined above R 4 3 is a hydrogen atom, a tri (C 1 to C 7 hydrocarbon) silyl group, a C 1 to C 7 acyl group, or represents an acetal group together with the oxygen atom of the hydroxyl group.

Inventors: GAO QUINGZHI, HAZATO ATSUO, MANABE KENJI, TABE MASAYASU, TANAKA HIROKO, GAO, QUINGZHI, HAZATO, ATSUO, MANABE, KENJI, TABE, MASAYASU, TANAKA, HIROKO
Applicants: TEIJIN LTD, TEIJIN LIMITED
Application year: 1995
Main classification: C07C401
IPC codes: C07C69, C07F7, C07D307, C07C401