WO2006093290A1

WO2006093290A1 - 9-substituted-19-norvitamin d derivative

Info

Publication number: WO2006093290A1
Application number: PCT/JP2006/304149
Authority: WO
Inventors: Masato Shimizu
Original assignee: Tokyo Medical And Dental University
Priority date: 2005-03-04
Filing date: 2006-03-03
Publication date: 2006-09-08
Also published as: JPWO2006093290A1; JP4887503B2

Abstract

A vitamin D derivative having a transcription activating capability which can activate the function of a mutated vitamin D receptor (W286R VDR), a process for producing the vitamin D derivative, and a pharmaceutical agent comprising the vitamin D derivative. The vitamin D derivative has a substituent at position 9 and therefore can fit into a binding pocket of a mutated vitamin D receptor. The substituent at position 9 is preferably an allyl group. The most preferred example of the vitamin D derivative is a 2-hydroxyethylidene-9-allyl-19-norvitamin D derivative having a hydroxyl ethylidene group at position 2. Since this derivative has an improved transcription activating capability, it can be used as an therapeutic agent, for example, for rachitis or osteomalacia.

Description

9-substituted one 19 one norvitamin D derivative

Technical field

[0001] The present invention relates to a 9-substituted 19-nor vitamin D derivative effective for congenital vitamin dependence type II rickets.

Background art

[0002] Active vitamin D derivatives are widely used clinically as therapeutic agents for bone diseases such as osteomalacia, osteoporosis, and rickets. In addition, vitamin D suppresses cell growth and induces differentiation and immune regulation, and is widely used as a specific drug for psoriasis of the skin, and is also being developed as a cancer therapeutic and immunomodulator.

[0003] In this regard, Patent Document 1 shown below has a substituent at the 2a position represented by the following general formula (a), and the hydroxyl groups at the 1 and 3 positions are the a configuration and j8, respectively. An arrangement, a vitamin D derivative, is disclosed. This vitamin D derivative can be used as a medicine, for example, for the purpose of a therapeutic agent, an antitumor agent or an immunomodulator for a disease associated with abnormal calcium metabolism.

[0004] [Chemical 1]

[0005] (However, R ³ and R ⁴ may be substituted with a hydroxy group and may be a linear or branched lower alkyl group.)

[0006] Patent Literature l: WO0lZ062723 Disclosure of the invention

Problems to be solved by the invention

[0007] However, type II rickets (HVDRR), an autosomal recessive inheritance resistant to active vitamin D derivatives, is caused by mutations in the vitamin D receptor (VDR). The VDR (W286R VDR) in which the 286th tryptophan (W) of VDR is mutated to an anoregine (R) 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.

[0008] [Chemical 2]

[0009] The present invention has been made in view of the problems as described above, and has transcriptional activity that activates the function of a mutant vitamin D receptor, and is a congenital vitamin dependence. The present invention provides a 9-substituted 19-norvitamin D derivative, a method for producing the same, and a pharmaceutical composition containing them.

Means for solving the problem

[0010] As a result of diligent studies to solve the above-mentioned problems, the present inventor has 9 substituted 19 norvitamin D derivative power represented by the following general formula (1): transcriptional activation for a mutant vitamin D receptor As a result, the present invention has been completed.

[0011] That is, the compound of the present invention is a 9-substituted 19 norbitamine D derivative represented by the following general formula (1).

[0012] [Chemical 3]

(Where 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.)

[0014] In the present invention, a 9-substituted 19 norbitamine D derivative represented by the following general formulas (2) and (3) is preferable.

[0015] [Chemical 4]

[0016] [Chemical 5]

(Where R ¹ is a butyl group, a hydroxypropyl group, an aryl group, or trans-CH 2 CH =

2

Represents CHCH. )

Three

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

[0019] [Chemical 6]

[0020] 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 the mutant VDR (W286R VDR). This is because the mutant VDR has a larger ligand-binding pocket than the wild-type VDR. For this reason, a natural ligand creates a space at a large site, but according to the compound of the present invention, the 9-position substituent is compatible with this space, so that the mutant VDR can be compared. Can also show transcription activation ability.

[0021] The 9-substituted 19 norvitamin D derivative represented by the above general formula (2) comprises a ring A ketone body and a CZD ring phosphine oxide body having a substituent at the 9-position, Wittig-Horner coupling. Can be synthesized by the method. The 9-substituted 19-norvitamin D derivative represented by the above general formula (3) is synthesized by a Julia coupling method by synthesizing A ring ketone body and CZD ring arylsulfone body having a substituent at the 9-position. can do.

[0022] The compound of the present invention can be used as a therapeutic agent for rickets or osteomalacia.

The invention's effect

[0023] According to the compound of the present invention, it is possible to provide a 9-substituted vitamin D derivative effective for congenital vitamin dependence type II rickets, a production method thereof and a pharmaceutical composition containing them. wear.

Brief Description of Drawings

[0024] FIG. 1 shows the transcriptional activity of 9-aryl derivatives (3b) and natural ligands.

BEST MODE FOR CARRYING OUT THE INVENTION

[0025] The 9-substituted 19-norvitamin D derivative represented by the above general formula (2) comprises a ring A ketone and a CZD ring phosphine oxide having a substituent at the 9-position by the Wittig-Horner coupling method. Can be synthesized. In addition, the 9-substituted 19-norvitamin D derivative represented by the above general formula (3) comprises a ring A ketone and a CZD ring arylsulfone having a substituent at the 9-position by the Julia coupling method. Can be synthesized.

[0026] Hereinafter, the production method of the 9-substituted 19-norvitamin D derivatives represented by the general formulas (2) and (3) will be specifically described.

[0027] <Method of synthesizing A ring ketone body>

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

[0028] [Chemical 7]

D- (-) -quinic acid

Five

[0029] <Method for synthesizing CZD ring synthon>

CZD ring phosphinoxide represented by structural formulas (15) and (20) starts from vitamin D

3 As a raw material, the CZD ring aryl sulfone represented by structural formulas (22) and (23) can be synthesized in 7 steps by 6 steps.

[0030] The compound (10) is obtained by a known method using vitamin D as a starting material. 9 Butyl

Three

The 8-keto body (11) is synthesized by converting the compound (10) into a silyl enol ether body under kinetic conditions, followed by treatment with butyl iodide. 9 Burylmagnesium bromide is attached to the butyl-8-keto body (11), which leads to the tertiary alcohol body (12), followed by PCC oxidation to obtain the allylaldehyde body (13). Reduction with NaBH

Four

After obtaining the ru form (14), tosylation, diphenylphosphination and oxidation reaction are performed at once to obtain the phosphine oxide form (15). Similarly, 9 aryl-phosphine oxide (20) can be obtained.

[0031] The arylsulfone form is obtained by carrying out the benzothiazole salt of the aryl alcohol forms (19) and (21), followed by an oxidation reaction to obtain the arylsulfone forms (22) and (23). be able to.

[0032] [Chemical 8]

"3"% (£ C5 (.¾3 ().

(/.IO (% 〇 IO (%) 3)) ω 卜 22 ""

(.

(% Ϋ s =

[0033] <Method for synthesizing 9-substituted 19-norvitamin D derivatives> 9-substituted 19-norvitamin D derivatives were synthesized by first reacting CZD-ring phosphine oxides (15) and (20) with A-ring ketone (8). (24) and (25) are obtained. Further, the protecting group is removed with camphorsulfonic acid (CSA) to obtain 9-butyl (2a) and 9-aryl (2b). The 9 α-hydroxybutyl compound (2d) is obtained by hydroborating the intermediate (25) with 9%, treating with alkaline hydrogen peroxide and deprotecting.

[0034] As the hydroxyethylidene derivative (3), first, a compound (26) is synthesized by a julia coupling method of a CZD ring aryl sulfone body (22) and a ring-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 cyanomylation with jetylcyanomethyl phosphonate to obtain the compound (27). The cyanide is converted to the aryl alcohol by -step reduction, and further deprotected with CSA to give the 9-aryl (3b). A 9-butylene compound (3c) is also obtained by the same method.

[0035] [Chemical 9]

2a: R = (CH ₂ ) ₃ CH ₃ (96%)

2b: R = CH ₂ CH = CH ₂ (90%)

2d: R = (CH ₂ ) ₃ OH (59%, 3 steps)

[0036] [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”).

[0037] <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 formulated with necessary additives and solid oral preparations, oral liquid preparations, or injections according to conventional methods. It can be prepared as a parenteral preparation such as an agent. Most preferred is a solid oral formulation.

[0038] When a solid oral preparation is prepared, after adding an excipient such as lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, etc., tablets, granules, powders, capsules, etc. can do. In addition to excipients, binders such as hydroxypropyl cellulose and hydroxypropyl methylcellulose (HPMC), lubricants such as magnesium stearate, polyethylene glycol, starch, and talc, calcium fibroglycolate, and carme as necessary. Mix and adjust disintegrants such as roast calcium, stabilizers such as ratatose, solubilizing agents such as dartamic acid or aspartic acid, plasticizers such as polyethylene glycol, and colorants such as titanium oxide, talc, and yellow iron oxide. can do. 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.

[0039] When preparing oral liquid preparations, inert diluent taste-masking agents such as purified water and ethanol

In addition, buffering agents, stabilizers, flavoring agents, and the like can be added to obtain internal liquids, syrups, jelly agents, elixirs, and the like.

[0040] 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 aqueous solution and suspension diluent include distilled water for injection and physiological saline. Examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and the like. In addition, if necessary, pH adjusters, buffers, preservatives, wetting agents, emulsifiers, dispersants, stabilizers ( For example, latatoses), isotonic agents, local anesthetics, solubilizing agents (eg, glutamic acid, aspartic acid), etc. may be added.

[0041] <Effective dose>

The effective dose of the 9-substituted 19-norvitamin D derivative of the present invention varies depending on the patient's body weight, age, sex, administration method, physical condition, symptoms, dosage form, etc. It is preferably not less than μg and not more than 50 μg, more preferably not less than 0.01 μg and not more than 10 μg, and is preferably taken once or divided into two to several times.

Example

[0042] <Synthesis of 9-methyl-19 norvitamin D derivative>

It was synthesized by the following procedure.

[0043] [Chemical 10]

Vitamin D

[0044] —In a solution of vitamin D (10. Og, 0.026 mol) in methanol (200 ml) cooled to 78 ° C

Three

Ozone gas was introduced 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 Z-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 Z-hexane) to obtain Compound 30 (6.8 g) quantitatively.

[0045] The compound SO: ¹ !! NMR (CDC1) δ: 0. 64 (3Η, s, H—18), 0. 868, 0. 871 (ea

Three

ch 3H, d, J = 6.6 Hz, H— 26, 27), 0. 95 (3H, d, J = 6.2 Hz, H— 21), 2.4 5 (1H, dd, J = l l. 6, 7. 3Hz, H-14).

[0046] [Chemical 11]

[0047] Compound 30 (6.8 g, 0.0257 mol) was added and dissolved in the order of carbon tetrachloride, acetonitrile, pH 7 phosphate buffer (105 ml, 105 ml, 126 ml), and then ruthenium chloride monohydrate (Ru C1 · Η 0, 533.9 mg, 2. 57 mmol) and sodium periodate (19.2 g, 0.090 mol)

3 2

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 Z-hexane) to obtain Compound 31 (2. 96 g, 41%).

[0048] Compound SI: ¹ !! NMR (CDCl) δ: 0. 64 (3 (, s, H— 18), 0.97 (3H, d, J = 6

Three

1Hz, H- 21), 1. 22 (6H, s, H- 26, 27), 2. 45 (1H, dd, J = l l. 6, 7.5 Hz, H- 14).

[0049] [Chemical 12]

[0050] Compound 31 (2. 7 g, 9. 62 mmol) cooled to 20 ° C was dissolved in anhydrous methylene chloride (35 ml) in diisopropylamine (5.03 ml, 0.0289 mol) and chloromethyl methyl ether (1. 46 ml, 0. 0192 mol). 1 hour at C, 0. The mixture was stirred at C for 6.5 hours. On the way, 6 hours later, diisopropylamine (2.51 ml, 0.0145 mol) and chloromethyl methyl ether (730 1, 9.62 mmol) were added. 7. After 5 hours, 1N hydrochloric acid was added to the reaction solution and extracted with methylene chloride. Organic layer with 5% sodium bicarbonate and saturated sodium chloride After washing with water, magnesium sulfate was dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (80 g, 10% ethyl acetate Z-hexane) to give compound 10 (2. 65 g, 8

5%) was obtained.

[0051] Compound lO ^ H NMR (CDCl) δ: 0. 64 (3Η, s, H— 18), 0.9.5 (3H, d, J = 6

Three

1Hz, H- 21), 1. 22 (6H, s, H— 26, 27), 2. 45 (1H, dd, J = l l. 6, 7.5 Hz, H- 14), 3. 37 (3H, s, OMe), 4.70 (2H, s, OCH O).

2

[0052] [Chemical 13]

[0053] n-Butyllithium (2.32 ml, 3.67 mmol, 1.58 M hexane solution) was added to a solution of diisopropylamine (594 μ 1, 4. 24 mmol) in anhydrous tetrahydrofuran (10 ml) cooled to 20 ° C. The mixture was further stirred for 15 minutes. Lithium diisopropylamide (LDA) was cooled to −78 ° C., and a solution of compound 10 (917. Omg, 2.83 mmol) in anhydrous tetrahydrofuran (10 ml) was charged. After stirring for 20 minutes, a supernatant of a mixed solution of chlorotrimethylsilane (717 1, 5.65 mmol) and triethylamine (788 1, 5.65 mmol) was prepared. The temperature was gradually raised, and the mixture was stirred for 1.5 hours until it reached 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).

[0054] 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 jetyl ether solution). And stirred at room temperature for 1.5 hours. In a separate container, a solution of methyl iodide (351 1, 5.64 mmol) in anhydrous tetrahydrofuran (10 ml) was prepared. After cooling to −78 ° C., the above lithium enolate was slowly added. The temperature at 78 ° C was gradually raised and stirred for 2.5 hours until it reached 0 ° C. 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 33 (70.2 mg, 81%) from the eluate of 5% ethyl acetate Z-hexane. [0055] Compound 32: H NMR (CDC1) δ: 0.17 (9H, s, SiMe x 3), 0.73 (3H, s,

Three

H-18), 0.94 (3H, d, J = 6.5Hz, H- 21), 1.21 (6H, s, H- 26, 27), 3.3 7 (3H, s, OMe), 4.62 (1H, m, H-9), 4.71 (2H, s, OCH O).

2

Compound 33: 11 NMR (CDCl) δ: 0.65 (3H, s, H-18), 0.95 (3H, d, J = 6

Three

.2Hz, H-21), 1.18 (3H, d, J = 7.4Hz, Me), 1.22 (6H, s, H— 26, 27), 2.45 (1H, m, H—9), 2.66 (1H, dd, J = ll.5, 7.4Hz, H-14), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O).

2

Mass m / z (%): 338 (M +, 1), 323 (9), 276 (82), 261 (24), 235 (50), 2 19 (37), 191 (21), 163 (38 ), 103 (100).

[0056] [Chemical 14]

[0057] Buresumagnesium bromide (3.37 ml, 3.37 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of the compound 33 (761.4 mg, 2.25 mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (8 ml). 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) to obtain Compound 34 (766.6 mg, 93%) from the eluate of 5% ethyl acetate Z hexane.

[0058] Compound NMR (CDCl) δ: 0.91 (3Η, d, J = 6.5Hz, H-21), 0.95 (3

Three

H, s, H-18), 0.97 (3H, d, J = 7.3Hz, 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, 1.5H z, H-6), 5.22 (1H, dd, J = 17.2, 1.5Hz, H-6), 5.90 (1H, dd , J = 17.2, 10.8Hz, H-7).

Mass m / z (%): 366 (no M ⁺ ), 304 (57), 286 (49), 271 (23), 247 (92), 191 (49), 175 (100)

[0059] [Chemical 15]

[0060] To a solution of Compound 34 (704.7 mg, 1.92 mmol) in anhydrous methylene chloride (20 ml) was added pyridi-mukuroguchi chromate (PCC, 1.48 g, 6.73 mmol) and Celite (1. Og), and the room temperature was increased. For 23 hours. The reaction solution was purified by silica gel column chromatography (35 g) to obtain Compound 35 (567.4 mg, 81%) from the eluate of 5% ethyl acetate Z-hexane.

[0061] Compound: ¹ !! NMR (CDCl) δ: 0.60 (3Η, s, H—18), 0.95 (3H, d, J = 5

Three

.7Hz, H-21), 1.22 (6H, s, H— 26, 27), 1.24 (3H, d, J = 7.2Hz, Me), 2.44 (1H, m, H— 14), 3.66 (1H, m, H—9), 3.37 (3H, s, OMe), 4.71 (2 H, s, OCH O), 5.67 (1H, dd, J = 8.3, 1.5Hz, H—7), 10.09 (1H, d , J = 8

2

.2Hz, CHO)

[0062] [Chemical 16]

[0063] Sodium borohydride (57.8 mg, 1.53 mmol) was added to a solution of aldehyde compound 35 (557. Omg, 1.53 mmol) cooled to 0 ° C in ethanol (10 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 the solvent was distilled off. The residue was purified by silica gel column chromatography (20 g) to obtain Compound 36 (473.8 mg, 85%) from the eluate of 15% ethyl acetate Z-hexane.

[0064] Compound Βδ ^ Η NMR (CDCl) δ: 0.55 (3Η, s, H—18), 0.95 (3H, d, J = 6

Three

.4Hz, H-21), 1.06 (3H, d, J = 7.2Hz, 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 (2 H, m, H-6), 4.71 (2H, s, OCH O), 5. 16 (1H, dt, J = 6.9, 1.8Hz, H—

2

7).

Mass m / z (%): 366 (no M +), 304 (18), 286 (50), 271 (20), 243 (8), 2 17 (13), 191 (29), 175 (100).

[0065] [Chemical 17]

[0066] n-Butyllithium (970 1, 1.53 mmol, 1.58M hexane solution) and tosyl chloride (318.7 mg) in a solution of compound 36 (510.8 mg, 1.39 mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (6 ml) , 1.67 mmol) in anhydrous tetrahydrofuran (lml) was stirred and stirred for 5 minutes. Make a solution of diphenylphosphine (485 1, 2.79 mmol) in anhydrous tetrahydrofuran (3 ml) in another container, cool to 0 ° C, and then add n-butyllithium (1.76 ml, 2.79 mmol, 1.58M hexane solution) ) (It becomes dark red)

[0067] At 0 ° C, the phosphine solution was slowly added to the tosyl body until the red color disappeared, and the mixture was stirred for 30 minutes, water (50 µ1) 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 solution (9 ml) was added, and the mixture was stirred at 0 ° C. for 1 hr. To the reaction solution was added 2N aqueous sodium thiosulfate solution, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (30 g) to obtain Compound 37 (670.5 mg, 88%) from the eluate of 40% ethyl acetate Z hexane.

[0068] Compound: ¹ !! NMR (CDCl) δ: 0.27 (3Η, s, H—18), 0.88 (3H, d, J = 6

Three

.4Hz, H-21), 0.91 (3H, d, J = 7.2Hz, 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 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), 20 2 (100).

[0069] [Chemical 18]

[0070] _n -Butyllithium (104 1, 0.165 mmol, 1.58M hexane solution) was added to a solution of phosphine oxide 37 (90.6 mg, 0.165 mmol) in anhydrous tetrahydrofuran (lml) cooled to 78 ° C. After stirring for 15 minutes, a solution of ketone body 8 (29.6 mg, 0.083 mmol) in anhydrous tetrahydrofuran (lml) 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 solution of ammonium chloride was added to the reaction 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. The residue was purified by silica gel column chromatography (8 g). Compound 38 (8.3 mg, 15%) was eluted from 2% ethyl acetate Z hexane eluate, and adduct 39 (8.3 mg, 15%) was eluted from 25% ethyl acetate Z hexane eluate. About 3: 1 mixture, 13.7 mg, 16%) was obtained, and phosphine oxide 37 (61.3 mg) was recovered from the eluate of 40% ethyl acetate Z-hexane.

[0071] 匕 Compound Βδ ^ Η NMR (CD OD) δ: 0.046, 0.13 (each 6Η, s, SiMe x 4)

Three

, 0.53 (3H, s, H-18), 0.87, 0.90 (each 9H, s, tBuSix 2), 0.93 (3H, d, J = 6.4Hz, 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 O), 5.77 (1H, d, J = ll.3Hz, H-7), 6.16 (1H, d, J = ll.3

2

Hz, H-6).

Compound 39: 丄 11 NMR (CD OD) δ: — 0.08, —0.04, —0.01, 0.03; — 0.0

Three

7, 0.00, 0.009, 0.0014 (3: 1) (each 3H, s, SiMe x 4), 0.44, 1.04 (3: 1) (3H, d, J = 7.1Hz, 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 = 6.4Hz, H-21), 1.2 0, 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, OCH O), 5.06, 5.15 (1: 3) (1H, m, H-7).

2

[Chemical 19]

[0073] Camphorsulfonic acid (46.3 mg, 0.200 mmol) was stirred in a methanol (lml) solution of Compound 38 (23. Omg, 0.033 mmol) for 1.5 hours at room temperature. 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 the 70% ethyl acetate / hexane eluate.

[0074] Compound Se: ¹ !! NMR (CDC1) δ: 0.54 (3Η, s, H—18), 0.94 (3H, d, J = 6.

Three

3Hz, H-21), 1.06 (3H, d, J = 7.2Hz, Me), 1.22 (6H, s, H-26, 27), 2.49 (1H, dd, J = 13.3, 3.3Hz, H — 4), 2.68 (1H, dd, J = 13.3, 3.6Hz, H -10), 3.05 (1H, m, H—9), 4.07 (2H, m, H— 1, 3), 5.80 (1H, d, J = ll .2Hz, H-7), 6.31 (1H, d, J = ll.2Hz, H-6).

UV λ max (EtOH): 244nm (ε = 27600), 252nm (ε = 31500), 261nm (ε = 21000).

Mass m / z (%): 418 (M ⁺ , 35), 400 (100), 382 (20), 357 (11), 289 (35), 271 (24), 253 (18), 194 (42) .

[0075] <Synthesis of 9-Butyl-19 Norvitamin D Derivatives>

It was synthesized by the following procedure. [0076] [Chemical 20]

[0077] To a solution of Compound 32 (500.5 mg, 1.262 mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (3 ml) was added methyllithium (1.16 ml, 1.388 mmol, 1.2 M solution of jetyl ether), Stir at room temperature for 1 hour. In a separate container, make a solution of 1-odobutane (718 1, 6.310 mmol) and hexamethylphosphorustriamide (HMPA, 439 1, 2.524 mmol) in anhydrous tetrahydrofuran (2 ml), cool to 0 ° C, Of lithium enolate was slowly added. The mixture was stirred at 0 ° C for 3 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride and 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 the eluate of 5% ethyl acetate Z-hexane.

[0078] Compound AO: ¹ !! NMR (CDCl) δ: 0.64 (3Η, s, H—18), 0.87 (3H, t, J = 7.

Three

1Hz, (CH) CH), 0.95 (3H, d, J = 6.1Hz, H— 21), 1.21 (6H, s, H— 26

2 3 3

, 27), 2.02 (1H, m, H—9), 2.60 (1H, dd, J = ll.6, 7.4Hz, H—14), 3.37 (3H, s, OMe), 4.70 (2H, s, OCH O).

2

Mass m / z (%): 380 (M +, 2), 365 (7), 318 (45), 227 (24), 262 (100), 219 (20), 103 (41).

[0079] [Chemical 21]

[0080] To a solution of Compound 40 (250. lmg, 0.830mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (3ml), burmagnesium bromide (1.66ml, 1.662mmol, 1. OM tetrahydrofuran solution) was added. 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 removed. The residue was purified by silica gel column chromatography (12 g) to obtain Compound 41 (297.5 mg, 88%) from a fraction eluted with 5% ethyl acetate Z hexane.

[0081] Compound l: ¹ !! NMR (CDC1) δ: 0.88 (3Η, t, J = 7.1 Hz, (CH) CH), 0.

3 2 3 3

91 (3H, d, J = 6.5Hz, 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 O)

2

, 5.02 (1H, dd, J = 10.8, 1.6Hz, H-6), 5.23 (1H, dd, J = 17.2, 1.6Hz, H-6), 5.94 (1H, dd, J = 17.2, 10.8Hz, H—7).

[0082] [Chemical 22]

[0083] Pyridi-mukuroguchi chromate (PCC, 723. Omg, 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) at room temperature. Stir for 20 hours. The reaction solution was purified by silica gel column chromatography (10 g) and protected from the compound 42 (215. Omg, 80%) and 15% ethyl acetate Z hexane elution from the 5% ethyl acetate Z hexane elution. An off-group aldehyde (24.6 mg, 10%) was obtained.

[0084] Compound 42 11 NMR (CDCl) δ: 0.61 (3Η, s, H— 18), 0.88 (3H, d, J = 7

Three

.2Hz, (CH) CH), 0.94 (3H, d, J = 5.7Hz, H—21), 1.21 (6H, s, H— 2

2 3 3

6, 27), 2.36 (1H, m, H— 14), 3.37 (3H, s, OMe), 3.39 (1H, m, H— 9), 4.71 (2H, s, OCH O), 5.78 (1H, d, J = 8.3Hz, H— 7), 10.06 (1H, d, J =

2

(8.3Hz, CHO). [0085] [Chemical 23]

[0086] 0. Sodium borohydride (13.9 mg, 0.367 mmol) was added to an ethanol (2 ml) solution of aldehyde 42 (200.5 mg, 0.493 mmol) cooled to C, and stirred for 1 hour. Ice water was added to the reaction solution and 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), and 43 (172.8 mg, 86%) was obtained from the fraction eluted with 15% ethyl acetate / hexane.

[0087] Compound 43 11 NMR (CDCl) δ: 0.56 (3Η, s, H—18), 0.88 (3H, d, J = 7

Three

.3Hz, (CH) CH), 0.92 (3H, d, J = 6.4Hz, H—21), 1.21 (6H, s, H— 2

2 3 3

6, 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 O), 5.23 (1H, m,

2

H-7).

Mass m / z (%): 408 (no M ⁺ ), 346 (11), 328 (58), 313 (23), 271 (19), 243 (33), 217 (100).

[0088] [Chemical 24]

Compound 43 (156. Omg, 0.382 mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (2 ml), n-butyllithium (266 1, 0.420 mmol, 1.58 M hexane solution), and tosyl chloride A solution of (87.4 mg, 0.458 mmol) in anhydrous tetrahydrofuran (0.2 ml) was stirred and stirred for 5 minutes. In a separate container diphenylphosphine (133 1, 0.764 mmol) An anhydrous tetrahydrofuran (lml) solution was made, cooled to 0 ° C., and n-butyllithium (484 1, 0.764 mmol, 1.58 M hexane solution) was added. (It becomes dark red)

[0090] Under 0 ° C, the phosphine solution was slowly added to the tosyl body until the red color disappeared, and the mixture was stirred for 30 minutes, water (20 µ1) 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 solution (3 ml) was added, and the mixture was stirred at 0 ° C. for 1 hr. To the reaction solution was added 2N aqueous sodium thiosulfate solution, and the mixture was extracted with methylene chloride. The organic layer was washed with water and 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 44 (173.7 mg, 77%) from the eluate of 40% ethyl acetate Z hexane.

[0091] Compound 44 11 NMR (CDCl) δ: 0.23 (3Η, s, H—18), 0.86 (3H, t, J = 7.

Three

4Hz, (CH) CH, overlapped with H— 21), 1.20, (6H, s, H— 26, 27),

2 3 3

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 O), 5.04 (1H, m, H-7),

2

7.43-7.78 (10H, m, arom-H).

Mass m / z (%): 592 (M ⁺ , 2), 530 (100), 473 (33), 419 (4), 216 (74), 2 02 (91).

[0092] [Chemical 25]

To a solution of phosphinoxide 44 (124. lmg, 0.209mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (2ml), hexamethylphosphorustriamide (36 1, 0.209mmol) and n-butyllithium (132 1, 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 (lml) was slowly added. Stir at 78 ° C for 1 hour, then gradually warm up and stir at room temperature for 3 hours. Stir. To the reaction solution was added a saturated aqueous solution of ammonium chloride and 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 2% ethyl acetate Z hexane eluate and the 40% ethyl acetate Z hexane eluate phosphine oxide. Body 44 (91.3 mg) was recovered.

[0094] Compound 45: Yeah! NMR (CD OD) δ: 0.048, 0.053 (each 6H, s, SiMe x 4

Three

), 0.54 (3H, s, H-18), 0.865, 0.871 (each 9H, tBuSi x 2, overlappe d with (CH) CH), 0.92 (3H, d, J = 6.3Hz, H—21), 1.21 (6H, s, H— 2

2 3 3

6, 27), 2.83 (1H, m), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O), 4.07 (

2

2H, m, H-l, 3), 5.83 (1H, d, J = ll.2Hz, H-7), 6.14 (1H, d, J = ll.2 Hz, H-6).

[0095] [Chemical 26]

45 2f

[0096] To a solution of Compound 45 (28.5 mg, 0.039 mmol) in methanol (l ml), camphorsulfonic acid (54.2 mg, 0.233 mmol) 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 2f (17.2 mg, 96%) from the 70% ethyl acetate / hexane eluate. This sample was further purified by HPLC [YMC-PackODS-AM SH-342 -5, 15% H 2 O / MeOH, 8 ml Zmin] to obtain 2f (ll. 8 mg).

2

[0097] Compound Sf: ¹ !! NMR (CDC1) δ: 0.54 (3H, s, H-18), 0.87 (3H, d, J = 7.

Three

2Hz, (CH) CH), 0.93 (3H, d, J = 6.4Hz, H— 21), 1.22 (6H, s, H— 26 , 27), 2.19 (2H, m, H— 4, OH), 2.27 (1H, dd, J = 13.2, 7.8Hz, H— 10), 2.49 (1H, dd, J = 13.3, 3.5Hz, H— 4), 2.68 (1H, dd, J = 13.2, 3.7Hz, H-10), 2.82 (1H, m, H—9), 4.07 (2H, m, H—1, 3), 5.87 (1H, d , J = 11.2Hz, H-7), 6.31 (1H, d, J = ll.2Hz, H-6).

UV λ max (EtOH): 244nm (ε = 27000), 252nm (ε = 31000), 261nm (ε = 21000).

Mass m / z (%): 460 (M ⁺ , 21), 442 (100), 424 (36), 406 (15), 331 (31), 313 (32), 295 (21).

[0098] <Synthesis of 9 CH CH = CHCH 19 norvitamin D derivative>

twenty three

It was synthesized by the following procedure.

[0099] [Chemical 27]

10 32 46 46 '

[0100] n-Butyllithium (1.22ml, 1.938mmol, 1.59M hexane solution, 1.3eq) was added to a solution of diisopropylamine (314 1, 2.237mmol, 1.5eq) in anhydrous tetrahydrofuran (5ml) 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, chlorotrimethylenosilane (284 1, 2.237 mmol, 1.5 eq) and triethylenoamine (312 1, 2.237 mmo 1, 1.5 eq) were added. The temperature was gradually raised and the mixture was stirred for 2 hours until it reached 0 ° C. The reaction solvent was distilled off, redissolved in hexane, and purified by filtration through Celite to obtain Compound 32 (590 mg).

[0101] To a solution of the compound 32 cooled to 0 ° C in anhydrous tetrahydrofuran (5 ml), methyllithium (1.36 ml, 1.640 mmol, 1.20 M jetyl ether solution, 1. leq) was added. Stir at C for 1 hour. Make a solution of crotyl alcohol (253 1, 2.982mmol, 2eq) in water-free tetrahydrofuran (5ml) in another container, cool to 0 ° C, and then add n-butyllithium (1.85ml, 2.982mmol, 1.59M hexane solution, 2eq), 卜 sil compound (568.5mg, 2.982mmol, 2eq) in anhydrous tetrahydrofuran (lml) was added. After stirring for 10 minutes, the above lithium enolate was slowly added and stirred at 0 ° C for 1.5 hours. Saturated salt solution in reaction solution Aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Silica gel column chromatography of the residue

The compound 46 (338.3 mg, 60%) was obtained from the elution part of 10% ethyl acetate Z hexane, and the protecting group was removed from the elution part of 25% ethyl acetate Z hexane. 46 ′ (9 1.5 mg, 18%) was obtained.

[0102] Compound 46 ^ 11 NMR (CDCl) δ: 0.65 (3Η, s, H—18), 0.95 (3H, d, J = 6

Three

1Hz, H-21), 1.22 (6H, s, H— 26, 27), 1.64 (3H, d, J = 6.3Hz, CH C

Three

H = CH), 2.56 (1H, dd, J = ll.6, 7.4Hz, H-14), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O), 5.29, 5.47 ( each 1H, m, CH = CH).

2

Mass m / z (%): 378 (no M +), 316 (100), 246 (35), 219 (25), 135 (26) Compound 46 'NMR (CDCl) δ: 0.65 (3H, s , H— 18), 0.96 (3H, d, J = 6

Three

1Hz, H-21), 1.22 (6H, s, H— 26, 27), 1.64 (3H, d, J = 6.3Hz, CH C

Three

H = CH), 2.56 (1H, dd, J = ll.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)

[0103] [Chemical 28]

To a solution of compound 46 (316.3 mg, 0.835 mmol) in anhydrous tetrahydrofuran (3 ml) cooled to 20 ° C., burmagnesium bromide (1.67 ml, 1.671 mmol, 1.0 M tetrahydrofuran solution) was added. 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 distilled off. The residue was purified by silica gel column chromatography (20 g) to obtain Compound 47 (298.7 mg, 88%) from the eluate of 8% ethyl acetate Z-hexane. [0105] Compound 47: H NMR (CDCl) δ: 0.91 (3H, d, J = 6.5Hz, H-21), 0.96 (3

Three

H, s, H-18), 1.21 (6H, s, H— 26, 27), 1.64 (3H, d, J = 6.2Hz, CH CH

Three

= CH), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O), 5.04 (1H, dd, J = 10

2

.8, 1.5Hz, H-6), 5.24 (1H, dd, J = 17.3, 1.5Hz, H—6), 5.30, 5.40 (each 1H, m, CH = CH), 5.91 (1H, dd, J = 17.3, 10.8Hz, H-7).

Mass m / z (%): 406 (M ⁺ , 1), 388 (2), 344 (65), 326 (100), 215 (16).

[0106] [Chemical 29]

[0107] To a solution of Compound 47 (260.5 mg, 0.641 mmol) in anhydrous dichloromethane (15 ml) were added pyridi-mukuroguchi chromate (563.6 mg, 2.562 mmol) and celite (560 mg), and the mixture was stirred at room temperature for 22 hours. The reaction solution was purified by silica gel column chromatography (20 g), and compound 48 (205.2 mg, 79%) and 15% ethyl acetate Z hexane eluate from 10% ethyl acetate Z hexane eluate. The detached aldehyde 48 '(34.2 mg, 15%) was obtained.

Compound 48 11 NMR (CDCl) δ: 0.61 (3Η, s, H-18), 0.94 (3H, d, J = 5

Three

.6Hz, 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 O) , 5.29, 5.41 (each 1H, m, CH = CH)

2

, 5.75 (1H, m, H-7), 9.98 (1H, d, J = 8.2Hz, CHO).

Mass m / z (%): 404 (M ⁺ , 16), 342 (100), 287 (27), 229 (10), 135 (20) Compound 48, NMR (CDCl) δ: 0.61 (3H , s, H-18), 0.95 (3H, d, J = 5

Three

.8Hz, 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, 1.6Hz, H--7), 9.98 (1H, d, J = 8.2Hz, CHO).

[0109] [Chemical 30]

[0110] To a solution of aldehyde compound 48 (198. lmg, 0.490 mmol) cooled to 0 ° C in ethanol (2 ml) was added sodium borohydride (18.5 mg, 0.490 mmol) 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 (10 g) to obtain Compound 21 (148.5 mg, 75%) from the 10% ethyl acetate Z hexane eluate, and 30% ethyl acetate Z hexane eluate Compound 21 (8.2 mg, 5%) was obtained from which the protecting group was further removed.

[0111] Compound SI: ¹ !! NMR (CDCl) δ: 0.56 (3Η, s, H—18), 0.93 (3H, d, J = 6

Three

.4Hz, H-21), 1.22 (6H, s, H— 26, 27), 1.65 (3H, d, J = 6.1Hz, CH C

Three

H = CH), 2.67 (1H, m, H-9), 3.37 (3H, s, OMe), 4.10 (2H, m, H-6), 4.71 (2H, s, OCH O), 5.27 (1H, dt, J = 7.11.7Hz, H— 7), 5.38 (2H,

2

m, CH = CH).

Mass m / z (%): 406 (no M +), 388 (9), 326 (97), 311 (31), 271 (43), 2 15 (100).

Compound 21 ,: "H NMR (CDCl) δ: 0.56 (3H, s, H—18), 0.93 (3H, d, J

Three

= 6.4Hz, H-21), 1.22 (6H, s, H— 26, 27), 1.65 (3H, d, J = 6.1Hz, CH CH = CH), 2.67 (1H, m, H— 9), 4.10 (2H, m, H-6), 5.27 (1H, dt, J

Three

= 7.1 1 1.7Hz, H-7), 5.38 (2H, m, CH = CH).

[0112] [Chemical 31]

[0113] Compound 21 (127.2mg, 0.313mmol) cooled to 0 ° C in anhydrous methylene chloride (2ml) Triphenylphosphine (123. lmg, 0. 469 mmol, 1.5 eq), 2-mercaptobenzothiazole (78.5 mg, 0. 469 mmol, 1.5 eq) and diisopropylazodicarboxylate (DIAD, 64 1, 0. 313 mmol, leq) was stirred for 1 hour. After the solvent was distilled off, the residue was dissolved in ethanol (2 ml) and cooled to 0 ° C. 30% peroxyhydrogen water (400 ΐ) and ammonium heptamolybdate tetrahydrate (NH) Mo O · 4Η

4 6 7 24 2

0 (77.4 mg, 0.063 mmol, 0.2 eq) was added, and the mixture was stirred at room temperature for 2 hours.

[0114] A 2N aqueous sodium sulfite solution was added to the reaction mixture, 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) to obtain Compound 23 (176.5 mg, 94%) from the eluate of 10% ethyl acetate / hexane.

[0115] Compound 23 11 NMR (CDCl) δ: 0.13 (3Η, s, H—18), 0.83 (3H, d, J = 6

Three

2Hz, H- 21), 1. 19 (6H, s, H— 26, 27), 1. 62 (3H, d, J = 5. 9Hz, CH C

Three

H = CH)), 2.61 (1H, m, H— 9), 3.36 (3H, s, OMe), 4.03 (1H, ddd, J = l 4. 5, 5. 9, 2 0Hz, H— 6), 4. 55 (1H, dd, J = 14. 5, 10. 0Hz, H— 6), 4. 6 9 (2H, s, OCH O), 5. 03 (1H, m, H— 7), 5. 28, 5. 36 (each 1H, m, CH

2

= CH), 7. 58, 7. 63, 7. 97, 8. 21 (each 1H, m, arom-H).

[0116] [Chemical 32]

28

— Lithium bis (trimethylsilyl) amide (242 μ 1, 0.224 mmol) in a solution of Compound 23 (163. 7 mg, 0.278 mmol, 1.5 eq) in anhydrous tetrahydrofuran (2 ml) cooled to 78 ° C. , 1.0 M tetrahydrofuran solution, 1.3 eq) was added, and the mixture was stirred for 30 minutes, and then a solution of ketone body 9 (83. Omg, 0.186 mmol) in anhydrous tetrahydrofuran (lml) was slowly added. After stirring at -78 ° C for 1 hour, the temperature was gradually raised and stirring was continued at 0 ° C for 1 hour. Saturated salt solution in reaction solution Aqueous solution was added and 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), and the compound 28 (139. Omg, 91%, about 5: 4 mixture) was obtained from the eluate of 2% ethyl acetate Z hexane, and 10% acetic acid. Compound 23 (48.3 mg) was recovered from the elution part of ethyl Z hexane.

[0118] 匕 Compound Ζδ ^ Η NMR (CD OD) δ: 0.042, 0.056, 0.065 (12H, s, SiMe x

Three

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 = 6.3Hz, H-21), 1.22 (6H, s, H- 26, 27), 1.64 (3H, d, J = 4.2Hz, CH CH = C

Three

H), 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 O), 5.39

2

(2H, m, CH = CH), 5.79 (1H, m, H-7), 6.09 (1H, m, H-6).

Mass m / z (%): 818 (no M +), 756 (15), 624 (26), 569 (100), 479 (28)

[0119] [Chemical 33]

28 28

[0120] Compound 28 (129.3 mg, 0.158 mmol, mixture of about 5: 4) was dissolved in tetrahydrofuran Z-acetic acid Z-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 evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 28 ′ (a mixture of 106. Omg, 90%, about 5: 4) from the eluate of 5% ethyl acetate Z-hexane.

[0121] Compound 28, a (major: 2α form) ¹ H NMR (CDC1) δ: 0.06 to 0.10 (12Η, Si— Me x 4), 0.55 (3H, s, H— 18), 0.88, 0.89 (each 9H, s, Si— tBu x 2), 0.93 (3H, d, J = 6.4Hz, H— 21), 1.22 ( 6H, s, H- 26, 27), 1.64 (3H, d, J = 4.9Hz, CH CH = CH), 2.83 (1H, m, H-9), 3.37 (3H, s, OMe), 3.

Three

52 (1H, m, H-2), 3.99 (1H, m, H— 3), 4.12 (1H, m, H— 1), 4.74 (2H, s, OCH O), 5.37 (2H, m, CH = CH), 5.79 (1H, d, J = ll.2Hz, H— 7), 6

2

16 (1H, d, J = ll.2Hz, H-6).

Compound 28, b (minor: 2 j8 form) ¹ H NMR (CDC1) δ: 0.06

3 to 0.10 (12H, Si—

Me x 4), 0.54 (3H, s, H— 18), 0.86, 0.90 (each 9H, s, Si— tBu x 2), 0.93 (3H, d, J = 6.4Hz, H— 21), 1.22 ( 6H, s, H- 26, 27), 1.64 (3H, d, J = 4.9Hz, CH CH = CH), 2.83 (1H, m, H-9), 3.37 (3H, s, OMe), 3.

Three

89 (1H, m, H-2), 4.12 (2H, m, H— 1, 3), 4.74 (2H, s, OCH O), 5.37 (

2

2H, m, CH = CH), 5.79 (1H, d, J = ll.2Hz, H-7), 6.15 (1H, d, J = ll. 2Hz, H-6).

Compound 28 'Mass m / z (%): 746 (M ⁺ , 14), 684 (30), 629 (39), 497 (94), 365 (54), 75 (100).

[0122] [Chemical 34]

28 '28 "

[0123] —Aqueous methylene chloride in dimethylsulfoxide (23 1, 0.322 mmol, 2.4 eq) in anhydrous methylene chloride (0.5 ml) in oxalyl dichloride (14 1, 0.161 mmol, 1.2 eq) cooled to 78 ° C After adding a (0.3 ml) solution and stirring for 10 minutes, an anhydrous methylene chloride (lml) solution of Compound 28 (100.3 mg, 0.134 mmol, about 5: 4 mixture) was added. After holding at 78 ° C for 15 minutes, 卜!; Ethinoreamine (93 1, 0.670 mmol, 5eq) was calo-free and at 78 ° C 10 And stirred 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 the eluate of 5% ethyl acetate Z-hexane.

[0124] Compound 28 ": NMR (CDC1) δ: 0.056, 0.066, 0.070, 0.099 (each 3

Three

H, s, Si— Me x 4), 0.55 (3H, s, H— 18), 0.87, 0.90 (each 9H, s, Si— tBu x 2), 0.93 (3H, d, J = 6.3Hz, H — 21), 1.22 (6H, s, H— 26, 27), 1.64 (3H, d, J = 5.5Hz, CH CH = CH), 2.45 (1H, dd, J = 13.6, 8.6Hz),

Three

2.53 (1H, dd, J = 14.1, 4.1Hz), 2.67 (1H, dd, J = 13.6, 5.6Hz), 2.73 (1H, dd, J = 14.1, 6.4Hz), 2.85 (1H, m, H- 9), 3.37 (3H, s, OMe), 4.36 (1H, dd, J = 6.4, 4.1Hz), 4.55 (1H, dd, J = 8.6, 5.6Hz), 4.74 (2H, s, OCH O), 5.39 (2H, m, CH = CH), 5.81 (1H, d, J = ll.1Hz, H-7), 6

2

.35 (1H, d, J = ll.1Hz, H-6).

Mass m / z (%): 744 (no M ⁺ ), 626 (100), 494 (29), 325 (15).

[0125] [Chemical 35]

[0126] — n-Butyllithium (167 1, 0.264 mmol, 1.59 M hexane) in a solution of jetyl cyanomethylphosphonate (43 μ 1, 0.264 mmol, 2 eq) in anhydrous tetrahydrofuran (lml) cooled to 40 ° C Solution, 2eq) was added and stirred for 15 minutes, then a solution of compound 28 "(98.5mg, 0.132mmol) in anhydrous tetrahydrofuran (1.5ml) was added slowly. — After stirring at 40 ° C for 2 hours, reaction A saturated aqueous solution of ammonium chloride was added to the 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 evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 29 (97.5 mg, 96%, approximately 1: 1 mixture) from the eluate of 1% ethyl acetate Z-hexane.

[0127] Compound 29: 11 NMR (CDC1) δ: 0.06— 0.12 (12H, Si—Me x 4), 0.54

Three

, 0.55 (1: 1) (3H, s, H-18), 0.83, 0.92 (1: 1) (9H, s, Si-tBu), 0.93 (9 H, 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 CH = CH), 2.85 (1H, m, H— 9) , 3.0

Three

0, 3.14 (1: 1) (1H, m, H— 10), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O

2

), 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 = 2.0Hz, C = CHCN), 5.79, 5.83 (1: 1) (1H, d, J = ll.1Hz, H-7), 6.19, 6.27 (1: 1) (1H, d, J = ll.2Hz, H-6).

Mass m / z (%): 768 (M ⁺ , 5), 706 (18), 651 (60), 626 (79), 518 (68), 7 3 (100).

[0128] [Chemical 36]

29 29 '

[0129] Compound 29 (97.5 mg, 0.127 mmol, mixture of E: Z = 1: 1) cooled to 78 ° C. was added to an anhydrous toluene (lml) solution with diisobutylaluminum hydride (190 1, 0.190 mmol, 1.0 M toluene). Solution, 1.5 eq) was added. After 1 hour, the reaction solution was diluted with hexane, purified by silica gel column chromatography (5 g), and the compound 29 '(87 mg, 89%, about 1: 1) was eluted from the elution part of 5% ethyl acetate Z hexane. A mixture) was obtained.

[0130] Compound 29 '(E form): ¾ NMR (CDC1) δ: 0.02, 0.07, 0.09, 0.10 (each 3

Three

H, s, Si— Me x 4), 0.56 (3H, s, H-18), 0.83, 0.92 (each 9H, s, Si— tBu x 2, overlapped with H— 21), 1.22 (6H, s, H— 26, 27), 1.65 (3H, d, J = 5.5Hz, CH CH = CH), 2.84 (1H, m, H— 9 ), 3.08 (1H, m, H-10

Three

), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O), 4.58 (1H, m, H— 1), 5.4

2

0 (2H, m, CH = CH), 5.47 (1H, m, H-3), 5.84 (1H, d, J = ll.0Hz, H-7), 6.16 (1H, m, C = CH), 6.19 (1H, d, J = ll.0Hz, H-6), 10.19 (1H, d, J = 7.8Hz, CHO).

Compound 29 '(Z form): ^X H NMR (CDC1) δ: 0.02, 0.07, 0. 10, 0.11 (each 3

Three

H, s, Si— Me x 4), 0.55 (3H, s, H— 18), 0.84, 0.93 (each 9H, s, Si— tBu x 2, overlapped with H— 21), 1.22 (6H, s, H- 26, 27), 1.63 (3H, d, J = 5.5Hz, CH CH = CH), 2.84 (1H, m, H-9), 3.00 (1H, m, H-10

Three

), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O), 4.67 (1H, m, H-3), 5.4

2

0 (2H, m, CH = CH), 5.53 (1H, m, H— 1), 5.80 (1H, d, J = ll.0Hz, H— 7), 6.16 (1H, m, C = CH), 6.28 (1H, d, J = ll.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), 5 21 (64), 75 (100).

[0131] [Chemical 37]

29 '29

[0132] Sodium borohydride (4.2 mg, 0.113 mmol, leq) in an ethanol (lml) solution of aldehyde 29, (87. Omg, 0.113 mmol, approximately 1: 1 mixture) 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. Silica gel column Purification by mass chromatography (6 g) gave Compound 29 (75.8 mg, 87%, approximately 1: 1 mixture) from the eluate of 5% ethyl acetate / hexane.

[0133] Compound 29 "(E form): ¹ H NMR (CDC1) δ: 0.01—0.10 (12H, Si—Me x 4)

Three

, 0.54 (3H, s, H-18), 0.84, 0.91 (each 9H, s, Si— tBu x 2, overlapp ed with H-21), 1.22 (6H, s, H— 26, 27), 1.63 ( 3H, d, J = 5.5Hz, CH CH = CH), 2.29 (2H, m, H—4), 2.80 (1H, m, H—9), 2.89 (1H, m, H

Three

-10), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH O), 4.20, 4.29 (2H, m,

2

CH OH), 4.30 (1H, m, H— 1), 4.81 (1H, m, H— 3), 5.37 (2H, m, CH =

2

CH), 5.70 (1H, m, C = CH), 5.84 (1H, d, J = ll.1Hz, H-7), 6.13 (1H, d, J = ll.1Hz, H-6).

Compound 29 "(Z form): ¹ H NMR (CDCl) δ: 0.01—0.10 (12H, Si—Me x 4)

Three

, 0.53 (3H, s, H-18), 0.82, 0.92 (each 9H, s, Si -tBu x 2, overlapp ed with H-21), 1.22 (6H, s, H— 26, 27), 1.62 ( 3H, d, J = 5.5Hz, CH CH = CH), 2.55 (1H, dd, J = 12.5, 5.0Hz, H—4), 2.83 (2H, m, H— 9,

Three

10), 3.37 (3H, s, OMe), 4.71 (2H, s, OCH 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

2

), 5.70 (1H, m, C = CH), 5.80 (1H, d, J = ll.1Hz, H-7), 6.20 (1H, d, J = ll.1Hz, H-6).

Compound 29 ": Mass m / z (%): 772 (M ⁺ , 5), 710 (6), 692 (8), 640 (37), 58 5 (87), 523 (100), 391 (twenty four).

[0134] [Chemical 38]

29 "3c [0135] Compound 29 "(16. Omg, 0.0207 mmol, approx. 1: 1 mixture) in methanol (0.5 ml) solution [camphors norephonic acid (28.8 mg, 0.124 mmol, 6 eq) dissolved in room temperature [Stirred 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 evaporated. The residue was purified by silica gel column chromatography (3 g) to obtain Compound 3c (10.9 mg, 98%, approximately 1: 1 mixture) from the eluate of 2% methanol Z ethyl acetate. Further HPLC [YMC— Pack ODS— AM SH— 342— 5, 15% HO / MeOH,

2

8mlZmin] to obtain compound 3c (E form) (3.8 mg) and compound 3c (Z form) (4.3 mg).

Compound 3c (E form): ^X H NMR (CDC1) δ: 0.55 (3H, s, H-18), 0.93 (3H, d,

Three

J = 6.3Hz, H-21), 1.22 (6H, s, H— 26, 27), 1.63 (3H, d, J = 5.6Hz, CH CH = CH), 2.44 (2H, m, H— 4) , 2.84 (1H, m, H-9), 3.13 (1H, dd, J

Three

= 13.1, 5.0Hz, H-10), 4.19 (1H, dd, J = 12.4, 6.1Hz, CH OH), 4.3

2

8 (1H, dd, J = 12.4, 7.9Hz, CH OH), 4.41 (1H, m, H-1), 4.84 (1H, m

2

, H-3), 5.38 (2H, m, CH = CH), 5.84 (1H, m, C = CH), 5.89 (1H, d, J = 11.1Hz, H-7), 6.27 (1H, d, J = ll.1Hz, H— 6).

UV Imax (EtOH): 247nm, 255nm, 264nm.

[0137] Compound 3c (Z form): ^X H NMR (CDC1) δ: 0.56 (3H, s, H-18), 0.93 (3H, d,

Three

J = 6.3Hz, H-21), 1.22 (6H, s, H- 26, 27), 1.62 (3H, d, J = 5.6Hz, CH CH = CH), 2.70 (1H, dd, J = 12.7, 4.7Hz, H— 4), 2.85 (2H, m, H— 9

Three

, 10), 3.37 (3H, s, OMe), 4.19 (1H, dd, J = 12.5, 6.0Hz, CH OH), 4.

2

38 (1H, dd, J = 12.5, 7.9Hz, CH OH), 4.45 (1H, m, H-3), 4.87 (1H,

2

m, Hl), 5.38 (2H, m, CH = CH), 5.82 (1H, m, C = CH), 5.84 (1H, d, J = ll.1Hz, H-7), 6.37 (1H, d, J = ll.1Hz, H— 6).

UV Imax (EtOH): 247nm, 255nm, 264nm.

[0138] <9-CH CH = CH 19 Synthesis of norvitamin D derivatives>

twenty two

It was synthesized by the following procedure.

[0139] [Chemical 39]

[0140] To a solution of diisopropylpropylamine (706 μ 1, 5. 04 mmol) in anhydrous tetrahydrofuran (10 ml) cooled to 20 ° C to n-butyllithium (2.8 ml, 4. 37 mmol, 1.58 M) The xylene solution was added and stirred for 15 minutes. Lithium diisopropylamide was cooled to −78 ° C., and a solution of grandman ketone 10 (1.09 g, 3.36 mmol) in anhydrous tetrahydrofuran (5 ml) was added. After stirring for 1 hour, a mixture of chlorotrimethylsilane (436 1, 5. 04 mmol) and triethylamine (702 ^ 1, 5. 04 mmol) was removed. The temperature was gradually increased, and the mixture was stirred for 1.5 hours until 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).

[0141] Compound 32 11—NMR (CDC1) δ: 0.17 (9H, s, SiMe x 3), 0.73 (3H, s,

Three

H- 18), 0. 94 (3H, d, J = 6.5 Hz, H— 21), 1. 22 (6H, s, H— 26, 27), 3.3 7 (3H, s, OCH) , 4.63 (1H, m, H-9), 4.71 (2H, s, OCH O).

3 2

[0142] [Chemical 40]

[0143] Methyllithium (3.4 ml, 4. 06 mmol, 1.2 M jetyl ether dissolved in a solution of silylenolate 32 (1.34 mg, 3. 38 mmol) in anhydrous tetrahydrofuran (5 ml) cooled to 0 ° C Liquid) and stirred for 1 hour. In a separate container, a solution of yowiaryl (631 1, 6. 77 mmol) in anhydrous tetrahydrofuran (2 ml) was made. After cooling to -78 ° C, the above lithium enolate was slowly added, and the temperature was gradually raised. After stirring for 1 hour (at 45 ° C), add a saturated aqueous solution of ammonium chloride to the reaction mixture, extract with ethyl acetate, wash the organic layer with saturated brine, The solvent was distilled off after drying the gnesium. The residue was purified by silica gel column chromatography (30 g) to obtain Compound 16 (887.7 mg, 73%) from the eluate of 8 to 10% ethyl acetate Z hexane.

[0144] Compound Ιδ ^ Η— NMR (CDC1) δ: 0.66 (3Η, s, H—18), 0.96 (3H, d, J = 6

Three

.2Hz, H-21), 1.22 (6H, s, H- 26, 27), 2.57 (1H, dd, J = ll.5, 7.4Hz, H-14), 3.37 (3H, s, OCH), 4.70 (2H, s, OCH O), 5.09 (2H, m, CH

3 2

CH = CH), 5.68 (1H, m, CH CH = CH).

2 2 2 2

Mass m / z (%): 364 (M ⁺ , 6), 323 (8), 302 (76), 261 (17), 219 (68), 19 1 (25), 55 (100).

[0145] [Chemical 41]

[0146] 9-Alinole 16 (887.7mg, 2.43mmol) anhydrous tetrahydrofuran cooled to 0 ° C

To the (7 ml) solution was added burmagnesium bromide (4.87 ml, 4.87 mmol, 1.0 M tetrahydrofuran solution) and stirred for 2.5 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. lmg, 79%) from the eluate of 10% ethyl acetate / hexane.

[0147] The compound T: ¹ !! — NMR (CDC1) δ: 0.91 (3Η, d, J = 6.5Hz, H-21), 0.97 (

Three

3H, s, H-18), 1.21 (6H, s, H— 26, 27), 3.37 (3H, s, OCH), 4.71 (2H

Three

, s, OCH O), 4.99 (2H, m, CH CH = CH), 5.05 (1H, dd, J = 10.8, 1.5

2 2 2

Hz, H-6), 5.25 (1H, dd, J = 17.2, 1.5Hz, H-6), 5.69 (1H, m, CH C

2

H = CH), 5.91 (1H, dd, J = 17.2, 10.8Hz, H-7).

2

Mass m / z (%): 392 (no M ⁺ ), 330 (53), 312 (50), 297 (14), 271 (20), 247 (87), 219 (20), 201 (49), 55 (100). [0148] [Chemical 42]

[0149] Pyridi-mukuroguchi chromate (1.67g, 7.73mmol) and Celite (1.7g) were dissolved in anhydrous methylene chloride (30ml) in bulle alcohol 17 (759. lmg, 1.93mmol) at room temperature. Stir for 23 hours. The reaction solution was purified by column chromatography (20 g) to obtain Compound 18 (669.3 mg, 89%) from the eluate of 2 o / o ethyl acetate Z-hexane.

[0150] Compound Ιδ ^ Η— NMR (CDC1) δ: 0.62 (3Η, s, H—18), 0.95 (3H, d, J = 5

Three

.7Hz, H-21), 1.22 (6H, s, H— 26, 27), 3.37 (3H, s, OCH), 3.47 (1H

Three

, m, H-9), 4.71 (2H, s, OCH O), 5.03 (2H, m, CH CH = CH), 5.68 (

2 2 2

1H, m, CH CH = CH), 5.76 (1H, dd, J = 8.3, 1.5Hz, H-7), 10.01 (1

twenty two

H, d, J = 8.2Hz, CHO).

Mass m / z (%): 390 (M ⁺ , 6), 328 (71), 287 (52), 217 (28), 215 (100).

[0151] [Chemical 43]

[0152] Sodium borohydride (63.9 mg, 1.69 mmol) was added to an ethanol (10 ml) solution of allylaldehyde 18 (660. lmg, 1.69 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 the solvent was evaporated. The residue was purified by silica gel column chromatography (20 g) to obtain Compound 19 (400. 6 mg, 60%) from the eluate of 20-25% ethyl acetate Z-hexane.

[0153] Compound ΙΘ Η— NMR (CDC1) δ: 0.56 (3Η, s, H—18), 0.93 (3H, d, J = 6 .4Hz, 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), 4.14 ( 2H, d, J = 6.8Hz, H— 6), 4.71 (2H

Three

, s, OCH O), 4.97 (2H, m, CH CH = CH), 5.28 (1H, dd, J = 7.1, 1.6H

2 2 2

z, H-7), 5.70 (1H, m, CH CH = CH).

twenty two

Mass m / z (%): 392 (no M ⁺ ), 330 (100), 312 (53), 299 (64), 289 (19), 271 (41), 245 (47), 219 (32), 217 (49), 201 (72).

[Chemical 44]

[0155] n-Butyllithium (710 1, 1. 12 mmol, 1.58M hexane) in a solution of aranolenoreconole isomer 19 (400.6 mg, 1.02 mmol) in anhydrous tetrahydrane-furan (lml) cooled to 0 ° C Solution) and tosyl chloride (252.9 mg, 1.33 mmol) in anhydrous tetrahydrofuran (500 1) were added and stirred for 7 minutes. In another container, make a solution of diphenylphosphine (355 1, 2.04 mmol) in anhydrous tetrahydrofuran (lml), cool to 0 ° C, and then add n-butyllithium (1.3 ml, 2.04 mmol, 1.58M hexane solution). ) Was added. 0. Under C, the phosphine solution was slowly added to the tosyl compound until the red color disappeared, and the mixture was stirred at 0 ° C for 30 minutes. Water (10 µ 1) 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 solution (6 ml) was added, and the mixture was stirred at 0 ° C. for 1 hr. 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), and compound 20 (319.0 mg, 54%) was obtained from the eluate of 40-50% ethyl acetate Z-hexane.

[0156] The compound SO: ¹ !! — NMR (CDC1) δ: 0.26 (3Η, s, H—18), 0.88 (3H, d, J = 6

Three

.4Hz, 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), 4.70 (2H, s, OCH O), 4. 94 (2H, m, CH CH = CH), 5.05 (1H, m, H— 7), 5.66 (1H, m, CH CH =

2 2 2

CH), 7.43-7.78 (10H, m, arom-H).

2

Mass m / z (%): 576 (M ⁺ , 3), 514 (51), 499 (45), 473 (56), 313 (27), 2 02 (100).

[0157] [Chemical 45]

[0158] Anhydrous THF of phosphoxide 20 (217.3mg, 0.377mmol) cooled to 78 ° C

Hexamethylphosphorustriamide (66 1, 0.377 mmol) and n-butyllithium (237 1, 0.377 mmol, 1.59 M hexane solution) were added to the (2 ml) solution and stirred for 15 minutes. A solution of (120. Omg, 0.335 mmol) in anhydrous tetrahydrofuran (lml) was charged. 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 solution of ammonium chloride 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 2% ethyl acetate / hexane eluate and compound 25 from the 30% ethyl acetate Z hexane eluate. '(49.2 mg, 16%) was obtained, and unreacted raw material 20 (96.9 mg, 45%) was recovered from the elution portion of 50% ethyl acetate Z-hexane.

[0159] Compound 25 11—NMR (CDC1) δ: 0.048, 0.053 (each 6H, s, Si—Me x

Three

4), 0.55 (3H, s, H-18), 0.865, 0.874 (each 9H, s, Si— tBu x 2), 0. 93 (3H, d, J = 6.6Hz, H— 21), 1.21 ( 6H, s, H— 26, 27), 2.92 (1H, dd, J = 12.7, 7.1Hz, H-9), 3.37 (3H, s, OCH), 4.06 (2H, m, H— 1, 3) , Four

Three

.71 (2H, s, OCH O), 4.97 (2H, m, CH CH = CH), 5.73 (1H, m, CH C

2 2 2 2

H = CH), 5.84 (1H, d, J = ll.2Hz, H-7), 6.14 (1H, d, J = ll.2Hz, H

2

6). Mass m / z (%): 716 (M ⁺ , 3), 654 (81), 613 (21), 597 (16), 522 (46), 4 81 (90), 390 (8), 349 (100 ).

[0160] [Chem 46]

[0161] Camphorsulfonic acid (23.7 mg, 0.102 mmol) was added to a methanol (500 / z 1) solution of 19-nonole 25 (12.2 mg, 0.0170 mmol), and the mixture was stirred at room temperature for 1.5 hours. A 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) to obtain Compound 2b (6.8 mg, 90%) from the eluate of 80% ethyl acetate / hexane.

[0162] Compound Sb ^ H— NMR (CDC1) δ: 0.55 (3Η, s, H—18), 0.94 (3H, d, J = 6

Three

.4Hz, H-21), 1.22 (6H, s, H- 26, 27), 2.49 (1H, dd, J = 13.2, 3.3Hz, H-4), 2.70 (1H, dd, J = 13.4, 3.7 Hz, H—10), 2.91 (1H, dd, J = 13.6, 7.1Hz, H-9), 4.05 (1H, m, H—3), 4.10 (1H, m, H—1), 4.97 (2H , m, CH CH = CH), 5.71 (1H, m, CH CH = CH), 5.88 (1H, d, J = ll.2H

2 2 2 2

z, H-7), 6.29 (1H, d, J = ll.2Hz, H-6).

Mass m / z (%): 444 (M ⁺ , 23), 426 (74), 408 (16), 385 (100), 367 (52), 349 (23).

UV Imax (EtOH): 245nm, 253nm, 262nm.

[0163] [Chemical 47]

[0164] A solution of 19-nor 25 (22.2 mg, 0.0310 mmol) in anhydrous tetrahydrofuran (300 1) The mixture was stirred at room temperature for 4 hours. Methanol (150 1) was added to the reaction solution to stop the reaction, and the mixture was stirred for 15 minutes. Next, this solution was cooled to 0 ^° C., 6M sodium hydroxide (103 1, 0.260 mmol) and 30% hydrogen peroxide aqueous solution (150 1) 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 the compound 25 "(18.5 mg, 81%) was obtained from the eluate of 8% ethyl acetate Z-hexane.

[0165] 匕 Compound Ζδ ": ¹ !! — NMR (CDC1) δ: 0.049, 0.054 (each 6H, s, Si— Me x

Three

4), 0.54 (3H, s, H-18), 0.86, 0.87 (each 9H, s, Si— tBu x 2), 0.9 2 (3H, d, J = 6.4Hz, H— 21), 1.22 (6H , s, H— 26, 27), 2.34 (1H, m, H -9), 3.37 (3H, s, OCH), 3.60 (2H, m, CH CH CH OH), 4.06 (2H, m

3 2 2 2

, H-l, 3), 4.71 (2H, s, OCH O), 5.88 (1H, d, J = ll.2Hz, H-7), 6.1

2

4 (1H, d, J = ll.2Hz, H-6).

Mass m / z (%): 735 (noM ⁺ ), 673 (20), 655 (20), 598 (31), 541 (52), 5 23 (20), 466 (15), 75 (100).

[0166] [Chemical 48] H

Camphorsulfonic acid (9.9 mg, 42.4 / zmol) was added to a methanol (250 1) solution of 19-nor 25, (5.2 mg, 7.07 mol), and the mixture was stirred at room temperature for 2 hours. A 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) to obtain Compound 2d (2.4 mg, 73%) from the eluate of 3% methanol Z ethyl acetate.

[0168] Compound Sd ^ H— NMR (CDC1) δ: 0.55 (3Η, s, H—18), 0.93 (3H, d, J = 6

Three

.4Hz, 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 OH), 4.04 (1H, m

2

, H-3), 4.12 (1H, m, H-1), 5.92 (1H, d, J = ll.1Hz, H-7), 6.28 (1 H, d, J = ll.1Hz, H-6 ).

Mass m / z (%): 462 (M ⁺ , 17), 444 (100), 426 (39), 408 (16) .UV Imax (EtOH): 244 nm, 252 nm, 262 nm.

[0169] Synthesis of 2-hydroxyethylidene 9-aryl 19-norvitamin D derivative>

[0170] [Chemical 49]

[0171] Compound 19 (100. Omg, 0.255mmol) cooled to 0 ° C in anhydrous methylene chloride (2ml) To the solution was added triphenylphosphine (100.2 mg, 0. 382 mmol, 1.5 eq), 2-mercap benzobenzothiazole (63.9 mg, 0. 382 mmol, 1.5 eq) and diisopropylazodicarboxylate (52 1, 0.255 mmol, leq) was added and the mixture was 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 μ 1) and ammonium heptamolybdate tetrahydrate (63. Omg, 0.051 mmol, 0.2 eq) were added to this and 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 11 NMR (CDCl) δ: 0.17 (3H, s, H—18), 0.84 (3H, d, J = 6

Three

2Hz, 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. 0Hz, H-6), 4.12 (1H, dd, J = 14. 3, 7. 1Hz, H-6), 4. 69 (2H, s, OCH O), 4. 95 (2H, m, CH = CH)

twenty two

, 5. 06 (1H, m, H-7), 5. 64 (1H, m, CH = CH), 7. 60, 7. 63, 8. 00, 8.

2

21 (each 1H, m, arom— H).

[0173] [Chemical 50]

26

— 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 1, 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 (lml) was slowly added. After stirring at -78 ° C for 1 hour, the temperature was gradually raised and stirring was continued at 0 ° C for 1 hour. Saturated salt solution in reaction solution -Aqueous solution was added and 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 (8g) to obtain 26 (112.4mg, 90%, about 5: 4 mixture) from the elution part of 2% ethyl acetate Z hexane, and 10% ethyl acetate Z hexane elution 22 (26. lmg) was recovered from the part.

[0175] Compound 26: 11 NMR (CD OD) δ: 0.03— 0.07 (12H, SiMe x 4), 0.12,

Three

0. 13 (9H, s, SiMe x 3), 0.54, 0.55 (4: 5) (3H, s, H— 18), 0.86, 0.8 9; 0.87, 0.88 (4: 5) (each 9 H, tBuSi x 2), 0.93 (3H, d, J = 6.4Hz, 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, OC HO), 4.95 (2H, m, CH = CH), 5.73 (1H, m, CH = CH), 5.81, 5.84 (

2 2 2

4: 5) (1H, d, J = ll.1Hz, H-7), 6.04, 6.07 (5: 4) (1H, d, J = ll.1Hz, H 6).

Mass m / z (%): 804 (M ⁺ , 3), 742 (53), 672 (7), 610 (100), 569 (84).

[0176] [Chemical 51]

26 26 '

[0177] Compound 26 (107.4 mg, 0.133 mmol, about 5: 4 mixture) was dissolved in tetrahydrofuran Z acetate Z 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 evaporated. The residue was purified by silica gel column chromatography (6 g) to obtain Compound 26 ′ (a mixture of 82.8 mg, 85%, approximately 5: 4) from the elution portion of 5% ethyl acetate Z-hexane. [0178] Compound 26, a (major: 2a): H NMR (CDC1) δ: 0.07 to 0.10 (12H, Si— M

Three

ex 4), 0.55 (3H, s, H— 18), 0.87, 0.89 (each 9H, s, Si— tBu x 2), 0.93 (3H, d, J = 6.3Hz, 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, Hl), 4.71 (2H, s, OCH O), 4.95 (2H, m, CH = CH), 5

twenty two

.74 (1H, m, CH = CH), 5.82 (1H, d, J = ll.2Hz, H-7), 6. 12 (1H, d, J

2

= 11.2Hz, H-6).

26 'b (minor: 2 j8): ¹ !! NMR (CDC1) δ: 0.07〜0.10 (12H, Si— M

Three

ex 4), 0.54 (3H, s, H— 18), 0.86, 0.90 (each 9 H, s, Si -tBu x 2), 0.93 (3H, d, J = 6.3Hz, 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, Hl, 3), 4.71 (2H, s, OCH O), 4.95 (2H, m, CH = CH), 5.74 (1H, m, CH

twenty two

= CH), 5.82 (1H, d, J = ll.2Hz, H-7), 6.15 (1H, d, J = ll.2Hz, H— 6

2

)

Compound 26 ': Mass m / z (%): 732 (M ⁺ , 8), 670 (24), 613 (28), 538 (9), 4 81 (100).

[0179] [Chemical 52]

OH 〇

26 '26 "

[0180] A solution of oxalyl dichloride (10 1, 0.119 mmol, 1.2 eq) in anhydrous methylene chloride (0.3 ml) cooled to 78 ° C in dimethyl sulfoxide (17 1, 0.238 mmol, 2.4 eq) in anhydrous methylene chloride ( 0.2 ml) solution was added and stirred for 10 minutes, and then a solution of Compound 26 (72.5 mg, 0.0 99 mmol, about 5: 4) in anhydrous methylene chloride (l ml) was prepared. 15 at 78 ° C After stirring for minutes, triethylamine (69 1, 0.495 mmol, 5 eq) was added 78. The mixture was stirred at 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 26 "(71.6 mg, 99%) from the eluate of 3% ethyl acetate Z-hexane.

[0181] 匕 Compound Ζδ ": ¹ !! NMR (CDC1) δ: 0.06, 0.07, 0.09 (3Η, 6Η, 3Η, s, Si—

Three

Me x 4), 0.56 (3H, s, H— 18), 0.88, 0.90 (each 9H, s, Si— tBu x 2), 0.95 (3H, d, J = 6.3Hz, H— 21), 1.22 ( 6H, s, H- 26, 27), 2.45 (1H, dd, J = 13.5, 8.4Hz), 2.57 (1H, dd, J = 14.2, 4.1Hz), 2.67 (2H, m), 2.95 ( 1H, m, H-9), 3.37 (3H, s, OMe), 4.38 (1H, dd, J = 6.6, 4.4Hz), 4.52 (1H, dd, J = 8.4, 5.4Hz), 4.71 ( 2H, s, OCH O), 4.95 (2H, m, CH

2

= CH), 5.74 (1H, m, CH = CH), 5.85 (1H, d, J = ll.0Hz, H-7), 6.3

twenty two

3 (1H, d, J = ll.0Hz, H-6).

Mass m / z (%): 730 (no M ⁺ ), 673 (6), 611 (100), 479 (52).

[0182] [Chemical 53]

26 "27

[0183] n-Butyllithium (115 1, 0.184 mmol, 1.59 M hexane solution) in a solution of jetyl cyanomethylphosphonate (30 / zl, 0.184 mmol, 2 eq) in anhydrous tetrahydrofuran (0.5 ml) cooled to 40 ° C 2eq) was added and stirred for 15 minutes, and then a solution of compound 26 "(67.3mg, 0.092mmol) in anhydrous tetrahydrofuran (lml) was slowly added. After stirring at 40 ° C for 2 hours, the reaction mixture was A saturated aqueous sodium chloride solution was added, 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 27 (65.2 mg, 94%, approximately 1: 1 mixture) from the eluate of 3% ethyl acetate Z hexane.

[0184] Compound 27: 11 NMR (CDC1) δ: 0.05— 0.13 (12H, Si—Me x 4), 0.54

Three

, 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— 2 6, 27), 2.91 (1H, m, H— 9), 2.99, 3. 14 (1: 1) (1H, m , H—10), 3.37 (3 H, s, OMe), 4.71 (2H, s, OCH O), 4.49, 4.57 (1: 1) (1H, m), 4.93— 5

2

.52 (3H, m, H-3orl, CH = CH), 5.47, 5.48 (1H, d, J = 3.6Hz, C = CH

2

), 5.71 (1H, m, CH = CH), 5.81, 5.84 (1: 1) (1H, d, J = ll.3Hz, H-7)

2

, 6.19, 6.28 (1: 1) (1H, d, J = ll.3Hz, H-6).

Mass m / z (%): 753 (M ⁺ , 2), 691 (24), 634 (90), 607 (58), 518 (57), 7 3 (100).

[0185] [Chemical 54]

27 27 '

[0186] Compound 27 (62.3 mg, 0.083 mmol, E: Z = 1: 1 mixture) cooled to 78 ° C in anhydrous toluene (lml) solution with diisobutylaluminum hydride (124 1, 0.124 mmol, 1.0 M toluene) 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 compound 27, (54.8 mg, 88%, approx. 1: 1 from the eluate of 5% ethyl acetate Z hexane. Of mixture).

[0187] Compound 27, (E form): ¾ NMR (CDC1) δ: 0.01—0.11 (12H, Si—Me x 4)

Three

, 0.56 (3H, s, H-18), 0.85, 0.93 (each 9H, s, Si-tBu x 2, overlapp ed 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 O), 4.59 (1H, m

2

, H-l), 5.00 (2H, m, CH = CH), 5.47 (1H, m, H-3), 5.71 (1H, m, C

2

H = CH), 5.82 (1H, d, J = ll.3Hz, H-7), 6.16 (1H, m, C = CH), 6.19

2

(1H, d, J = ll.3Hz, H-6), 10.18 (1H, d, J = 7.9Hz, CHO).

Compound 27, (Z form): ^X H NMR (CDC1) δ: 0.01—0.11 (12H, Si—Me x 4)

Three

, 0.55 (3H, s, H-18), 0.84, 0.93 (each 9H, s, Si— tBu x 2, overlapp ed 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 O), 4.68 (1H, m

2

, H— 3), 5.00 (2H, m, CH = CH), 5.52 (1H, m, H-l), 5.71 (1H, m, C

2

H = CH), 5.88 (1H, d, J = ll.3Hz, H— 7), 6.16 (1H, m, C = CH), 6.27

2

(1H, d, J = ll.3Hz, H-6), 10.17 (1H, d, J = 7.9Hz, CHO).

[Chemical 55]

[0189] Sodium borohydride (2.5 mg, 0.066 mmol, leq) was added to an ethanol (lml) solution of aldehyde 27, (50.3 mg, 0.066 mmol, approximately 1: 1 mixture) cooled to 0 ° C. Well, it 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 (5 g) to obtain Compound 27 ”(42. Omg, 83%, approximately 1: 1 mixture) from the eluate of 5% ethyl acetate / hexane.

[0190] Compound 27 "(E form): ¹ H NMR (CDCl) δ: 0.01—0.10 (12H, Si—Me x 4)

Three

, 0.552 (3H, s, H-18), 0.84, 0.91 (each 9H, s, Si— tBu x 2, overlap ped with H-21), 1.22 (6H, s, H— 26, 27), 3.37 ( 3H, s, OMe), 4.71 ( 2H, s, OCH O), 4.20, 4.30 (2H, m, CH OH), 4.38 (1H, m, H— 1), 4.

twenty two

81 (1H, m, H-3), 4.96 (2H, m, CH = CH), 5.72 (2H, m, CH = CH, C

twenty two

= CH), 5.88 (1H, d, J = ll.0Hz, H-7), 6.13 (1H, d, J = ll.0Hz, H-6).

Compound 27 "(Z form): ¹ H NMR (CDCl) δ: 0.01—0.10 (12H, Si—Me x 4)

Three

, 0.547 (3H, s, H-18), 0.83, 0.92 (each 9H, s, Si— tBu x 2, overlap ped with H— 21), 1.22 (6H, s, H— 26, 27), 3.37 ( 3H, s, OMe), 4.71 (2H, s, OCH O), 4.20, 4.30 (2H, m, CH OH), 4.46 (1H, m, H-3), 4.

twenty two

84 (1H, m, H-l), 4.96 (2H, m, CH = CH), 5.72 (2H, m, CH = CH, C

twenty two

= CH), 5.83 (1H, d, J = ll.0Hz, H-7), 6.22 (1H, d, J = ll.0Hz, H-6).

[0191] [Chemical 56]

[0192] Compound 27 "(42. Omg, 0.055mmol, mixture of about 1: 1) in methanol (lml) [Camphors norephonic acid (77. Omg, 0.332mmol, 6eq) Stir at room temperature [trowel 1.5 hours. Add 5% aqueous sodium hydrogen carbonate solution to the reaction mixture, extract with ethyl acetate, wash the organic layer with saturated brine, dry anhydrous magnesium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography (3 g) to obtain Compound 3b (24.2 mg, 90%, approximately 1: 1 mixture) from the elution part of 2% methanol Z acetate. HPLC [YMC— Pack ODS— AM SH— 342— 5, 20% HO / MeOH, 8 ml

2

Compound 3b (E form) (8.4 mg) and Compound 3b (Z form) (4.8 mg) were obtained. [0193] Compound 3b (E form): H NMR (CDC1) δ: 0.01— 0.10 (12H, Si-Me x 4),

Three

0.54 (3H, s, H-18), 0.84, 0.91 (each 9H, s, Si— tBu x 2, overlappe d with H-21), 1.22 (6H, s, H— 26, 27), 1.63 (3H , d, J = 5.5Hz, CH

Three

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 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

2

), 5.70 (1H, m, C = CH), 5.84 (1H, d, J = ll.1Hz, H-7), 6.13 (1H, d, J = ll.1Hz, H-6).

UV Imax (EtOH): 247nm (ε = 30800), 255nm (ε = 34500), 264nm (ε = 22400).

Compound 3b (Z form): ¹ H NMR (CDC1) δ: 0.01— 0.10 (12H, Si-Me x 4),

Three

0.53 (3H, s, H-18), 0.82, 0.92 (each 9H, s, Si -tBu x 2, overlappe d with H-21), 1.22 (6H, s, H— 26, 27), 1.62 (3H , d, J = 5.5Hz, CH

Three

CH = CH), 2.55 (1H, dd, J = 12.5, 5.0Hz, H—4), 2.83 (2H, m, H— 9, 10), 3.37 (3H, s, OMe), 4.71 (2H, s , OCH 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

2

UV Imax (EtOH): 247nm, 255nm, 264nm.

[0194] [Chemical 57]

— Compound 22 (158. Omg, 0.269 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (1.5 ml) was added to lithium bis (卜 -methylsilyl) amide (230 1, 0.230 mmol, 1.0 M tetrahydrofuran solution, 1. Oeq) was added to compound 22, and the mixture was stirred for 30 minutes, and then a solution of keton 49 (69.3 mg, 0.155 mmol) in anhydrous tetrahydrofuran (lml) was slowly added. — After stirring at 78 ° C for 1 hour, the temperature was gradually raised, and stirring was continued at 0 ° C for 1 hour. To the reaction solution was added saturated aqueous sodium chloride 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 (10 g) to obtain Compound 50 (1 12.4 mg, 57%, E: Z = 5: 3) from the eluate of 3% ethyl acetate Z-hexane. Compound 22 (64.8 mg, 41%) was recovered from the eluate with% ethyl acetate Z-hexane.

[0196] Compound 50a (E form) ^ H-NMRCCDCl) δ: 0.05 to 0.09 (18H, Si -Me x 6)

Three

, 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) , 4.25-4.45 (3H, m, H— 1, CH

Three

OTBS), 4.71 (2H, s, OCH O), 4.78 (1H, m, H-3), 4.97 (2H, m, CH

twenty two

= CH), 5.61 (1H, m, C = CH), 5.72 (1H, m, CH = CH), 5.89 (1H, d, J

twenty two

= 11.1Hz, H-7), 6.12 (1H, d, J = ll.1Hz, H-6).

Compound 50b (Z form) ^ H-NMRCCDCl) δ: 0.05 to 0.09 (18H, Si-Me x 6)

Three

, 0.54 (3H, s, H-18), 0.82 to 0.94 (30H, Si— tBu x 3, H— 21), 1.22 (6H, s, H-26, 27), 3.37 (3H, s, OCH) , 4.25-4.45 (3H, m, H— 3, CH

Three

OTBS), 4.71 (2H, s, OCH O), 4.78 (1H, m, H— 1), 4.97 (2H, m, CH

twenty two

= CH), 5.61 (1H, m, C = CH), 5.72 (1H, m, CH = CH), 5.83 (1H, d, J

twenty two

= 10.4Hz, H-7), 6.22 (1H, d, J = 10.4Hz, H-6).

Mass m / z (%): 872 (M ⁺ , 3), 740 (68), 678 (100), 621 (8).

[0197] [Chemical 58]

[0198] To a solution of 19-nor 50 (57.7 mg, 0.0661 mmol) in anhydrous tetrahydrofuran (300 1) was added 9 boronbicyclo [3.3.1] nonane (1.32 ml, 0.661 mmol, 10. Oeq). In addition, the mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with methanol (220 1) and stirred for 15 minutes. Next, the solution was cooled to 0 ° C, and 6M sodium hydroxide (20.2μ \, 1. 32 mmol, 20. Oeq) and 30% hydrogen peroxide (220 1) were added at room temperature. And stirred for 1 hour. 2N hydrochloric acid 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 evaporated. The residue was purified by silica gel column chromatography (10 g), and the compound 51a (E-form, 13. lmg, 22%) was obtained from the eluate of 8% ethyl acetate Z hexane, and 10% ethyl acetate Z hexane was obtained. Compound 51b (Z-form, 11.1 mg, 19%) was obtained from the eluate.

[0199] The Compound Sla: ¹ !! — NMR (CDC1) δ: 0: 05〜0.08 (18H, Si -Me x 6), 0.5

Three

5 (3H, s, H-18), 0. 83, 0. 89, 0. 93 (each 9H, s, Si— tBu x 3, overlap ped 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), 3.61 (2H, m, C

Three

HOH), 4.25-4.38 (3H, m, H— 1, CH OTBS), 4.71 (2H, s, OCH O),

2 2 2

4. 78 (1H, m, H-3), 5.61 (1H, m, C = CH), 5.93 (1H, d, J = ll. 1Hz, H -7), 6.11 (1H , d, J = ll. 1Hz, H— 6).

Mass m / z (%): 890 (M ⁺ , 2), 828 (5), 758 (52), 696 (100), 626 (10), 7 5 (93).

Sib: ¹ !! — NMR (CDC1) δ: 0.06 to 0.09 (18H, Si-Me x 6), 0.5

Three

4 (3H, s, H-18), 0. 82, 0. 90, 0. 93 (each 9H, s, Si— tBu x 3, overlap ped with H— 21), 1. 22 (6H, s, H- 26, 27), 3.37 (3H, s, OCH), 3.61

Three

(2H, m, CH OH), 4.30 (2H, m, CH OTBS), 4.44 (1H, m, H-3), 4. 71

twenty two

(2H, s, OCH O), 4. 83 (1H, m, H— 1), 5. 61 (1H, m, C = CH), 5. 87 (1H

2

, d, J = 10.4Hz, H-7), 6.22 (1H, d, J = 10.4Hz, H-6).

Mass m / z (%): 890 (M ⁺ , 1), 828 (1), 758 (20), 696 (22), 626 (4), 75 (100).

[0200] [Chemical 59]

[0201] 19-Nonole isomer 51a (E isomer, 13. lmg, 0.0147 mmol) in methanol (300 / z 1) solution was added with nephrosulfonic acid (34. lmg, 0.147 mmol, 10. Oeq) at room temperature The mixture was stirred for 2 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 evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain compound 3d (5.7 mg, 77%) from the 5% methanol / ethyl acetate eluate.

[0202] Compound Sd: ¹ !! — NMR (CDC1) δ: 0.56 (3Η, s, H—18), 0.94 (3H, d, J = 6

Three

OHz, H-21), 1.22 (6H, s, H— 26, 27), 2.17 (1H, t, J = 8.7Hz), 2.29, 2.41 (each IH, m, H— 4), 2.89 (1H , m, H—9), 3.16 (1H, m, H—10), 3.48, 3.60 (each IH, m, CH CH OH), 4.09 (IH, m, CH OH), 4.31 (

2 2 2

3H, m, H-l, CH OH, OH), 4.40 (1H, br.s, OH), 4.80 (1H, m, H-3)

2

, 5.74 (IH, m, C = CH), 5.97 (1H, d, J = 10.6Hz, H-7), 6.11 (1H, d, J = 10.6Hz, H-6).

Mass m / z (%): 504 (M ⁺ , 1), 486 (10), 468 (34), 450 (57), 432 (24), 3 86 (100), 339 (14).

UV Imax (EtOH): 246nm, 254nm, 264nm.

[0203] [Evaluation of transcription activation ability]

Evaluation was performed using E-form (3b-2E) of 9-aryl derivative (3b) and 1, 25- (OH) D which is a natural ligand as a comparative example. Measurements were taken in COS-7 cells, 9-substituents.

twenty three

Using a luciferase reporter gene incorporating W286R VDR created by site-directed mutagenesis with analog, the transcriptional activity of each ligand was measured. It was. The results are shown in Figure 1.

1, 25- (OH) D did not show any activity even at a concentration of 1 μΜ 9

twenty three

It was confirmed that the allyl derivative (3b) rod (3b-2Ε) induces transcription of mutant VDR, although it is weak.

Claims

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

[Chemical 1]

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

[2] The 9-substituted 19-norbita according to claim 1, wherein R ¹ in the general formula (1) is a methyl group, a butyl group, a hydroxypropyl group, a allyl group, or a trans-CH 2 CH = CHCH group.

twenty three

Min D derivative.

[3] 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.

[4] The 9-substituted 19 norbitamine D derivative according to any one of claims 1 to 3, represented by the following structural formula (3b):

[Chemical 2]

[5] The 9-substituted norvitamin D derivative according to any one of claims 1 to 4 as an active ingredient, Drugs for rickets or osteomalacia.