JP4887503B2 - 9-Substituted-19-norvitamin D derivatives - Google Patents

Description

  The present invention relates to a 9-substituted-19-norvitamin D derivative effective for congenital vitamin dependence type II rickets.

  Active vitamin D derivatives are widely used clinically as therapeutic agents for bone diseases such as osteomalacia, osteoporosis, and rickets. In addition, attention is focused on cell growth suppression / differentiation inducing action and immunoregulatory action of vitamin D, and it is widely used as a specific drug for psoriasis of the skin, and is also being developed as a cancer therapeutic agent and an immunomodulator.

  In this regard, in Patent Document 1 below, vitamin D represented by the following general formula (a) has a substituent at the 2α-position, and the hydroxyl groups at the 1-position and the 3-position are in the α-configuration and β-configuration, respectively. Derivatives are disclosed. This vitamin D derivative can be used as a medicine, and can be used for the purpose of, for example, a therapeutic agent for diseases associated with abnormal calcium metabolism, an antitumor agent or an immunomodulator.

(However, R ³ and R ⁴ represent a linear or branched lower alkyl group which may be substituted with a hydroxy group.)

WO01 / 062723

  However, type II rickets (HVDRR), which is an autosomal recessive inheritance resistant to active vitamin D derivatives, is caused by mutations in the vitamin D receptor (VDR). VDR in which 286th tryptophan (W) of VDR is mutated to arginine (R) (W286R VDR) is a natural ligand represented by the following structural formula (b) or the vitamin D derivative of Patent Document 1 above It is known that it causes severe illness because it does not respond at all.

  The present invention has been made in view of the problems as described above, has a transcriptional activation ability to activate the function of mutant vitamin D receptor, and is effective for congenital vitamin addiction type II rickets 9 -Substituted-19-norvitamin D derivatives, processes for their preparation and pharmaceutical compositions containing them.

  As a result of intensive studies to solve the above problems, the present inventor has found that a 9-substituted-19-norvitamin D derivative represented by the following general formula (1) is transcriptionally active against a mutant vitamin D receptor. The present inventors have found that it has a chemical ability and have completed the present invention.

  That is, the compound of the present invention is a 9-substituted-19-norvitamin D derivative represented by the following general formula (1).

(However, R ¹ represents an alkyl group, an alkenyl group, or a hydroxyalkyl group, and R ² represents hydrogen or a hydroxyalkylidene group bonded through a double bond.)

  In the present invention, 9-substituted-19-norvitamin D derivatives represented by the following general formulas (2) and (3) are preferable.

(Wherein, ^{R 1} represents butyl group, hydroxypropyl group, an allyl group, or, a _{trans-CH 2 CH = CHCH 3} .)

  Furthermore, in the present invention, a 9-substituted 19-norvitamin D derivative represented by the following structural formula (3b) is preferable.

  According to the compound of the present invention, since it has a substituent at the 9-position, it can be adapted to the binding pocket of mutant VDR (W286R VDR). This is because the mutant-type VDR has a larger ligand-binding pocket than the wild-type VDR. Therefore, with natural ligands, a space is formed at the enlarged site. However, according to the compound of the present invention, the 9-position substituent is compatible with this space, so that transcriptional activity is also exerted on mutant VDR. Can show abilities.

  The 9-substituted-19-norvitamin D derivative represented by the above general formula (2) comprises a Wittig-Horner coupling between a ring A ketone body and a C / D ring phosphine oxide body having a substituent at the 9-position. Can be synthesized by the method. In addition, the 9-substituted-19-norvitamin D derivative represented by the general formula (3) is obtained by combining a ring A ketone body and a C / D ring allyl sulfone body having a substituent at the 9-position with a julia coupling. Can be synthesized by the method.

  The compound of the present invention can be used as a therapeutic agent for rickets or osteomalacia.

  According to the compound of the present invention, a 9-substituted vitamin D derivative effective for congenital vitamin dependence type II rickets, a process for producing the same, and a pharmaceutical composition containing them can be provided.

It is a figure which shows the transcriptional activity of 9-allyl derivative (3b) and a natural ligand.

BEST MODE FOR CARRYING OUT THE INVENTION

  The 9-substituted-19-norvitamin D derivative represented by the above general formula (2) comprises a Wittig-Horner coupling between a ring A ketone body and a C / D ring phosphine oxide body having a substituent at the 9-position. Can be synthesized by the method. In addition, the 9-substituted-19-norvitamin D derivative represented by the above general formula (3) includes an A ring portion ketone body and a C / D ring portion allyl sulfone body having a substituent at the 9-position. It can be synthesized by a coupling method.

  Hereinafter, the production method of the 9-substituted-19-norvitamin D derivatives of the general formulas (2) and (3) will be specifically described.

<Method for synthesizing ring A ketone body>
A ring part ketone body (8) was obtained from DeLuca H. et al. F. et. al, Tetrahedron Lett, 1991, 32, 7663-7666, and can be easily obtained by a synthesis method using (−)-quinic acid. After introducing (−)-quinic acid to a methyl ester form, the hydroxyl group is regioselectively protected to obtain a silyl ether form (4). Subsequently, the hydroxyl group at the 4-position is removed by the Barton method to obtain a 4-deoxy form (6). Reduction of the ester followed by sodium periodate oxidation gives the 1-keto form (8). TMS ether body (9) was obtained from Shimizu M et. al, Bioorg Med. Chem. It can be obtained by the method described in Lett, 2003, 13, 809-812.

<Method for synthesizing C / D ring synthon>
The C / D ring phosphine oxide represented by the structural formulas (15) and (20) can be obtained from C / D represented by the structural formulas (22) and (23) in six steps using vitamin D ₃ as a starting material. The ring allyl sulfone can be synthesized by 7 steps.

Compound (10) is obtained by a known method using vitamin D ₃ as a starting material. The 9-butyl-8 keto form (11) is synthesized by converting the compound (10) to a silyl enol ether form under kinetic conditions, followed by treatment with butyl iodide. Vinylmagnesium bromide is added to the 9-butyl-8-keto body (11), which is led to a tertiary alcohol body (12), followed by PCC oxidation to obtain an allylaldehyde body (13). After reduction with NaBH ₄ to obtain an allyl alcohol form (14), tosylation, diphenylphosphineization and oxidation reaction are performed at once to obtain a phosphine oxide form (15). Similarly, a 9-allyl-phosphine oxide (20) can also be obtained.

  The allyl sulfone body can be obtained by benzothiazolization of allyl alcohol bodies (19) and (21), followed by an oxidation reaction to obtain allyl sulfone bodies (22) and (23).

<Synthesis Method of 9-Substituted-19-Norvitamin D Derivative>
The synthesis of the 9-substituted-19-norvitamin D derivative is performed by first reacting the C / D ring phosphine oxide body (15) and (20) with the A ring ketone body (8). Substituted 19-nor isomers (24) and (25) are obtained. Further, the protecting group is removed with camphorsulfonic acid (CSA) to obtain 9-butyl (2a) and 9-allyl (2b). The 9α-hydroxybutyl compound (2d) is obtained by hydroborating the intermediate (25) with 9-BBN, treating with alkaline hydrogen peroxide, and deprotecting.

  As the hydroxyethylidene derivative (3), first, a compound (26) is synthesized by a julia coupling method of a C / D ring allyl sulfone body (22) and an A ring ketone body (9). Subsequently, the TMS group is selectively removed and the hydroxyl group at the 2-position is subjected to Swern oxidation, followed by cyanomethyleneation with diethylcyanomethylphosphonate to obtain the compound (27). The cyano form is converted to an allyl alcohol form by two-step reduction, and further deprotected with CSA to obtain the 9-allyl form (3b). A 9-butylene body (3c) is also obtained by the same method.

[Drug]
The 9-substituted-19-norvitamin D derivative of the present invention can be used as a therapeutic agent for rickets or a therapeutic agent for osteomalacia (hereinafter also referred to as “therapeutic agent”).

<Dosage form>
In addition to containing the 9-substituted-19-norvitamin D derivative of the present invention as an active ingredient, the therapeutic agent is blended with necessary additives, and according to conventional methods, solid oral preparations, oral liquid preparations, or It can be prepared as a parenteral preparation such as an injection. Most preferred is a solid oral formulation.

  When preparing a solid oral preparation, after adding excipients such as lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch and the like, it can be made into tablets, granules, powders, capsules and the like. In addition to excipients, if necessary, binders such as hydroxypropyl cellulose and hydroxypropyl methylcellulose (HPMC), lubricants such as magnesium stearate, polyethylene glycol, starch, and talc, calcium calcium glycolate, carmellose Mix and adjust disintegrants such as calcium, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid, plasticizers such as polyethylene glycol, and colorants such as titanium oxide, talc, and yellow iron oxide. it can. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

  When preparing liquid preparations for oral use, add inactive diluents such as purified water, ethanol, buffering agents, stabilizers, flavoring agents, etc. to obtain internal liquids, syrups, jellies, elixirs, etc. be able to.

  The injection may be a sterile aqueous or non-aqueous solution, suspension, emulsion, etc., and may be a subcutaneous, intramuscular and intravenous injection. Examples of the diluent for the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and the like. Furthermore, if necessary, a pH adjuster, buffer, preservative, wetting agent, emulsifier, dispersant, stabilizer (eg lactose), tonicity agent, local anesthetic, solubilizer (eg glutamic acid, Aspartic acid) or the like may be added.

<Effective dose>
The effective dose of the 9-substituted-19-norvitamin D derivative of the present invention varies depending on the body weight, age, sex, administration method, physical condition, symptom, dosage form, etc. of the patient. 0.001 μg or more and 50 μg or less, more preferably 0.01 μg or more and 10 μg or less, and it is preferable to take one or two or several times.

<Synthesis of 9-methyl-19-norvitamin D derivative>
It was synthesized by the following procedure.

Ozone gas was introduced into a methanol (200 ml) solution of vitamin D ₃ (10.0 g, 0.026 mol) cooled to −78 ° C. for 8 hours. Next, oxygen gas was introduced for 1 hour, dimethyl sulfide (0.6 ml) was added at -78 ° C., the temperature was gradually raised, and the mixture was stirred until it reached room temperature. After concentrating the solvent, ice water was added and the mixture was extracted with ethyl acetate / hexane (1: 1). The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (180 g, 5% ethyl acetate / hexane) to quantitatively obtain compound 30 (6.8 g).

Compound 30: ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H, s, H-18), 0.868, 0.871 (each 3H, d, J = 6.6 Hz, H-26, 27) , 0.95 (3H, d, J = 6.2 Hz, H-21), 2.45 (1H, dd, J = 11.6, 7.3 Hz, H-14).

Compound 30 (6.8 g, 0.0257 mol) was added and dissolved in the order of carbon tetrachloride, acetonitrile, and pH 7 phosphate buffer (105 ml, 105 ml, 126 ml), and then ruthenium chloride monohydrate (RuCl ₃ .H ₂ O). 533.9 mg, 2.57 mmol) and sodium periodate (19.2 g, 0.090 mol) were added and stirred at 40 ° C. for 5 days. Ice water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (200 g, 20% ethyl acetate / hexane) to obtain Compound 31 (2.96 g, 41%).

Compound 31: ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H, s, H-18), 0.97 (3H, d, J = 6.1 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.45 (1H, dd, J = 11.6, 7.5 Hz, H-14).

  Diisopropylamine (5.03 ml, 0.0289 mol) and chloromethyl methyl ether (1.46 ml, 0.0192 mol) were added to a solution of compound 31 (2.7 g, 9.62 mmol) in anhydrous methylene chloride (35 ml) cooled to −20 ° C. ) And stirred at −20 ° C. for 1 hour and at 0 ° C. for 6.5 hours. On the way, 6 hours later, diisopropylamine (2.51 ml, 0.0145 mol) and chloromethyl methyl ether (730 μl, 9.62 mmol) were added. After 7.5 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with 5% sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (80 g, 10% ethyl acetate / hexane) to obtain Compound 10 (2.65 g, 85%).

Compound 10: ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H, s, H-18), 0.95 (3H, d, J = 6.1 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.45 (1H, dd, J = 11.6, 7.5 Hz, H-14), 3.37 (3H, s, OMe), 4.70 (2H, s) , OCH ₂ O).

  N-Butyllithium (2.32 ml, 3.67 mmol, 1.58 M hexane solution) was added to a solution of diisopropylamine (594 μl, 4.24 mmol) in anhydrous tetrahydrofuran (10 ml) cooled to −20 ° C. and stirred for 15 minutes. Lithium diisopropylamide (LDA) was cooled to −78 ° C., and a solution of compound 10 (917.0 mg, 2.83 mmol) in anhydrous tetrahydrofuran (10 ml) was added. After stirring for 20 minutes, a supernatant of a mixed solution of chlorotrimethylsilane (717 μl, 5.65 mmol) and triethylamine (788 μl, 5.65 mmol) was added. The temperature was gradually raised and the mixture was stirred for 1.5 hours until reaching 0 ° C. After the reaction solvent was distilled off, the residue was redissolved in hexane and purified by filtration through celite to obtain Compound 32 (1.12 g).

  To a solution of compound 32 (1.12 g, 2.82 mmol) cooled to 0 ° C. in anhydrous tetrahydrofuran (10 ml) was added methyllithium (2.82 ml, 3.39 mmol, 1.20 M diethyl ether solution), and 1. Stir for 5 hours. In a separate container, a solution of methyl iodide (351 μl, 5.64 mmol) in anhydrous tetrahydrofuran (10 ml) was prepared. After cooling to −78 ° C., the above lithium enolate was slowly added. The temperature was gradually raised from −78 ° C. and stirred for 2.5 hours until reaching 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (30 g), and Compound 33 (770.2 mg, 81%) was obtained from a fraction eluted with 5% ethyl acetate / hexane.

Compound 32: ¹ H NMR (CDCl ₃ ) δ: 0.17 (9H, s, SiMe x 3), 0.73 (3H, s, H-18), 0.94 (3H, d, J = 6. 5Hz, H-21), 1.21 (6H, s, H-26, 27), 3.37 (3H, s, OMe), 4.62 (1H, m, H-9), 4.71 ( _{2H, s, OCH 2 O)} .
Compound 33: ¹ H NMR (CDCl ₃ ) δ: 0.65 (3H, s, H-18), 0.95 (3H, d, J = 6.2 Hz, H-21), 1.18 (3H, d, J = 7.4 Hz, Me), 1.22 (6H, s, H-26, 27), 2.45 (1H, m, H-9), 2.66 (1H, dd, J = 11) .5, 7.4 Hz, H-14), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH ₂ O).
Mass m / z (%): 338 (M +, 1), 323 (9), 276 (82), 261 (24), 235 (50), 219 (37), 191 (21), 163 (38), 103 (100).

  Vinyl magnesium bromide (3.37 ml, 3.37 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of compound 33 (761.4 mg, 2.25 mmol) in anhydrous tetrahydrofuran (8 ml) cooled to 0 ° C. After stirring for 3 hours, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (30 g), and Compound 34 (766.6 mg, 93%) was obtained from a fraction eluted with 5% ethyl acetate / hexane.

Compound 34 ¹ H NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.5 Hz, H-21), 0.95 (3H, s, H-18), 0.97 (3H, d , J = 7.3 Hz, Me), 1.22 (6H, s, H-26, 27), 2.18 (1H, m, H-14), 3.37 (3H, s, OMe), 5 .02 (1H, dd, J = 10.8, 1.5 Hz, H-6), 5.22 (1H, dd, J = 17.2, 1.5 Hz, H-6), 5.90 (1H , Dd, J = 17.2, 10.8 Hz, H-7).
Mass m / z (%): 366 (no M ⁺ ), 304 (57), 286 (49), 271 (23), 247 (92), 191 (49), 175 (100)

  To a solution of compound 34 (704.7 mg, 1.92 mmol) in anhydrous methylene chloride (20 ml) were added pyridinium chlorochromate (PCC, 1.48 g, 6.73 mmol) and celite (1.0 g), and the mixture was stirred at room temperature for 23 hours. . The reaction solution was purified by silica gel column chromatography (35 g), and compound 35 (567.4 mg, 81%) was obtained from a fraction eluted with 5% ethyl acetate / hexane.

Compound 35: ¹ H NMR (CDCl ₃ ) δ: 0.60 (3H, s, H-18), 0.95 (3H, d, J = 5.7 Hz, H-21), 1.22 (6H, s, H-26, 27), 1.24 (3H, d, J = 7.2 Hz, Me), 2.44 (1H, m, H-14), 3.66 (1H, m, H-9) _{), 3.37 (3H, s,} OMe), 4.71 (2H, s, OCH 2 O), 5.67 (1H, dd, J = 8.3,1.5Hz, H-7), 10 .09 (1H, d, J = 8.2 Hz, CHO).

  Sodium borohydride (57.8 mg, 1.53 mmol) was added to an ethanol (10 ml) solution of the aldehyde compound compound 35 (557.0 mg, 1.53 mmol) cooled to 0 ° C. and stirred for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (20 g), and compound 36 (473.8 mg, 85%) was obtained from the fraction eluted with 15% ethyl acetate / hexane.

Compound 36: ¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s, H-18), 0.95 (3H, d, J = 6.4 Hz, H-21), 1.06 (3H, d, J = 7.2 Hz, Me), 1.22 (6H, s, H-26, 27), 2.20 (1H, m, H-14), 2.86 (1H, m, H-9) ), 3.37 (3H, s, OMe), 4.24 (2H, m, H-6), 4.71 (2H, s, OCH 2 O), 5.16 (1H, dt, J = 6 .9, 1.8 Hz, H-7).
Mass m / z (%): 366 (no M ⁺ ), 304 (18), 286 (50), 271 (20), 243 (8), 217 (13), 191 (29), 175 (100).

  To a solution of compound 36 (510.8 mg, 1.39 mmol) cooled to 0 ° C. in anhydrous tetrahydrofuran (6 ml), n-butyllithium (970 μl, 1.53 mmol, 1.58 M hexane solution) and tosyl chloride (318.7 mg, 1.67 mmol) in anhydrous tetrahydrofuran (1 ml) was added and stirred for 5 minutes. Make a solution of diphenylphosphine (485 μl, 2.79 mmol) in anhydrous tetrahydrofuran (3 ml) in another container, cool to 0 ° C., and add n-butyllithium (1.76 ml, 2.79 mmol, 1.58 M hexane solution). It was. (It becomes dark red)

The phosphine solution was slowly added to the tosyl body at 0 ° C. until the red color disappeared, and the mixture was stirred for 30 minutes, water (50 μl) was added to stop the reaction, and the solvent was distilled off.
Next, the residue was dissolved in methylene chloride (6 ml), 10% aqueous hydrogen peroxide (9 ml) was added, and the mixture was stirred at 0 ° C. for 1 hour. A 2N aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (30 g), and compound 37 (670.5 mg, 88%) was obtained from the eluate of 40% ethyl acetate / hexane.

Compound 37: ¹ H NMR (CDCl ₃ ) δ: 0.27 (3H, s, H-18), 0.88 (3H, d, J = 6.4 Hz, H-21), 0.91 (3H, d, J = 7.2 Hz, Me), 1.20 (6H, s, H-26, 27), 2.09 (1H, m, H-14), 2.70 (1H, m, H-9) ), 3.05,3.26 (each 1H, m , H-6), 3.36 (3H, s, OMe), 4.67 (2H, s, OCH 2 O), 4.95 (1H, m, H-7), 7.43-7.78 (10H, m, arom-H).
Mass m / z (%): 550 (M ⁺ , 1), 488 (83), 473 (14), 377 (3), 216 (56), 202 (100).

  N-Butyllithium (104 μl, 0.165 mmol, 1.58 M hexane solution) was added to a solution of phosphine oxide 37 (90.6 mg, 0.165 mmol) in anhydrous tetrahydrofuran (1 ml) cooled to −78 ° C. and stirred for 15 minutes. After that, a solution of ketone body 8 (29.6 mg, 0.083 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. After stirring at −78 ° C. for 1.5 hours, the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (8 g), compound 38 (8.3 mg, 15%) was eluted from the 2% ethyl acetate / hexane eluate, and adduct 39 (about 3% from the 25% ethyl acetate / hexane eluate). 1 mixture, 13.7 mg, 16%), and phosphine oxide 37 (61.3 mg) was recovered from the eluate of 40% ethyl acetate / hexane.

Compound 38: ¹ H NMR (CD ₃ OD) δ: 0.046, 0.13 (each 6H, s, SiMe x 4), 0.53 (3H, s, H-18), 0.87, 0. 90 (each 9H, s, tBuSix 2), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.04 (3H, d, J = 7.2 Hz, Me), 1.22 (6H, s, H-26, 27), 3.06 (1H, m), 3.37 (3H, s, OMe), 4.07 (2H, m, H-1, 3), 4.71 _{(2H, s, OCH 2 O} ), 5.77 (1H, d, J = 11.3Hz, H-7), 6.16 (1H, d, J = 11.3Hz, H-6).
Compound 39: ¹ H NMR (CD ₃ OD) δ: −0.08, −0.04, −0.01, 0.03; −0.07, 0.00, 0.009, 0.0014 (3 : 1) (each 3H, s, SiMe x 4), 0.44, 1.04 (3: 1) (3H, d, J = 7.1 Hz, Me), 0.54 (3H, s, H− 18), 0.78, 0.81; 0.69, 0.84 (3: 1) (each 9H, s, tBuSi x 2), 0.89 (3H, d, J = 6.4 Hz, H− 21), 1.20, 1.21 (3: 1) (6H, s, H-26, 27), 3.36, 3.37 (1: 3) (3H, s, OMe), 3.43 3.64 (3: 1) (1H, m, H-6), 4.16, 4.28 (each 1H, m, H-1, 3), 4.69, 4.70 (1: 3 ) (2H, s, _{CH 2 O), 5.06,5.15 (1} : 3) (1H, m, H-7).

  Camphorsulfonic acid (46.3 mg, 0.200 mmol) was added to a methanol (1 ml) solution of compound 38 (23.0 mg, 0.033 mmol), and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (4 g) to obtain 2e (13.3 mg, 96%) from a 70% ethyl acetate / hexane eluate.

Compound 2e: ¹ H NMR (CDCl ₃ ) δ: 0.54 (3H, s, H-18), 0.94 (3H, d, J = 6.3 Hz, H-21), 1.06 (3H, d, J = 7.2 Hz, Me), 1.22 (6H, s, H-26, 27), 2.49 (1H, dd, J = 13.3, 3.3 Hz, H-4), 2 .68 (1H, dd, J = 13.3, 3.6 Hz, H-10), 3.05 (1H, m, H-9), 4.07 (2H, m, H-1, 3), 5.80 (1H, d, J = 11.2 Hz, H-7), 6.31 (1H, d, J = 11.2 Hz, H-6).
UV λmax (EtOH): 244 nm (ε = 27600), 252 nm (ε = 31500), 261 nm (ε = 21000).
Mass m / z (%): 418 (M ⁺ , 35), 400 (100), 382 (20), 357 (11), 289 (35), 271 (24), 253 (18), 194 (42) .

<Synthesis of 9-butyl-19-norvitamin D derivative>
It was synthesized by the following procedure.

  Methyllithium (1.16 ml, 1.388 mmol, 1.2 M diethyl ether solution) was added to a solution of compound 32 (500.5 mg, 1.262 mmol) in anhydrous tetrahydrofuran (3 ml) cooled to 0 ° C., and the mixture was stirred at room temperature for 1 hour. Stir. In a separate container, make a solution of 1-iodobutane (718 μl, 6.310 mmol) and hexamethylphosphorustriamide (HMPA, 439 μl, 2.524 mmol) in anhydrous tetrahydrofuran (2 ml) and cool to 0 ° C. Slowly added. Stir at 0 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (20 g), and compound 40 (249.2 mg, 52%) and compound 10 (85.8 mg, 20%) were obtained from a 5% ethyl acetate / hexane eluate.

Compound 40: ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H, s, H-18), 0.87 (3H, t, J = 7.1 Hz, (CH ₂ ) ₃ CH ₃ ), 0. 95 (3H, d, J = 6.1 Hz, H-21), 1.21 (6H, s, H-26, 27), 2.02 (1H, m, H-9), 2.60 (1H , Dd, J = 11.6, 7.4 Hz, H-14), 3.37 (3H, s, OMe), 4.70 (2H, s, OCH ₂ O).
Mass m / z (%): 380 (M +, 2), 365 (7), 318 (45), 227 (24), 262 (100), 219 (20), 103 (41).

  To a solution of compound 40 (250.1 mg, 0.830 mmol) in anhydrous tetrahydrofuran (3 ml) cooled to 0 ° C., vinylmagnesium bromide (1.66 ml, 1.661 mmol, 1.0 M tetrahydrofuran solution) was added. After stirring for 6 hours, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (12 g), and Compound 41 (297.5 mg, 88%) was obtained from a fraction eluted with 5% ethyl acetate / hexane.

Compound 41: ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.1 Hz, (CH ₂ ) ₃ CH ₃ ), 0.91 (3H, d, J = 6.5 Hz, H -21), 0.96 (3H, s, H-18), 1.21 (6H, s, H-26, 27), 2.03 (1H, m, H-14), 3.37 (3H , S, OMe), 4.70 (2H, s, OCH ₂ O), 5.02 (1H, dd, J = 10.8, 1.6 Hz, H-6), 5.23 (1H, dd, J = 17.2, 1.6 Hz, H-6), 5.94 (1H, dd, J = 17.2, 10.8 Hz, H-7).

  Pyridinium chlorochromate (PCC, 723.0 mg, 3.288 mmol) and celite (800 mg) were added to a solution of compound 41 (268.7 mg, 0.657 mmol) in anhydrous methylene chloride (10 ml), and the mixture was stirred at room temperature for 20 hours. The reaction solution was purified by silica gel column chromatography (10 g), and compound 42 (215.0 mg, 80%) was eluted from the 5% ethyl acetate / hexane eluate, and the aldehyde from which the protecting group was removed from the 15% ethyl acetate / hexane eluate. A body (24.6 mg, 10%) was obtained.

Compound 42: ¹ H NMR (CDCl ₃ ) δ: 0.61 (3H, s, H-18), 0.88 (3H, d, J = 7.2 Hz, (CH ₂ ) ₃ CH ₃ ), 0. 94 (3H, d, J = 5.7 Hz, H-21), 1.21 (6H, s, H-26, 27), 2.36 (1H, m, H-14), 3.37 (3H , s, OMe), 3.39 ( 1H, m, H-9), 4.71 (2H, s, OCH 2 O), 5.78 (1H, d, J = 8.3Hz, H-7) , 10.06 (1H, d, J = 8.3 Hz, CHO).

  Sodium borohydride (13.9 mg, 0.367 mmol) was added to an ethanol (2 ml) solution of the aldehyde 42 (200.5 mg, 0.493 mmol) cooled to 0 ° C. and stirred for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain 43 (172.8 mg, 86%) from a fraction eluted with 15% ethyl acetate / hexane.

Compound 43: ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s, H-18), 0.88 (3H, d, J = 7.3 Hz, (CH ₂ ) ₃ CH ₃ ), 0. 92 (3H, d, J = 6.4 Hz, H-21), 1.21 (6H, s, H-26, 27), 2.12 (1H, m, H-14), 2.62 (1H , m, H-9), 3.37 (3H, s, OMe), 4.15,4.25 (each 1H, m, H-6), 4.71 (2H, s, OCH 2 O), 5.23 (1H, m, H-7).
Mass m / z (%): 408 (no M ⁺ ), 346 (11), 328 (58), 313 (23), 271 (19), 243 (33), 217 (100).

  To a solution of compound 43 (156.0 mg, 0.382 mmol) cooled to 0 ° C. in anhydrous tetrahydrofuran (2 ml), n-butyllithium (266 μl, 0.420 mmol, 1.58 M hexane solution) and tosyl chloride (87.4 mg, 0.458 mmol) in anhydrous tetrahydrofuran (0.2 ml) was added and stirred for 5 minutes. In a separate container, a solution of diphenylphosphine (133 μl, 0.764 mmol) in anhydrous tetrahydrofuran (1 ml) was prepared. After cooling to 0 ° C., n-butyllithium (484 μl, 0.764 mmol, 1.58 M hexane solution) was added. (It becomes dark red)

The phosphine solution was slowly added to the tosyl body at 0 ° C. until the red color disappeared, and the mixture was stirred for 30 minutes, water (20 μl) was added to stop the reaction, and the solvent was distilled off.
Next, the residue was dissolved in methylene chloride (2 ml), 10% aqueous hydrogen peroxide (3 ml) was added, and the mixture was stirred at 0 ° C. for 1 hour. A 2N aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 44 (173.7 mg, 77%) from a fraction eluted with 40% ethyl acetate / hexane.

Compound 44: ¹ H NMR (CDCl ₃ ) δ: 0.23 (3H, s, H-18), 0.86 (3H, t, J = 7.4 Hz, (CH ₂ ) ₃ CH ₃ , overlapped with H -21), 1.20, (6H, s, H-26, 27), 2.02 (1H, m, H-14), 2.49 (1H, m, H-9), 2.98, 3.34 (each 1H, m, H -6), 3.36 (3H, s, OMe), 4.70 (2H, s, OCH 2 O), 5.04 (1H, m, H-7) , 7.43-7.78 (10H, m, arom-H).
Mass m / z (%): 592 (M ⁺ , 2), 530 (100), 473 (33), 419 (4), 216 (74), 202 (91).

  A solution of phosphine oxide 44 (124.1 mg, 0.209 mmol) cooled to −78 ° C. in anhydrous tetrahydrofuran (2 ml) was added with hexamethylphosphorustriamide (36 μl, 0.209 mmol) and n-butyllithium (132 μl, 0.209 mmol). , 1.58 M hexane solution) was added and stirred for 15 minutes, and then a solution of ketone body 8 (37.5 mg, 0.105 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. After stirring at -78 ° C for 1 hour, the temperature was gradually raised, and stirring was continued at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 45 (15.7 mg, 21%) from the eluate of 2% ethyl acetate / hexane, and the phosphine oxide 44 (from the eluate of 40% ethyl acetate / hexane). 91.3 mg) was recovered.

Compound 45: ¹ H NMR (CD ₃ OD) δ: 0.048, 0.053 (each 6H, s, SiMe x 4), 0.54 (3H, s, H-18), 0.865, 0. 871 (each 9H, tBuSi x 2, overlapped with (CH ₂ ) ₃ CH ₃ ), 0.92 (3H, d, J = 6.3 Hz, H-21), 1.21 (6H, s, H-26 , 27), 2.83 (1H, m), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH 2 O), 4.07 (2H, m, H-1,3 ), 5.83 (1H, d, J = 11.2 Hz, H-7), 6.14 (1H, d, J = 11.2 Hz, H-6).

Camphorsulfonic acid (54.2 mg, 0.233 mmol) was added to a solution of compound 45 (28.5 mg, 0.039 mmol) in methanol (1 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (4 g), and 2f (17.2 mg, 96%) was obtained from the eluate of 70% ethyl acetate / hexane. This sample was further purified by HPLC [YMC-PackODS-AM SH-342-5, 15% H ₂ O / MeOH, 8 ml / min] to obtain 2f (11.8 mg).

Compound 2f: ¹ H NMR (CDCl ₃ ) δ: 0.54 (3H, s, H-18), 0.87 (3H, d, J = 7.2 Hz, (CH ₂ ) ₃ CH ₃ ), 0. 93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.19 (2H, m, H-4, OH), 2.27 (1H, dd, J = 13.2, 7.8 Hz, H-10), 2.49 (1H, dd, J = 13.3, 3.5 Hz, H-4), 2.68 (1H, dd , J = 13.2, 3.7 Hz, H-10), 2.82 (1H, m, H-9), 4.07 (2H, m, H-1, 3), 5.87 (1H, d, J = 11.2 Hz, H-7), 6.31 (1H, d, J = 11.2 Hz, H-6).
UV λmax (EtOH): 244 nm (ε = 27000), 252 nm (ε = 31000), 261 nm (ε = 21000).
Mass m / z (%): 460 (M ⁺ , 21), 442 (100), 424 (36), 406 (15), 331 (31), 313 (32), 295 (21).

<Synthesis of _{9-CH 2 CH = CHCH 3} -19- nor vitamin D derivatives>
It was synthesized by the following procedure.

  N-Butyllithium (1.22 ml, 1.938 mmol, 1.59 M hexane solution, 1.3 eq) in a solution of diisopropylamine (314 μl, 2.237 mmol, 1.5 eq) in anhydrous tetrahydrofuran (5 ml) cooled to −78 ° C. After stirring for 15 minutes, a solution of compound 10 (510.8 mg, 1.491 mmol) in anhydrous tetrahydrofuran (5 ml) was added. After stirring for 20 minutes, chlorotrimethylsilane (284 μl, 2.237 mmol, 1.5 eq) and triethylamine (312 μl, 2.237 mmol, 1.5 eq) were added. The temperature was gradually raised and the mixture was stirred for 2 hours until reaching 0 ° C. After the reaction solvent was distilled off, the residue was redissolved in hexane and purified by celite filtration to obtain Compound 32 (590 mg).

  Methyl lithium (1.36 ml, 1.640 mmol, 1.20 M diethyl ether solution, 1.1 eq) was added to a solution of compound 32 in anhydrous tetrahydrofuran (5 ml) cooled to 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Make a solution of crotyl alcohol (253 μl, 2.982 mmol, 2 eq) in anhydrous tetrahydrofuran (5 ml) in another container, cool to 0 ° C., and then n-butyllithium (1.85 ml, 2.982 mmol, 1.59 M hexane). Solution, 2 eq), a solution of tosyl (568.5 mg, 2.982 mmol, 2 eq) in anhydrous tetrahydrofuran (1 ml) was added. After stirring for 10 minutes, the above lithium enolate was slowly added and stirred at 0 ° C. for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (30 g) to obtain Compound 46 (338.3 mg, 60%) from the eluate of 10% ethyl acetate / hexane, and the protecting group was removed from the eluate of 25% ethyl acetate / hexane. Compound 46 ′ (91.5 mg, 18%) was obtained.

Compound 46: ¹ H NMR (CDCl ₃ ) δ: 0.65 (3H, s, H-18), 0.95 (3H, d, J = 6.1 Hz, H-21), 1.22 (6H, _{s, H-26,27), 1.64} (3H, d, J = 6.3Hz, CH 3 CH = CH), 2.56 (1H, dd, J = 11.6,7.4Hz, H- _{14), 3.37 (3H, s} , OMe), 4.71 (2H, s, OCH 2 O), 5.29,5.47 (each 1H, m, CH = CH).
Mass m / z (%): 378 (no M ⁺ ), 316 (100), 246 (35), 219 (25), 135 (26).
Compound 46 ′ ¹ H NMR (CDCl ₃ ) δ: 0.65 (3H, s, H-18), 0.96 (3H, d, J = 6.1 Hz, H-21), 1.22 (6H, _{s, H-26,27), 1.64} (3H, d, J = 6.3Hz, CH 3 CH = CH), 2.56 (1H, dd, J = 11.5,7.4Hz, H- 14), 5.29, 5.48 (each 1H, m, CH = CH).
Mass m / z (%): 334 (M ⁺ , 13), 316 (100), 246 (52), 219 (32), 135 (41).

  Vinyl magnesium bromide (1.67 ml, 1.671 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of compound 46 (316.3 mg, 0.835 mmol) in anhydrous tetrahydrofuran (3 ml) cooled to −20 ° C. After stirring for 5 hours, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (20 g), and Compound 47 (298.7 mg, 88%) was obtained from the eluate of 8% ethyl acetate / hexane.

Compound 47: ¹ H NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.5 Hz, H-21), 0.96 (3H, s, H-18), 1.21 (6H, _{s, H-26,27), 1.64} (3H, d, J = 6.2Hz, CH 3 CH = CH), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH ₂ O), 5.04 (1H, dd, J = 10.8, 1.5 Hz, H-6), 5.24 (1H, dd, J = 17.3, 1.5 Hz, H-6), 5.30, 5.40 (each 1H, m, CH = CH), 5.91 (1H, dd, J = 17.3, 10.8 Hz, H-7).
Mass m / z (%): 406 (M ⁺ , 1), 388 (2), 344 (65), 326 (100), 215 (16).

  Pyridinium chlorochromate (563.6 mg, 2.562 mmol) and celite (560 mg) were added to a solution of compound 47 (260.5 mg, 0.641 mmol) in anhydrous dichloromethane (15 ml), and the mixture was stirred at room temperature for 22 hours. The reaction solution was purified by silica gel column chromatography (20 g), and the compound 48 (205.2 mg, 79%) eluted from the 10% ethyl acetate / hexane eluate and the aldehyde from which the protecting group was removed from the 15% ethyl acetate / hexane eluate. Body 48 ′ (34.2 mg, 15%) was obtained.

Compound 48: ¹ H NMR (CDCl ₃ ) δ: 0.61 (3H, s, H-18), 0.94 (3H, d, J = 5.6 Hz, H-21), 1.22 (6H, s, H-26,27), 3.37 (3H, s, OMe), 3.39 (1H, m, H-9), 4.71 (2H, s, OCH 2 O), 5.29, 5.41 (each 1H, m, CH = CH), 5.75 (1H, m, H-7), 9.98 (1H, d, J = 8.2 Hz, CHO).
Mass m / z (%): 404 (M ⁺ , 16), 342 (100), 287 (27), 229 (10), 135 (20).
Compound 48 ′ ¹ H NMR (CDCl ₃ ) δ: 0.61 (3H, s, H-18), 0.95 (3H, d, J = 5.8 Hz, H-21), 1.22 (6H, s, H-26, 27), 3.39 (1H, m, H-9), 5.29, 5.41 (each 1H, m, CH = CH), 5.75 (1H, dd, J = 8.2, 1.6 Hz, H-7), 9.98 (1H, d, J = 8.2 Hz, CHO).

  Sodium borohydride (18.5 mg, 0.490 mmol) was added to a solution of aldehyde compound 48 (198.1 mg, 0.490 mmol) cooled to 0 ° C. in ethanol (2 ml), and the mixture was stirred for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (10 g) to obtain Compound 21 (148.5 mg, 75%) from the eluate of 10% ethyl acetate / hexane, and the protecting group was removed from the eluate of 30% ethyl acetate / hexane. Compound 21 ′ (8.2 mg, 5%) was obtained.

Compound 21: ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s, H-18), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H, _{s, H-26,27), 1.65} (3H, d, J = 6.1Hz, CH 3 CH = CH), 2.67 (1H, m, H-9), 3.37 (3H, s _{, OMe), 4.10 (2H,} m, H-6), 4.71 (2H, s, OCH 2 O), 5.27 (1H, dt, J = 7.11.7Hz, H-7) , 5.38 (2H, m, CH = CH).
Mass m / z (%): 406 (no M ⁺ ), 388 (9), 326 (97), 311 (31), 271 (43), 215 (100).
Compound 21 ′: ′ ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s, H-18), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 ( _{6H, s, H-26,27)} , 1.65 (3H, d, J = 6.1Hz, CH 3 CH = CH), 2.67 (1H, m, H-9), 4.10 (2H , M, H-6), 5.27 (1H, dt, J = 7.1 1.7 Hz, H-7), 5.38 (2H, m, CH = CH).

To a solution of compound 21 (127.2 mg, 0.313 mmol) cooled to 0 ° C. in anhydrous methylene chloride (2 ml) was added triphenylphosphine (123.1 mg, 0.469 mmol, 1.5 eq) and 2-mercaptobenzothiazole (78. 5 mg, 0.469 mmol, 1.5 eq) and diisopropyl azodicarboxylate (DIAD, 64 μl, 0.313 mmol, 1 eq) were added and stirred for 1 hour. After the solvent was distilled off, the residue was dissolved in ethanol (2 ml) and cooled to 0 ° C. 30% hydrogen peroxide in the (400 [mu] l) and ammonium heptamolybdate tetrahydrate _{(NH 4) 6 Mo 7 O} 24 · 4H 2 O (77.4mg, 0.063mmol, 0.2eq) was added, Stir at room temperature for 2 hours.

  To the reaction solution was added 2N aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (10 g), and compound 23 (176.5 mg, 94%) was obtained from the eluate of 10% ethyl acetate / hexane.

Compound 23: ¹ H NMR (CDCl ₃ ) δ: 0.13 (3H, s, H-18), 0.83 (3H, d, J = 6.2 Hz, H-21), 1.19 (6H, _{s, H-26,27), 1.62} (3H, d, J = 5.9Hz, CH 3 CH = CH)), 2.61 (1H, m, H-9), 3.36 (3H, s, OMe), 4.03 (1H, ddd, J = 14.5, 5.9, 2.0 Hz, H-6), 4.55 (1H, dd, J = 14.5, 10.0 Hz, _{H-6), 4.69 (2H} , s, OCH 2 O), 5.03 (1H, m, H-7), 5.28,5.36 (each 1H, m, CH = CH), 7 58, 7.63, 7.97, 8.21 (each 1H, m, arom-H).

  Compound 23 (163.7 mg, 0.278 mmol, 1.5 eq) cooled to −78 ° C. in anhydrous tetrahydrofuran (2 ml) was added to lithium bis (trimethylsilyl) amide (242 μl, 0.242 mmol, 1.0 M tetrahydrofuran solution, 1. 3 eq) was added and stirred for 30 minutes, and then a solution of ketone body 9 (83.0 mg, 0.186 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. After stirring at −78 ° C. for 1 hour, the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 28 (139.0 mg, 91%, approximately 5: 4 mixture) from a 2% ethyl acetate / hexane eluate, and eluted with 10% ethyl acetate / hexane. Compound 23 (48.3 mg) was recovered from the portion.

Compound 28: ¹ H NMR (CD ₃ OD) δ: 0.042, 0.056, 0.065 (12H, s, SiMe x 4), 0.12 (9H, s, SiMe x 3), 0.53 , 0.55 (4: 5) (3H, s, H-18), 0.86, 0.89; 0.87, 0.88 (4: 5) (each 9H, tBuSi x 2), 0. 93 (3H, d, J = 6.3 Hz, H-21), 1.22 (6H, s, H-26, 27), 1.64 (3H, d, J = 4.2 Hz, CH ₃ CH = CH), 2.82 (1H, m), 3.37 (3H, s, OMe), 3.54, 3.59 (5: 4) (1H, m, H-2), 3.80 (1H , m), 3.88,3.93 (5: 4) (1H, m), 4.71 (2H, s, OCH 2 O), 5.39 (2H, m, CH = CH), 5. 7 (1H, m, H-7), 6.09 (1H, m, H-6).
Mass m / z (%): 818 (no M ⁺ ), 756 (15), 624 (26), 569 (100), 479 (28).

  Compound 28 (129.3 mg, 0.158 mmol, about 5: 4 mixture) was dissolved in tetrahydrofuran / acetic acid / water (8: 8: 1, 8.5 ml) and stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (8 g), and compound 28 '(106.0 mg, 90%, approximately 5: 4 mixture) was obtained from a fraction eluted with 5% ethyl acetate / hexane.

Compound 28′a (major: 2α form) ¹ H NMR (CDCl ₃ ) δ: 0.06 to 0.10 (12H, Si-Mex 4), 0.55 (3H, s, H-18), 0 .88, 0.89 (each 9H, s, Si-tBux 2), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H, s, H-26, _{27), 1.64 (3H, d} , J = 4.9Hz, CH 3 CH = CH), 2.83 (1H, m, H-9), 3.37 (3H, s, OMe), 3. 52 (1H, m, H- 2), 3.99 (1H, m, H-3), 4.12 (1H, m, H-1), 4.74 (2H, s, OCH 2 O), 5.37 (2H, m, CH = CH), 5.79 (1H, d, J = 11.2 Hz, H-7), 6.16 (1H, d, J = 11.2 Hz, H-6) .
Compound 28′b (minor: 2β form) ¹ H NMR (CDCl ₃ ) δ: 0.06 to 0.10 (12H, Si-Mex 4), 0.54 (3H, s, H-18), 0 .86, 0.90 (each 9H, s, Si-tBux 2), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H, s, H-26, _{27), 1.64 (3H, d} , J = 4.9Hz, CH 3 CH = CH), 2.83 (1H, m, H-9), 3.37 (3H, s, OMe), 3. 89 (1H, m, H- 2), 4.12 (2H, m, H-1,3), 4.74 (2H, s, OCH 2 O), 5.37 (2H, m, CH = CH ), 5.79 (1H, d, J = 11.2 Hz, H-7), 6.15 (1H, d, J = 11.2 Hz, H-6).
Compound 28 'Mass m / z (%): 746 (M ^<+> , 14), 684 (30), 629 (39), 497 (94), 365 (54), 75 (100).

  To a solution of oxalyl dichloride (14 μl, 0.161 mmol, 1.2 eq) in anhydrous methylene chloride (0.5 ml) cooled to −78 ° C., dimethyl sulfoxide (23 μl, 0.322 mmol, 2.4 eq) in anhydrous methylene chloride (0 .3 ml) solution was added and stirred for 10 minutes, followed by addition of a solution of compound 28 ′ (100.3 mg, 0.134 mmol, approximately 5: 4) in anhydrous methylene chloride (1 ml). After stirring at −78 ° C. for 15 minutes, triethylamine (93 μl, 0.670 mmol, 5 eq) was added, and the mixture was stirred at −78 ° C. for 10 minutes and at 0 ° C. for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 28 ″ (98.5 mg, 99%) from a fraction eluted with 5% ethyl acetate / hexane.

Compound 28 ″: ¹ H NMR (CDCl ₃ ) δ: 0.056, 0.066, 0.070, 0.099 (each 3H, s, Si-Mex 4), 0.55 (3H, s, H -18), 0.87, 0.90 (each 9H, s, Si-tBux 2), 0.93 (3H, d, J = 6.3 Hz, H-21), 1.22 (6H, s , H-26, 27), 1.64 (3H, d, J = 5.5 Hz, CH ₃ CH = CH), 2.45 (1H, dd, J = 13.6, 8.6 Hz), 2. 53 (1H, dd, J = 14.1, 4.1 Hz), 2.67 (1H, dd, J = 13.6, 5.6 Hz), 2.73 (1H, dd, J = 14.1, 6.4 Hz), 2.85 (1H, m, H-9), 3.37 (3H, s, OMe), 4.36 (1H, dd, J = 6.4, 4.1) z), 4.55 (1H, dd , J = 8.6,5.6Hz), 4.74 (2H, s, OCH 2 O), 5.39 (2H, m, CH = CH), 5. 81 (1H, d, J = 11.1 Hz, H-7), 6.35 (1H, d, J = 11.1 Hz, H-6).
Mass m / z (%): 744 (no M ⁺ ), 626 (100), 494 (29), 325 (15).

  N-Butyllithium (167 μl, 0.264 mmol, 1.59 M hexane solution, 2 eq) was added to a solution of diethylcyanomethylphosphonate (43 μl, 0.264 mmol, 2 eq) in anhydrous tetrahydrofuran (1 ml) cooled to −40 ° C., After stirring for 15 minutes, a solution of compound 28 ″ (98.5 mg, 0.132 mmol) in anhydrous tetrahydrofuran (1.5 ml) was slowly added. After stirring at −40 ° C. for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.The residue was purified by silica gel column chromatography (8 g) and eluted with 1% ethyl acetate / hexane. Compound 29 (97.5 mg, 96%, approximately 1: 1 mixture) was obtained from a portion.

Compound 29: ¹ H NMR (CDCl ₃ ) δ: 0.06-0.12 (12H, Si-Mex 4), 0.54, 0.55 (1: 1) (3H, s, H-18) , 0.83, 0.92 (1: 1) (9H, s, Si-tBu), 0.93 (9H, s, tBu-Si, overlapped with H-21), 1.22 (6H, s, H-26,27), 1.63,1.65 (1 : 1) (3H, d, J = 5.5Hz, CH 3 CH = CH), 2.85 (1H, m, H-9), 3.00,3.14 (1: 1) (1H , m, H-10), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH 2 O), 4.48, 5.00 (1: 1) (1H, m, H-1), 4.57, 5.03 (1: 1) (1H, m, H-3), 5.40 (2H, m, CH = CH 5.47, 5.48 (1: 1) (1H, d, J = 2.0 Hz, C = CHCN), 5.79, 5.83 (1: 1) (1H, d, J = 1.11. 1 Hz, H-7), 6.19, 6.27 (1: 1) (1H, d, J = 11.2 Hz, H-6).
Mass m / z (%): 768 (M ⁺ , 5), 706 (18), 651 (60), 626 (79), 518 (68), 73 (100).

  Compound 29 (97.5 mg, 0.127 mmol, E: Z = 1: 1 mixture) cooled to −78 ° C. in anhydrous toluene (1 ml) was added to diisobutylaluminum hydride (190 μl, 0.190 mmol, 1.0 M toluene). Solution, 1.5 eq) was added. After 1 hour, the reaction solution was diluted with hexane and purified by silica gel column chromatography (5 g). Compound 29 ′ (87 mg, 89%, approximately 1: 1 mixture) was eluted from the 5% ethyl acetate / hexane eluate. Obtained.

Compound 29 ′ (E form): ¹ H NMR (CDCl ₃ ) δ: 0.02, 0.07, 0.09, 0.10 (each 3H, s, Si-Mex 4), 0.56 (3H , S, H-18), 0.83, 0.92 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 1 _{.65 (3H, d, J =} 5.5Hz, CH 3 CH = CH), 2.84 (1H, m, H-9), 3.08 (1H, m, H-10), 3.37 ( _{3H, s, OMe), 4.71} (2H, s, OCH 2 O), 4.58 (1H, m, H-1), 5.40 (2H, m, CH = CH), 5.47 ( 1H, m, H-3), 5.84 (1H, d, J = 11.0 Hz, H-7), 6.16 (1H, m, C = CH), 6.19. 1H, d, J = 11.0Hz, H-6), 10.19 (1H, d, J = 7.8Hz, CHO).
Compound 29 ′ (Z form): ¹ H NMR (CDCl ₃ ) δ: 0.02, 0.07, 0.10, 0.11 (each 3H, s, Si-Mex 4), 0.55 (3H , S, H-18), 0.84, 0.93 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 1 _{.63 (3H, d, J =} 5.5Hz, CH 3 CH = CH), 2.84 (1H, m, H-9), 3.00 (1H, m, H-10), 3.37 ( _{3H, s, OMe), 4.71} (2H, s, OCH 2 O), 4.67 (1H, m, H-3), 5.40 (2H, m, CH = CH), 5.53 ( 1H, m, H-1), 5.80 (1H, d, J = 11.0 Hz, H-7), 6.16 (1H, m, C = CH), 6.28. 1H, d, J = 11.0Hz, H-6), 10.17 (1H, d, J = 7.7Hz, CHO).
Compound 29 ': Mass m / z (%): 770 (M ^<+> , 1), 708 (8), 651 (18), 576 (30), 521 (64), 75 (100).

  Sodium borohydride (4.2 mg, 0.113 mmol, 1 eq) was added to a solution of aldehyde 29 ′ (87.0 mg, 0.113 mmol, approximately 1: 1 mixture) in ethanol (1 ml) cooled to 0 ° C., Stir for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (6 g) to obtain Compound 29 ″ (75.8 mg, 87%, approximately 1: 1 mixture) from a fraction eluted with 5% ethyl acetate / hexane.

Compound 29 ″ (E form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.10 (12H, Si-Me x 4), 0.54 (3H, s, H-18), 0.84 0.91 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 1.63 (3H, d, J = 5. 5 Hz, CH ₃ CH═CH), 2.29 (2H, m, H-4), 2.80 (1H, m, H-9), 2.89 (1H, m, H-10), 3. _{37 (3H, s, OMe)} , 4.71 (2H, s, OCH 2 O), 4.20,4.29 (2H, m, CH 2 OH), 4.30 (1H, m, H-1 ), 4.81 (1H, m, H-3), 5.37 (2H, m, CH = CH), 5.70 (1H, m, C = CH), 5.84 ( H, d, J = 11.1Hz, H-7), 6.13 (1H, d, J = 11.1Hz, H-6).
Compound 29 ″ (Z form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.10 (12H, Si-Me x 4), 0.53 (3H, s, H-18), 0.82 , 0.92 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 1.62 (3H, d, J = 5. 5 Hz, CH ₃ CH = CH), 2.55 (1H, dd, J = 12.5, 5.0 Hz, H-4), 2.83 (2H, m, H-9, 10), 3.37 _{(3H, s, OMe),} 4.71 (2H, s, OCH 2 O), 4.20,4.29 (2H, m, CH 2 OH), 4.47 (1H, m, H-3) 4.84 (1H, m, H-1), 5.37 (2H, m, CH = CH), 5.70 (1H, m, C = CH), 5.80. 1H, d, J = 11.1Hz, H-7), 6.20 (1H, d, J = 11.1Hz, H-6).
Compound 29 ": Mass m / z (%): 772 (M ^<+> , 5), 710 (6), 692 (8), 640 (37), 585 (87), 523 (100), 391 (24).

Camphorsulfonic acid (28.8 mg, 0.124 mmol, 6 eq) was added to a methanol (0.5 ml) solution of compound 29 ″ (16.0 mg, 0.0207 mmol, approximately 1: 1 mixture) at room temperature for 1.5. The reaction mixture was added with 5% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. (3g) to obtain Compound 3c (10.9 mg, 98%, approximately 1: 1 mixture) from the eluate of 2% methanol / ethyl acetate, which was further analyzed by HPLC [YMC-Pack ODS-AM. _{SH-342-5,15% H 2 O /} MeOH, and purified by 8 ml / min], compound 3c (E substance) (3.8 mg) and compound To give c a (Z bodies) (4.3 mg).

Compound 3c (E form): ¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s, H-18), 0.93 (3H, d, J = 6.3 Hz, H-21), 1. 22 (6H, s, H- 26,27), 1.63 (3H, d, J = 5.6Hz, CH 3 CH = CH), 2.44 (2H, m, H-4), 2.84 (1H, m, H-9), 3.13 (1H, dd, J = 13.1, 5.0 Hz, H-10), 4.19 (1H, dd, J = 12.4, 6.1 Hz) , CH ₂ OH), 4.38 (1H, dd, J = 12.4, 7.9 Hz, CH ₂ OH), 4.41 (1H, m, H−1), 4.84 (1H, m, H-3), 5.38 (2H, m, CH = CH), 5.84 (1H, m, C = CH), 5.89 (1H, d, J = 11.1 Hz, H-7), 6.27 (1H, d, J = 11.1 Hz, H-6).
UV λmax (EtOH): 247 nm, 255 nm, 264 nm.

Compound 3c (Z form): ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s, H-18), 0.93 (3H, d, J = 6.3 Hz, H-21), 1. 22 (6H, s, H-26, 27), 1.62 (3H, d, J = 5.6 Hz, CH ₃ CH = CH), 2.70 (1H, dd, J = 12.7, 4. 7 Hz, H-4), 2.85 (2H, m, H-9, 10), 3.37 (3H, s, OMe), 4.19 (1H, dd, J = 12.5, 6.0 Hz) , CH ₂ OH), 4.38 (1H, dd, J = 12.5, 7.9 Hz, CH ₂ OH), 4.45 (1H, m, H-3), 4.87 (1H, m, H-1), 5.38 (2H, m, CH = CH), 5.82 (1H, m, C = CH), 5.84 (1H, d, J = 11.1 Hz, H-7), 6.37 (1H, d, J = 11.1 Hz, H-6).
UV λmax (EtOH): 247 nm, 255 nm, 264 nm.

<Synthesis of _{9-CH 2 CH = CH 2} -19- nor vitamin D derivatives>
It was synthesized by the following procedure.

N-Butyllithium (2.8 ml, 4.37 mmol, 1.58 M hexane solution) was added to a solution of diisopropylpropylamine (706 μl, 5.04 mmol) in anhydrous tetrahydrofuran (10 ml) cooled to −20 ° C. for 15 minutes. Stir. Lithium diisopropylamide was cooled to −78 ° C., and a solution of grandman ketone body 10 (1.09 g, 3.36 mmol) in anhydrous tetrahydrofuran (5 ml) was added. After stirring for 1 hour, a mixture of chlorotrimethylsilane (436 μl, 5.04 mmol) and triethylamine (702 μl, 5.04 mmol) was added. The temperature was gradually raised and the mixture was stirred for 1.5 hours until it reached -20 ° C. After the reaction solvent was distilled off, the residue was redissolved in hexane and purified by filtration through celite to obtain Compound 32 (1.34 g).

Compound 32: ¹ H-NMR (CDCl ₃ ) δ: 0.17 (9H, s, SiMe x 3), 0.73 (3H, s, H-18), 0.94 (3H, d, J = 6) .5 Hz, H-21), 1.22 (6H, s, H-26, 27), 3.37 (3H, s, OCH ₃ ), 4.63 (1H, m, H-9), 4. _{71 (2H, s, OCH 2} O).

  Methyllithium (3.4 ml, 4.06 mmol, 1.2 M diethyl ether solution) was added to a solution of silylenolate 32 (1.34 mg, 3.38 mmol) in anhydrous tetrahydrofuran (5 ml) cooled to 0 ° C. and stirred for 1 hour. did. In a separate container, a solution of allyl iodide (631 μl, 6.77 mmol) in anhydrous tetrahydrofuran (2 ml) was prepared and cooled to −78 ° C. Then, the above lithium enolate was slowly added, and the temperature was gradually raised. After stirring for 1 hour (−45 ° C.), a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (30 g), and compound 16 (887.7 mg, 73%) was obtained from the eluate of 8 to 10% ethyl acetate / hexane.

Compound 16: ¹ H-NMR (CDCl ₃ ) δ: 0.66 (3H, s, H-18), 0.96 (3H, d, J = 6.2 Hz, H-21), 1.22 (6H , s, H-26,27), 2.57 (1H, dd, J = 11.5,7.4Hz, H-14), 3.37 (3H, s, OCH 3), 4.70 (2H , S, OCH ₂ O), 5.09 (2H, m, CH ₂ CH═CH ₂ ), 5.68 (1H, m, CH ₂ CH═CH ₂ ).
Mass m / z (%): 364 (M ⁺ , 6), 323 (8), 302 (76), 261 (17), 219 (68), 191 (25), 55 (100).

  1. To a solution of 9-allyl compound 16 (887.7 mg, 2.43 mmol) cooled to 0 ° C. in anhydrous tetrahydrofuran (7 ml) was added vinylmagnesium bromide (4.87 ml, 4.87 mmol, 1.0 M tetrahydrofuran solution). Stir for 5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (10 g) to obtain Compound 17 (759.1 mg, 79%) from a 10% ethyl acetate / hexane eluate.

Compound 17: ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.5 Hz, H-21), 0.97 (3H, s, H-18), 1.21 (6H _{, s, H-26,27),} 3.37 (3H, s, OCH 3), 4.71 (2H, s, OCH 2 O), 4.99 (2H, m, CH 2 CH = CH 2) , 5.05 (1H, dd, J = 10.8, 1.5 Hz, H-6), 5.25 (1H, dd, J = 17.2, 1.5 Hz, H-6), 5.69 _{(1H, m, CH 2 CH} = CH 2), 5.91 (1H, dd, J = 17.2,10.8Hz, H-7).
Mass m / z (%): 392 (no M ⁺ ), 330 (53), 312 (50), 297 (14), 271 (20), 247 (87), 219 (20), 201 (49), 55 (100).

  Pyridinium chlorochromate (1.67 g, 7.73 mmol) and celite (1.7 g) were added to a solution of vinyl alcohol 17 (759.1 mg, 1.93 mmol) in anhydrous methylene chloride (30 ml), and the mixture was stirred at room temperature for 23 hours. did. The reaction solution was purified by column chromatography (20 g) to obtain Compound 18 (669.3 mg, 89%) from a fraction eluted with 2% ethyl acetate / hexane.

Compound 18: ¹ H-NMR (CDCl ₃ ) δ: 0.62 (3H, s, H-18), 0.95 (3H, d, J = 5.7 Hz, H-21), 1.22 (6H _{, s, H-26,27),} 3.37 (3H, s, OCH 3), 3.47 (1H, m, H-9), 4.71 (2H, s, OCH 2 O), 5. _{03 (2H, m, CH 2} CH = CH 2), 5.68 (1H, m, CH 2 CH = CH 2), 5.76 (1H, dd, J = 8.3,1.5Hz, H- 7), 10.01 (1H, d, J = 8.2 Hz, CHO).
Mass m / z (%): 390 (M ⁺ , 6), 328 (71), 287 (52), 217 (28), 215 (100).

  Sodium borohydride (63.9 mg, 1.69 mmol) was added to a solution of allyl aldehyde 18 (660.1 mg, 1.69 mmol) in ethanol (10 ml) cooled to 0 ° C. and stirred for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (20 g), and compound 19 (400.6 mg, 60%) was obtained from the eluate of 20 to 25% ethyl acetate / hexane.

Compound 19: ¹ H-NMR (CDCl ₃ ) δ: 0.56 (3H, s, H-18), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H , s, H-26,27), 2.73 (1H, dd, J = 13.9,7.1Hz, H-9), 3.37 (3H, s, OCH 3), 4.14 (2H _{, d, J = 6.8Hz, H} -6), 4.71 (2H, s, OCH 2 O), 4.97 (2H, m, CH 2 CH = CH 2), 5.28 (1H, dd , J = 7.1,1.6Hz, H-7 ), 5.70 (1H, m, CH 2 CH = CH 2).
Mass m / z (%): 392 (no M ⁺ ), 330 (100), 312 (53), 299 (64), 289 (19), 271 (41), 245 (47), 219 (32), 217 (49), 201 (72).

  To a solution of allyl alcohol 19 (400.6 mg, 1.02 mmol) in anhydrous tetrahydrofuran (1 ml) cooled to 0 ° C., n-butyllithium (710 μl, 1.12 mmol, 1.58 M hexane solution) and tosyl chloride (252.9 mg). , 1.33 mmol) in anhydrous tetrahydrofuran (500 μl) was added and stirred for 7 minutes. In a separate container, a solution of diphenylphosphine (355 μl, 2.04 mmol) in anhydrous tetrahydrofuran (1 ml) was prepared, and after cooling to 0 ° C., n-butyllithium (1.3 ml, 2.04 mmol, 1.58 M hexane solution) was added. added. At 0 ° C., the phosphine solution was slowly added to the tosyl body until the red color disappeared, and the mixture was stirred at 0 ° C. for 30 minutes, water (10 μl) was added to stop the reaction, and the solvent was distilled off. Next, the residue was redissolved in methylene chloride (4 ml), 10% aqueous hydrogen peroxide (6 ml) was added, and the mixture was stirred at 0 ° C. for 1 hour. A 2N aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (25 g) to obtain Compound 20 (319.0 mg, 54%) from a fraction eluted with 40-50% ethyl acetate / hexane.

Compound 20: ¹ H-NMR (CDCl ₃ ) δ: 0.26 (3H, s, H-18), 0.88 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H , S, H-26, 27), 2.58 (1H, m, H-9), 2.99, 3.29 (each 1H, m, H-6), 3.36 (3H, s, OCH) _{3), 4.70 (2H, s} , OCH 2 O), 4.94 (2H, m, CH 2 CH = CH 2), 5.05 (1H, m, H-7), 5.66 (1H _{, m, CH 2 CH = CH} 2), 7.43~7.78 (10H, m, arom-H).
Mass m / z (%): 576 (M ⁺ , 3), 514 (51), 499 (45), 473 (56), 313 (27), 202 (100).

  A solution of phosphioxide 20 (217.3 mg, 0.377 mmol) in anhydrous THF (2 ml) cooled to −78 ° C. was added to hexamethylphosphorustriamide (66 μl, 0.377 mmol) and n-butyllithium (237 μl, 0.37 mmol). 377 mmol, 1.59 M hexane solution) was added, and the mixture was stirred for 15 minutes, and then a solution of keto compound 8 (120.0 mg, 0.335 mmol) in anhydrous tetrahydrofuran (1 ml) was added. After stirring at −78 ° C. for 1 hour, the temperature was gradually raised over 2 hours, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (6 g) to obtain Compound 25 (28.3 mg, 12%) from the eluate of 2% ethyl acetate / hexane, and Compound 25 ′ (49 from the eluate of 30% ethyl acetate / hexane). 0.2 mg, 16%) was obtained, and unreacted raw material 20 (96.9 mg, 45%) was recovered from the fraction eluted with 50% ethyl acetate / hexane.

Compound 25: ¹ H-NMR (CDCl ₃ ) δ: 0.048, 0.053 (each 6H, s, Si-Mex 4), 0.55 (3H, s, H-18), 0.865, 0.874 (each 9H, s, Si-tBux 2), 0.93 (3H, d, J = 6.6 Hz, H-21), 1.21 (6H, s, H-26, 27), 2.92 (1H, dd, J = 12.7, 7.1 Hz, H-9), 3.37 (3H, s, OCH ₃ ), 4.06 (2H, m, H-1, 3), _{4.71 (2H, s, OCH 2} O), 4.97 (2H, m, CH 2 CH = CH 2), 5.73 (1H, m, CH 2 CH = CH 2), 5.84 (1H , D, J = 11.2 Hz, H-7), 6.14 (1H, d, J = 11.2 Hz, H-6).
Mass m / z (%): 716 (M ⁺ , 3), 654 (81), 613 (21), 597 (16), 522 (46), 481 (90), 390 (8), 349 (100) .

  Camphorsulfonic acid (23.7 mg, 0.102 mmol) was added to a solution of 19-nor 25 (12.2 mg, 0.0170 mmol) in methanol (500 μl), and the mixture was stirred at room temperature for 1.5 hours. 5% Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (3 g), and compound 2b (6.8 mg, 90%) was obtained from the eluate of 80% ethyl acetate / hexane.

Compound 2b: ¹ H-NMR (CDCl ₃ ) δ: 0.55 (3H, s, H-18), 0.94 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H , S, H-26, 27), 2.49 (1H, dd, J = 13.2, 3.3 Hz, H-4), 2.70 (1H, dd, J = 13.4, 3.7 Hz) , H-10), 2.91 (1H, dd, J = 13.6, 7.1 Hz, H-9), 4.05 (1H, m, H-3), 4.10 (1H, m, _{H-1), 4.97 (2H} , m, CH 2 CH = CH 2), 5.71 (1H, m, CH 2 CH = CH 2), 5.88 (1H, d, J = 11.2Hz , H-7), 6.29 (1H, d, J = 11.2 Hz, H-6).
Mass m / z (%): 444 (M ⁺ , 23), 426 (74), 408 (16), 385 (100), 367 (52), 349 (23).
UV λmax (EtOH): 245 nm, 253 nm, 262 nm.

  To a solution of 19-nor 25 (22.2 mg, 0.0310 mmol) in anhydrous tetrahydrofuran (300 μl), 9-borobicyclo- [3.3.1] nonane (9-BBN, 619 μl, 0.310 mmol) was added and brought to room temperature. And stirred for 4 hours. Methanol (150 μl) was added to the reaction solution to stop the reaction and stirred for 15 minutes. Next, this solution was cooled to 0 ° C., 6M sodium hydroxide (103 μl, 0.260 mmol) and 30% aqueous hydrogen peroxide (150 μl) were added, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (4 g), and compound 25 ″ (18.5 mg, 81%) was obtained from the eluate of 8% ethyl acetate / hexane.

Compound 25 ″: ¹ H-NMR (CDCl ₃ ) δ: 0.049, 0.054 (each 6H, s, Si—Mex 4), 0.54 (3H, s, H-18), 0.86 , 0.87 (each 9H, s, Si-tBux 2), 0.92 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H, s, H-26, 27) _{, 2.34 (1H, m, H} -9), 3.37 (3H, s, OCH 3), 3.60 (2H, m, CH 2 CH 2 CH 2 OH), 4.06 (2H, m , H-1,3), 4.71 (2H, s, OCH ₂ O), 5.88 (1H, d, J = 11.2 Hz, H-7), 6.14 (1H, d, J = 11.2 Hz, H-6).
Mass m / z (%): 735 (noM ⁺ ), 673 (20), 655 (20), 598 (31), 541 (52), 523 (20), 466 (15), 75 (100).

  Camphorsulfonic acid (9.9 mg, 42.4 μmol) was added to a solution of 19-nor 25 ′ (5.2 mg, 7.07 μmol) in methanol (250 μl), and the mixture was stirred at room temperature for 2 hours. 5% Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (3 g), and compound 2d (2.4 mg, 73%) was obtained from the eluate of 3% methanol / ethyl acetate.

Compound 2d: ¹ H-NMR (CDCl ₃ ) δ: 0.55 (3H, s, H-18), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H , S, H-26, 27), 2.46 (1H, m, H-4), 2.70 (1H, m, H-10), 2.91 (1H, m, H-9), 3 .61 (2H, m, CH ₂ OH), 4.04 (1H, m, H-3), 4.12 (1H, m, H-1), 5.92 (1H, d, J = 1.11. 1 Hz, H-7), 6.28 (1H, d, J = 11.1 Hz, H-6).
Mass m / z (%): 462 (M ⁺ , 17), 444 (100), 426 (39), 408 (16).
UV λmax (EtOH): 244 nm, 252 nm, 262 nm.

<Synthesis of 2-hydroxyethylidene-9-allyl-19-norvitamin D derivative>

To a solution of compound 19 (100.0 mg, 0.255 mmol) cooled to 0 ° C. in anhydrous methylene chloride (2 ml), triphenylphosphine (100.2 mg, 0.382 mmol, 1.5 eq), 2-mercaptobenzothiazole (63. 9 mg, 0.382 mmol, 1.5 eq) and diisopropyl azodicarboxylate (52 μl, 0.255 mmol, 1 eq) were added and stirred for 1 hour.
After the solvent was distilled off, the residue was dissolved in ethanol (2 ml) and cooled to 0 ° C. 30% hydrogen peroxide (300 μl) and ammonium heptamolybdate tetrahydrate (63.0 mg, 0.051 mmol, 0.2 eq) were added thereto, and the mixture was stirred at room temperature for 1.5 hours.
To the reaction solution was added 2N aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 22 (133.5 mg, 91%) from a 10% ethyl acetate / hexane eluate.

Compound 22: ¹ H NMR (CDCl ₃ ) δ: 0.17 (3H, s, H-18), 0.84 (3H, d, J = 6.2 Hz, H-21), 1.20 (6H, s, H-26, 27), 2.70 (1H, m, H-9), 3.36 (3H, s, OMe), 4.07 (1H, ddd, J = 14.5, 5.9) , 2.0 Hz, H-6), 4.12 (1H, dd, J = 14.3, 7.1 Hz, H-6), 4.69 (2H, s, OCH ₂ O), 4.95 ( _{2H, m, CH = CH 2} ), 5.06 (1H, m, H-7), 5.64 (1H, m, CH = CH 2), 7.60,7.63,8.00,8 21 (each 1H, m, arom-H).

  Compound 22 (133.5 mg, 0.233 mmol, 1.5 eq) cooled to −78 ° C. in anhydrous tetrahydrofuran (1.5 ml) was added to lithium bis (trimethylsilyl) amide (230 μl, 0.230 mmol, 1.0 M tetrahydrofuran solution, 1.5 eq) was added, and the mixture was stirred for 30 minutes, and then a solution of ketone body 9 (69.3 mg, 0.155 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. After stirring at −78 ° C. for 1 hour, the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (8 g) to obtain 26 (112.4 mg, 90%, approximately 5: 4 mixture) from 2% ethyl acetate / hexane eluate, 10% ethyl acetate / hexane eluate. 22 (26.1 mg) was recovered.

Compound 26: ¹ H NMR (CD ₃ OD) δ: 0.03-0.07 (12H, SiMe x 4), 0.12, 0.13 (9H, s, SiMe x 3), 0.54, 0 .55 (4: 5) (3H, s, H-18), 0.86, 0.89; 0.87, 0.88 (4: 5) (each 9 H, tBuSi x 2), 0.93 (3H, d, J = 6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.90 (1H, m, H-9), 3.37 (3H, s, OMe), 3.56 (1H , m, H-2), 3.80-3.94 (2H, m, H-1,3), 4.71 (2H, s, OCH 2 O), _{4.95 (2H, m, CH =} CH 2), 5.73 (1H, m, CH = CH 2), 5.81,5.84 (4: 5) (1H, d, J = 11.1Hz , H-7 ), 6.04, 6.07 (5: 4) (1H, d, J = 11.1 Hz, H-6).
Mass m / z (%): 804 (M ⁺ , 3), 742 (53), 672 (7), 610 (100), 569 (84).

  Compound 26 (107.4 mg, 0.133 mmol, about 5: 4 mixture) was dissolved in tetrahydrofuran / acetic acid / water (8: 8: 1, 8.5 ml) and stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (6 g) to obtain Compound 26 '(82.8 mg, 85%, approximately 5: 4 mixture) from a fraction eluted with 5% ethyl acetate / hexane.

Compound 26′a (major: 2α): ¹ H NMR (CDCl ₃ ) δ: 0.07 to 0.10 (12H, Si-Mex 4), 0.55 (3H, s, H-18), 0 .87, 0.89 (each 9H, s, Si-tBux 2), 0.93 (3H, d, J = 6.3 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.92 (1H, m, H-9), 3.37 (3H, s, OMe), 3.53 (1H, m, H-2), 3.91 (1H, m, H- _{3), 4.01 (1H, m} , H-1), 4.71 (2H, s, OCH 2 O), 4.95 (2H, m, CH = CH 2), 5.74 (1H, m , CH = CH ₂ ), 5.82 (1H, d, J = 11.2 Hz, H-7), 6.12 (1H, d, J = 11.2 Hz, H-6).
Compound 26′b (minor: 2β): ¹ H NMR (CDCl ₃ ) δ: 0.07 to 0.10 (12H, Si-Mex 4), 0.54 (3H, s, H-18), 0 .86, 0.90 (each 9H, s, Si-tBux 2), 0.93 (3H, d, J = 6.3 Hz, H-21), 1.22 (6H, s, H-26) 27), 2.92 (1H, m, H-9), 3.37 (3H, s, OMe), 3.58 (1H, m, H-2), 4.01 (2H, m, H) −1, 3), 4.71 (2H, s, OCH ₂ O), 4.95 (2H, m, CH═CH ₂ ), 5.74 (1H, m, CH═CH ₂ ), 5.82 (1H, d, J = 11.2 Hz, H-7), 6.15 (1H, d, J = 11.2 Hz, H-6).
Compound 26 ': Mass m / z (%): 732 (M ^<+> , 8), 670 (24), 613 (28), 538 (9), 481 (100).

  To a solution of oxalyl dichloride (10 μl, 0.119 mmol, 1.2 eq) in anhydrous methylene chloride (0.3 ml) cooled to −78 ° C., dimethyl sulfoxide (17 μl, 0.238 mmol, 2.4 eq) in anhydrous methylene chloride (0 .2 ml) solution was added and stirred for 10 minutes, followed by the addition of a solution of compound 26 ′ (72.5 mg, 0.099 mmol, about 5: 4) in anhydrous methylene chloride (1 ml). After stirring at −78 ° C. for 15 minutes, triethylamine (69 μl, 0.495 mmol, 5 eq) was added, and the mixture was stirred at −78 ° C. for 10 minutes and at 0 ° C. for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5 g), and Compound 26 ″ (71.6 mg, 99%) was obtained from the eluate of 3% ethyl acetate / hexane.

Compound 26 ″: ¹ H NMR (CDCl ₃ ) δ: 0.06, 0.07, 0.09 (3H, 6H, 3H, s, Si—Mex 4), 0.56 (3H, s, H— 18), 0.88, 0.90 (each 9H, s, Si-tBux 2), 0.95 (3H, d, J = 6.3 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.45 (1H, dd, J = 13.5, 8.4 Hz), 2.57 (1H, dd, J = 14.2, 4.1 Hz), 2.67 (2H , M), 2.95 (1H, m, H-9), 3.37 (3H, s, OMe), 4.38 (1H, dd, J = 6.6, 4.4 Hz), 4.52 (1H, dd, J = 8.4, 5.4 Hz), 4.71 (2H, s, OCH ₂ O), 4.95 (2H, m, CH = CH ₂ ), 5.74 (1H, m , C _{H = CH 2), 5.85 (} 1H, d, J = 11.0Hz, H-7), 6.33 (1H, d, J = 11.0Hz, H-6).
Mass m / z (%): 730 (no M ⁺ ), 673 (6), 611 (100), 479 (52).

  N-Butyllithium (115 μl, 0.184 mmol, 1.59 M hexane solution, 2 eq) was added to a solution of diethylcyanomethylphosphonate (30 μl, 0.184 mmol, 2 eq) in anhydrous tetrahydrofuran (0.5 ml) cooled to −40 ° C. After stirring for 15 minutes, a solution of compound 26 ″ (67.3 mg, 0.092 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. After stirring at −40 ° C. for 2 hours, saturated aqueous ammonium chloride solution was added to the reaction solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.The residue was purified by silica gel column chromatography (5 g) and purified with 3% ethyl acetate / hexane. Compound 27 (65.2 mg, 94%, approximately 1: 1 mixture) was obtained from the eluate.

Compound 27: ¹ H NMR (CDCl ₃ ) δ: 0.05-0.13 (12H, Si-Mex 4), 0.54, 0.56 (1: 1) (3H, s, H-18) , 0.83, 0.85 (1: 1) (9H, s, Si-tBu), 0.92, 0.93 (1: 1) (9H, s, tBu-Si, overlapped with H-21) , 1.22 (6H, s, H-26, 27), 2.91 (1H, m, H-9), 2.99, 3.14 (1: 1) (1H, m, H-10) _{, 3.37 (3H, s, OMe} ), 4.71 (2H, s, OCH 2 O), 4.49,4.57 (1: 1) (1H, m), 4.93-5.52 _{(3H, m, H-3or1} , CH = CH 2), 5.47,5.48 (1H, d, J = 3.6Hz, C = CH), 5.71 (1H, m, CH = _{H 2), 5.81,5.84 (1:} 1) (1H, d, J = 11.3Hz, H-7), 6.19,6.28 (1: 1) (1H, d, J = 11.3 Hz, H-6).
Mass m / z (%): 753 (M ⁺ , 2), 691 (24), 634 (90), 607 (58), 518 (57), 73 (100).

  Diisobutylaluminum hydride (124 μl, 0.124 mmol, 1.0 M toluene) was added to a solution of compound 27 (a mixture of 62.3 mg, 0.083 mmol, E: Z = 1: 1) in anhydrous toluene (1 ml) cooled to −78 ° C. Solution, 1.5 eq) was added. After 2 hours, the reaction solution was diluted with hexane, purified by silica gel column chromatography (5 g), and a mixture of compound 27 ′ (54.8 mg, 88%, about 1: 1) from a 5% ethyl acetate / hexane eluate. )

Compound 27 ′ (E form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.11 (12H, Si-Mex 4), 0.56 (3H, s, H-18), 0.85 , 0.93 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 2.92 (1H, m, H-9) , 3.09 (1H, m, H -10), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH 2 O), 4.59 (1H, m, H-1) _{, 5.00 (2H, m, CH} = CH 2), 5.47 (1H, m, H-3), 5.71 (1H, m, CH = CH 2), 5.82 (1H, d, J = 11.3 Hz, H-7), 6.16 (1H, m, C = CH), 6.19 (1H, d, J = 11.3 Hz, H-6), 10.1. (1H, d, J = 7.9Hz, CHO).
Compound 27 ′ (Z form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.11 (12H, Si-Mex 4), 0.55 (3H, s, H-18), 0.84 , 0.93 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 2.92 (1H, m, H-9) , 3.00 (1H, m, H -10), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH 2 O), 4.68 (1H, m, H-3) _{, 5.00 (2H, m, CH} = CH 2), 5.52 (1H, m, H-1), 5.71 (1H, m, CH = CH 2), 5.88 (1H, d, J = 11.3 Hz, H-7), 6.16 (1H, m, C = CH), 6.27 (1H, d, J = 11.3 Hz, H-6), 10.1. (1H, d, J = 7.9Hz, CHO).

  Sodium borohydride (2.5 mg, 0.066 mmol, 1 eq) was added to an ethanol (1 ml) solution of aldehyde 27 ′ (50.3 mg, 0.066 mmol, approximately 1: 1 mixture) cooled to 0 ° C., Stir for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 27 ″ (42.0 mg, 83%, approximately 1: 1 mixture) from a fraction eluted with 5% ethyl acetate / hexane.

Compound 27 ″ (E form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.10 (12H, Si-Me x 4), 0.552 (3H, s, H-18), 0.84 , 0.91 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 3.37 (3H, s, OMe), 4 .71 (2H, s, OCH ₂ O), 4.20, 4.30 (2H, m, CH ₂ OH), 4.38 (1H, m, H-1), 4.81 (1H, m, _{H-3), 4.96 (2H} , m, CH = CH 2), 5.72 (2H, m, CH = CH 2, C = CH), 5.88 (1H, d, J = 11.0Hz , H-7), 6.13 (1H, d, J = 11.0 Hz, H-6).
Compound 27 ″ (Z form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.10 (12H, Si-Me x 4), 0.547 (3H, s, H-18), 0.83 , 0.92 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 3.37 (3H, s, OMe), 4 .71 (2H, s, OCH ₂ O), 4.20, 4.30 (2H, m, CH ₂ OH), 4.46 (1H, m, H-3), 4.84 (1H, m, _{H-1), 4.96 (2H} , m, CH = CH 2), 5.72 (2H, m, CH = CH 2, C = CH), 5.83 (1H, d, J = 11.0Hz , H-7), 6.22 (1H, d, J = 11.0 Hz, H-6).

Camphorsulfonic acid (77.0 mg, 0.332 mmol, 6 eq) was added to a solution of compound 27 ″ (42.0 mg, 0.055 mmol, approximately 1: 1 mixture) in methanol (1 ml) and stirred at room temperature for 1.5 hours. To the reaction solution was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The compound 3b (24.2 mg, 90%, about 1: 1 mixture) was obtained from the eluate of 2% methanol / ethyl acetate, and the compound 3b was further purified by HPLC [YMC-Pack ODS-AM SH- 342-5, 20% H ₂ O / MeOH, 8 ml / min] to obtain compound 3b (E form) (8.4 mg) and compound 3b (Z Body) (4.8 mg).

Compound 3b (E form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.10 (12H, Si-Me x 4), 0.54 (3H, s, H-18), 0.84 0.91 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 1.63 (3H, d, J = 5.5 Hz) , CH ₃ CH═CH), 2.29 (2H, m, H-4), 2.80 (1H, m, H-9), 2.89 (1H, m, H-10), 3.37. _{(3H, s, OMe),} 4.71 (2H, s, OCH 2 O), 4.20,4.29 (2H, m, CH 2 OH), 4.30 (1H, m, H-1) , 4.81 (1H, m, H-3), 5.37 (2H, m, CH = CH), 5.70 (1H, m, C = CH), 5.84 (1 , D, J = 11.1Hz, H-7), 6.13 (1H, d, J = 11.1Hz, H-6).
UV λmax (EtOH): 247 nm (ε = 30800), 255 nm (ε = 34500), 264 nm (ε = 22400).
Compound 3b (Z-form): ¹ H NMR (CDCl ₃ ) δ: 0.01-0.10 (12H, Si-Mex 4), 0.53 (3H, s, H-18), 0.82, 0.92 (each 9H, s, Si-tBux 2, overlapped with H-21), 1.22 (6H, s, H-26, 27), 1.62 (3H, d, J = 5.5 Hz) , CH ₃ CH = CH), 2.55 (1H, dd, J = 12.5, 5.0 Hz, H-4), 2.83 (2H, m, H-9, 10), 3.37 ( _{3H, s, OMe), 4.71} (2H, s, OCH 2 O), 4.20,4.29 (2H, m, CH 2 OH), 4.47 (1H, m, H-3), 4.84 (1H, m, H-1), 5.37 (2H, m, CH = CH), 5.70 (1H, m, C = CH), 5.80 ( H, d, J = 11.1Hz, H-7), 6.20 (1H, d, J = 11.1Hz, H-6).
UV λmax (EtOH): 247 nm, 255 nm, 264 nm.

  Compound 22 (158.0 mg, 0.269 mmol) cooled to −78 ° C. in anhydrous tetrahydrofuran (1.5 ml) was added to lithium bis (trimethylsilyl) amide (230 μl, 0.230 mmol, 1.0 M tetrahydrofuran solution, compound 22 1.0 eq) was added and stirred for 30 minutes, and then a solution of ketone body 49 (69.3 mg, 0.155 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. After stirring at −78 ° C. for 1 hour, the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (10 g) to obtain Compound 50 (112.4 mg, 57%, E: Z = 5: 3) from the eluate of 3% ethyl acetate / hexane, and 10% ethyl acetate / hexane. Compound 22 (64.8 mg, 41%) was recovered from the eluate.

Compound 50a (E-form): ¹ H-NMR (CDCl ₃ ) δ: 0.05 to 0.09 (18H, Si-Mex 6), 0.56 (3H, s, H-18), 0.82 ~0.94 (30H, Si-tBu x 3, H-21), 1.22 (6H, s, H-26,27), 3.37 (3H, s, OCH 3), 4.25~4 _{.45 (3H, m, H-} 1, CH 2 OTBS), 4.71 (2H, s, OCH 2 O), 4.78 (1H, m, H-3), 4.97 (2H, m, _{CH = CH 2), 5.61 (} 1H, m, C = CH), 5.72 (1H, m, CH = CH 2), 5.89 (1H, d, J = 11.1Hz, H-7 ), 6.12 (1H, d, J = 11.1 Hz, H-6).
Compound 50b (Z-form): ¹ H-NMR (CDCl ₃ ) δ: 0.05 to 0.09 (18H, Si-Mex 6), 0.54 (3H, s, H-18), 0.82 ~0.94 (30H, Si-tBu x 3, H-21), 1.22 (6H, s, H-26,27), 3.37 (3H, s, OCH 3), 4.25~4 _{.45 (3H, m, H-} 3, CH 2 OTBS), 4.71 (2H, s, OCH 2 O), 4.78 (1H, m, H-1), 4.97 (2H, m, _{CH = CH 2), 5.61 (} 1H, m, C = CH), 5.72 (1H, m, CH = CH 2), 5.83 (1H, d, J = 10.4Hz, H-7 ), 6.22 (1H, d, J = 10.4 Hz, H-6).
Mass m / z (%): 872 (M ⁺ , 3), 740 (68), 678 (100), 621 (8).

  To a solution of 19-nor 50 (57.7 mg, 0.0661 mmol) in anhydrous tetrahydrofuran (300 μl) was added 9-borobicyclo- [3.3.1] nonane (1.32 ml, 0.661 mmol, 10.0 eq), Stir at room temperature for 1.5 hours. Methanol (220 μl) was added to the reaction solution to stop the reaction and stirred for 15 minutes. Next, this solution was cooled to 0 ° C., 6M sodium hydroxide (220.2 μl, 1.32 mmol, 20.0 eq) and 30% aqueous hydrogen peroxide (220 μl) were added, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (10 g) to obtain Compound 51a (E-form, 13.1 mg, 22%) from the elution portion of 8% ethyl acetate / hexane, Compound 51b from the elution portion of 10% ethyl acetate / hexane. (Z-form, 11.1 mg, 19%) was obtained.

Compound 51a: ¹ H-NMR (CDCl ₃ ) δ: 0.05 to 0.08 (18H, Si-Mex 6), 0.55 (3H, s, H-18), 0.83, 0.89 , 0.93 (each 9H, s, Si-tBux 3, overlapped with H-21), 1.22 (6H, s, H-26, 27), 2.86 (1H, m, H-9) , 3.00 (1H, dd, J = 12.7,4.7Hz, H-10), 3.37 (3H, s, OCH 3), 3.61 (2H, m, CH 2 OH), 4 _{.25~4.38 (3H, m, H-} 1, CH 2 OTBS), 4.71 (2H, s, OCH 2 O), 4.78 (1H, m, H-3), 5.61 ( 1H, m, C = CH), 5.93 (1H, d, J = 11.1 Hz, H-7), 6.11 (1H, d, J = 11.1) z, H-6).
Mass m / z (%): 890 (M ⁺ , 2), 828 (5), 758 (52), 696 (100), 626 (10), 75 (93).
Compound 51b: ¹ H-NMR (CDCl ₃ ) δ: 0.06-0.09 (18H, Si-Mex 6), 0.54 (3H, s, H-18), 0.82, 0.90 , 0.93 (each 9H, s, Si-tBux 3, overlapped with H-21), 1.22 (6H, s, H-26, 27), 3.37 (3H, s, OCH ₃ ), _{3.61 (2H, m, CH 2} OH), 4.30 (2H, m, CH 2 OTBS), 4.44 (1H, m, H-3), 4.71 (2H, s, OCH 2 O ), 4.83 (1H, m, H-1), 5.61 (1H, m, C = CH), 5.87 (1H, d, J = 10.4 Hz, H-7), 6.22 (1H, d, J = 10.4 Hz, H-6).
Mass m / z (%): 890 (M ⁺ , 1), 828 (1), 758 (20), 696 (22), 626 (4), 75 (100).

  Camphorsulfonic acid (34.1 mg, 0.147 mmol, 10.0 eq) was added to a solution of 19-nor 51a (E-form, 13.1 mg, 0.0147 mmol) in methanol (300 μl), and the mixture was stirred at room temperature for 2 hours. . 5% Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain compound 3d (5.7 mg, 77%) from a 5% methanol / ethyl acetate eluate.

Compound 3d: ¹ H-NMR (CDCl ₃ ) δ: 0.56 (3H, s, H-18), 0.94 (3H, d, J = 6.0 Hz, H-21), 1.22 (6H , S, H-26, 27), 2.17 (1H, t, J = 8.7 Hz), 2.29, 2.41 (each 1H, m, H-4), 2.89 (1H, m , H-9), 3.16 ( 1H, m, H-10), 3.48,3.60 (each 1H, m, CH 2 CH 2 OH), 4.09 (1H, m, CH 2 OH _{), 4.31 (3H, m,} H-1, CH 2 OH, OH), 4.40 (1H, br.s, OH), 4.80 (1H, m, H-3), 5.74 (1H, m, C = CH), 5.97 (1H, d, J = 10.6 Hz, H-7), 6.11 (1H, d, J = 10.6 Hz, H-6).
Mass m / z (%): 504 (M ⁺ , 1), 486 (10), 468 (34), 450 (57), 432 (24), 386 (100), 339 (14).
UV λmax (EtOH): 246 nm, 254 nm, 264 nm.

[Evaluation of transcription activation ability]
Evaluation was performed using E-form (3b-2E) of 9-allyl derivative (3b) and 1,25- (OH) ₂ D ₃ which is a natural ligand as a comparative example. The measurement was performed in COS-7 cells using a luciferase reporter gene incorporating W286R VDR prepared by site-directed mutagenesis with 9-substituted analogs, and the transcription activation ability of each ligand was measured. The results are shown in FIG.

1,25- (OH) ₂ D ₃ showed no activity even at a concentration of 1 μM, but the E-form (3b-2E) of the 9-allyl derivative (3b) was weak, but induced transcription of mutant VDR. Confirmed to do.

Claims (8)

A 9-substituted-19-norvitamin D derivative represented by the following general formula (1).

(However, R ¹ represents an alkyl group, an alkenyl group, or a hydroxyalkyl group, and R ² represents hydrogen or a hydroxyalkylidene group bonded through a double bond.) The 9-substituted-19-nor according to claim 1, wherein R ¹ in the general formula (1) is a methyl group, a butyl group, a hydroxypropyl group, an allyl group, or a trans-CH ₂ CH = CHCH ₃ group. Vitamin D derivative. The 9-substituted-19-norvitamin D derivative according to claim 1 or 2, wherein R ² in the general formula (1) is a hydroxyethylidene group. The 9-substituted-19-norvitamin D derivative according to any one of claims 1 to 3, represented by the following structural formula (3b).

  A therapeutic agent for a disease related to vitamin D receptor mutation, comprising the 9-substituted-norvitamin D derivative according to any one of claims 1 to 4 as an active ingredient.   The therapeutic agent according to claim 5, wherein the vitamin D receptor mutation is one in which 286th tryptophan of the vitamin D receptor is substituted with arginine.   The therapeutic agent according to claim 5 or 6, wherein the related disease is type II rickets.   The therapeutic agent according to claim 5 or 6, wherein the related disease is osteomalacia.

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