WO2006093291A1 - 19-norvitamin d derivative - Google Patents

Abstract

Disclosed is a 19-norvitamin D derivative which has enhanced pharmacological effects compared with a 1,25-(OH)2D3 derivative and is not accompanied by an adverse side effect of causing hypercalcemia. Also disclosed is a process for producing the derivative. The vitamin D derivative is 16-ene-22-thio-19-norvitamin D having all of the following three partial structures: (1) the introduction of a hetero atom (e.g., an oxygen or sulfur atom) into position 22 of the side chain in the vitamin D; (2) the introduction of a double bond into 16-17 positions of the D ring moiety; and (3) the removal of a 19-exomethylene group. Because this derivative is improved in transcription activity, osteoclast differentiation promoting activity, and activity of suppressing the differentiation into mature dendritic cells, it can be used as a therapeutic agent for osteoporosis, an autoimmune disease, rachtis or osteomalacia or a carcinostatic agent.

Description

 19_Norvitamin D derivative

 Technical field

 [0001] The present invention relates to a 16-ene 19-norvitamin D derivative having a hetero atom at the 22-position, which is useful as a pharmaceutical product.

 Background art

 [0002] Active 1,25 dihydroxyvitamin D (1, 25— (OH) represented by the following structural formula (a)

 Three

 ) D) regulates the metabolism of calcium through the vitamin D receptor present in the nucleus,

twenty three

 It expresses various biological effects such as cell division induction and growth inhibition. In addition, 1, 25- (O H) D has a strong differentiation-inducing activity against tumor cells and has a growth-suppressing action.

twenty three

 The application is being considered.

[0003] [Chemical 1]

[0004] However, 1, 25- (OH) D is a concentration that exerts an anticancer effect and also has a calcium concentration in serum.

 twenty three

 Increases and induces hypercalcemia. Therefore, while it has an effect of inducing differentiation of tumor cells, the effect of increasing calcium in blood is weak! Development of a vitamin D derivative having characteristics is desired.

[0005] In this regard, the following Non-Patent Document 1 discloses that the biological activity of a vitamin D derivative having a hydroxyethoxy group introduced at the 2-position of the A ring portion has a stronger activity than that of a natural ligand. . For example, in the 20-epoxy-2 18-hydroxyethoxy compound represented by the following structural formula (b), 1, 25- (OH) D has a VDR affinity of 1, 25- (OH) D. 5 times, COS— Transcriptional activity in 7 is 30 times higher, and in the osteoclast fraction inducing action, the activity is about 100 times higher.

 [Chemical 2]

[0007] In addition, 2MD having a structure in which the 19-exomethylene group of vitamin D is moved to the 2-position represented by the following structural formula (c) has a VDR affinity of 1, 25- (OH) D. Somewhat weaker than

 twenty three

 It is a 19-norvitamin D derivative that is about 100 times more potent in terms of transcriptional activity in COS-7 cells, promotion of RANKL transcription, and osteoclast induction.

[0008] [Chemical 3]

[0009] Non-patent literature l: Shimizu M et al, J Steroid Biochem Mol Biol, 2004, 89/90, 7 5-81

 Disclosure of the invention

 Problems to be solved by the invention

[0010] However, the biological activity of the compound of Non-Patent Document 1 or the vitamin D derivative having the above partial structure is still insufficient. For this reason, higher biological activity is demonstrated at lower doses. There is a need for the development of composites.

 [0011] The present invention has been made in view of the above problems, and its purpose is to clarify the enhancement of the pharmacological effect of the 1,25- (OH) D derivative and the side effect of hypercalcemia. In isolation

twenty three

 It is to provide a vitamin D derivative and a method for producing the same.

 Means for solving the problem

[0012] As a result of intensive studies to solve the above-mentioned problems, the present inventor has structurally the following characteristics of the vitamin D derivative that enhances the differentiation-inducing action of cells with weak blood calcium increasing activity. I found out. [1] Introduction of a heteroatom (oxygen atom) at position 22 in the side chain of vitamin D, [2] Introduction of a double bond at positions 22–23, [3] D ring 16– 17 [4] Removal of 19-exomethylene group.

[0013] Then, the present inventors have found that a norbitamin D derivative having the three partial structures of [1], [3] and [4] out of the above four exhibits strong activity, and completes the present invention. It came to. More specifically, the present invention provides the following.

[0014] (1) represented by the following general formula (1) or (2), having a substituent at the 2-position, a heteroatom at the 22-position, and a double bond at positions 16-17 of the D ring part 19—Norvitamin D derivative.

[0015] [Chemical 4]

[0016] [Chemical 5]

(Where, is a hydroxyalkoxyl group, a hydroxyalkylidene group, X is a heteroatom, and n is an integer of 1 to 4.)

[0017] (2) The 19 norbitamine D derivative according to (1), wherein the heteroatom is a sulfur atom or an oxygen atom.

 [0018] (3) The 19 norvitamin D derivative according to (1) or (2), which is the R 1S hydroxyethoxy group or hydroxyethylidene group in the general formula (1) or (2).

 [0019] (4) A 19-nor vitamin D conductor represented by the following structural formulas (11a), (12a), (lib), and (12b). Of these, the 19 norvitamin D derivative represented by the structural formula (12a) is particularly preferable.

[0020] [Chemical 6]

§S

[0024] (5) Synthesizing a CD ring synthon and an A ring phosphinoxide, producing a 19-norvitamin D skeleton by coupling reaction, and then modifying the structure to the 2-position. (1) to (4 ) A method for producing a 19 norvitamin D derivative according to any one of the above.

[0025] (6) Osteoporosis therapeutic agent, anticancer agent, autoimmune disease therapeutic agent, rickets therapeutic agent, comprising 19 norvitamin D derivative according to any one of (1) to (4) as an active ingredient, or A drug to treat osteomalacia. [0026] (7) A 19-norvitamin D derivative represented by the following general formula (3), having a heteroatom at the 22-position and a double bond at the 16-17-position of the D ring portion.

[0027] [Chemical 10]

(However, X is a heteroatom, and n is an integer from 1 to 4.)

[0028] (8) 19 norvitamin D represented by the following general formula (4), having a substituent at the 2-position, a heteroatom at the 22-position, and a double bond at positions 16-17 of the D ring part Derivative.

[0029] [Chemical 11]

(Where R is a linear or branched alkyl group having 1 to 4 carbon atoms, X is a heteroatom, n Indicates an integer from 1 to 4. )

[0030] (9) The 19-nor vitamin D derivative according to (7) or (8), wherein the heteroatom is a sulfur atom or an oxygen atom.

[0031] (10) An osteoporosis therapeutic agent, an anticancer agent, an autoimmune disease therapeutic agent, a rickets therapeutic agent, or osteomalacia, comprising the 19 norvitamin D derivative according to any one of (7) to (9) as an active ingredient Therapeutic drugs.

 The invention's effect

 [0032] As described above, the 19-nor vitamin D derivative of the present invention is structurally [1] introduction of a heteroatom (oxygen or iow atom) into the 22-position of the side chain of vitamin D; [3] D ring Part 16—A structure that combines three partial structures: introduction of a double bond at positions 17 and [4] removal of the 19-exomethylene group. Thereby, transcription activity, osteoclast differentiation promoting activity, and activity of inhibiting the differentiation to mature rod cells are improved. Among them, the compound of the above structural formula (lb) has particularly strong activity.

 [0033] Therefore, the 19 norvitamin D derivative of the present invention is particularly preferably used as an osteoporosis therapeutic agent, an anticancer agent, an autoimmune disease therapeutic agent, a rickets therapeutic agent, or an osteomalacia therapeutic agent. I'll do it.

 [0034] Further, according to the production method of the present invention, the CD ring synthon and the A ring part are separately synthesized, and the 19-norvitamin D skeleton is produced by a coupling reaction, followed by structural modification at the 2-position. Thus, the 19-norvitamin D derivative having a substituent at the 2-position can be easily produced.

 Brief Description of Drawings

 [0035] FIG. 1 is a diagram showing the evaluation of transcription activation ability of vitamin D derivatives represented by structural formulas (lla) and (12a).

 FIG. 2 is a diagram showing the evaluation of transcription activation ability of vitamin D derivatives represented by structural formulas (l ib) and (12b).

 FIG. 3 shows the evaluation of 1, 25- (OH) D and 2MD for osteoclast differentiation.

 twenty three

FIG. 4 is a graph showing the evaluation of osteoclast differentiation of vitamin D derivatives represented by structural formulas (11a) and (12a). FIG. 5 is a graph showing the evaluation of osteoclast differentiation of vitamin D derivatives represented by structural formulas (l ib) and (12b).

 FIG. 6 is a graph showing the inhibitory effect of 2-substituted 19 norvitamin D derivatives on mature rod cells.

 FIG. 7 is a graph showing the biological activity of a 2-substituted 19 norvitamin D derivative.

 FIG. 8 is a graph showing evaluation of VDR binding activity of vitamin D derivatives represented by structural formulas (15a) and (15b).

 FIG. 9 is a graph showing evaluation of VDR binding activity of vitamin D derivatives represented by structural formulas (16a) and (16b).

 FIG. 10 is a graph showing evaluation of VDR binding activity of vitamin D derivatives represented by structural formulas (17a) and (17b).

 FIG. 11 is a diagram showing the evaluation of transcription activation ability of vitamin D derivatives represented by structural formulas (15a) and (15b).

 FIG. 12 is a diagram showing the evaluation of transcriptional activity of vitamin D derivatives represented by structural formulas (16a) and (16b).

 FIG. 13 is a graph showing the evaluation of transcriptional activity of vitamin D derivatives represented by structural formulas (17a) and (17b).

 [Figure 14] Diagram showing biological activity of 19-norvitamin D derivative

 BEST MODE FOR CARRYING OUT THE INVENTION

[0036] [Method for Synthesizing Vitamin D Derivatives Represented by General Formulas (1) and (2)]

 In the 19-nor vitamin D derivative of the present invention (hereinafter also simply referred to as vitamin D derivative)

The vitamin D derivatives represented by the general formulas (1) and (2) were synthesized separately from the CD ring synthon and the A ring part, respectively, and the 19-nor vitamin D skeleton was constructed by a coupling reaction. Can be manufactured by structural modification.

[0037] Hereinafter, an example of a method for producing the compounds of the general formulas (1) and (2) will be specifically described.

 [0038] <Method of synthesizing CD ring synthon>

CD ring synthons represented by structural formulas (3 la) and (3 lb) , 11 steps or 12 steps.

[0039] After ozonolysis using vitamin D as a starting material, it is reduced with sodium borohydride.

 2

 To obtain the diol (21). In the diol (21), the primary hydroxyl group is tosylated, and the hydroxyl group at the 8-position is protected with TBS to obtain a compound (22), which is then converted into an aldehyde (23) with DMSO acid. The aldehyde form (23) is attached to oxygenate to form 20 keto form (24), and the keto group is reduced to obtain 20 alcohol form (7). The ratio of isomers was about 8: 1, and many 20-epide forms were synthesized. 20 After dehydration of the alcohol (25a) with phosphoryl chloride, a hydroxyl group is stereoselectively introduced into the 16-position with selenium dioxide ZT BHP to give compound (27a). When the compound (27a) is treated with phenol chlorothionoformate, the [3, 3] sigmatropic rearrangement proceeds smoothly, and the 20S form (28a) of the thiocarbonate form can be obtained as a single solid. I'll do it.

 [0040] The 20R form of thiocarbonate (28b) is obtained by subjecting compound (27a) to Swern oxidation followed by NaBH.

 4 Subsequent to reduction to give the 16 | 8-alcohol (27b) and then treated in the same manner as compound (27a). The 20S form (28a) of the thiocarbonate form is introduced into the methyl ester form (29a) by introducing a side chain unit into the ethyl bromoacetate under alcoholysis conditions and treating the resulting carboxylic acid with diazomethane. The methyl ester compound is converted into a diol compound (30a) by removing the protecting group at the 8-position after introducing a jetyl group by Grignard reaction. The 8th alcohol is swern oxidized to a ketone body, and finally the 25th hydroxyl group is protected to obtain the 20S form (3 la). Treat the 20R body (28b) of the thiocarbonate body in the same way to obtain the 20R body (3 lb).

[0041] [Chemical 12]

[0042] <Method for synthesizing 22 thia 19 norvitamin D derivatives>

 Next, a 22-thia 19 norvitamin D analog is synthesized by a coupling reaction between the synthesized CD ring synthon and the A ring phosphine oxide. Coupling of the 20S form (31 a) of CD ring synthon and the A ring phosphine oxide form (32) by using LiHMDS as the base, the 19 nor form (ratio of the 2-position isomer: about 3: 2) (33a) is obtained. The 19-nor compound (33a) selectively removes the TMS group under acidic conditions under acetic acid and leads to the 2-alcohol compound (34a). 2 Alcohol (34a) is etherified, followed by deprotection reaction to give (20S) -2 hydroxyethoxy 19 norvitamin D derivative (1 la), (12a). The two stereoisomers are separated by HPLC using an ODS column. Similarly, (20R) -2 hydroxyethoxy 19 norvitamin D derivatives (1 lb) and (12b) are obtained from the 20R form (3 lb) of the CD ring synthon.

[0043] [Chemical 13]

 #) M. Shimizu, et a ^ ioolg. Med. ChemLett '2003, 13, 809812.

 United States Patent, No, 6,844,461

[0044] The above is the force when is a hydroxyethoxy group. In the present invention, is, for example, (20S) -2 hydroxyethylidene 19 norvitamin D derivative (13a) (14a) as shown below. In this case, from the above structural formula (33a), it can be produced by the following method in 6 steps.

[0045] [Chemical 14]

[0046] Also, (20R) -2-hydroxyethylidene 19-norvitamin D derivative (13b), (14b

) Can be produced from structural formula (33b) by the following method in 6 steps.

[0047] [Chemical 15]

[0048] [Method for Synthesizing Vitamin D Derivatives Represented by General Formulas (3) and (4)]

 Similarly, for the vitamin D derivatives represented by the general formulas (3) and (4), a CD ring synthon and an A ring part are separately synthesized, and a 19-nor vitamin D derivative is produced by a coupling reaction. be able to. Hereinafter, an example of the manufacturing method will be specifically described.

 [0049] (20S) -22 thia-19, 24 Dinorvitamin D derivative (15a) is converted into (20R) -22 thia-19,24 dinorvitamin D derivative (15b) by the seven steps from structural formula (28a). From formula (28b), it can be produced by the following method in 7 steps.

[0050] [Chemical 16]

[0051] [Chemical 17]

[0052] (20S) -22 thia-19 norvitamin D derivative (16a) is represented by the structural formula (28a) to about 7 from (20R) -22 thia-19 norvitamin D derivative (16b) From 28b), it can be produced by the following method in 7 steps.

[0053] [Chemical 18]

(20S) —22 thia-24 homo-19 norvitamin D derivative (17a) is composed of (20R) -22 thia-24 homo-19 norvitamin D derivative (1b) according to the structural formula (28) through 7 steps. From (28b), it can be produced by the following method in 7 steps. [0056] [Chemical 20]

 [0057] [Chemical 21]

[0058] (20S) -2 α-methyl-2 j8-hydroxy 19 norvitamin D derivative (18a), (20 S) -2 j8-methyl-2 α hydroxy-19 norvitamin D derivative (19a) It can be produced by the following method by a coupling reaction of a 20S form (31a) of a synthon and an A ring phosphine oxide form (54). In addition, (20R) -2α-methyl 2 | 8-hydroxy 1 19 norvitamin D derivative (18b), (20R) -2 j8-methyl-2 α-hydroxy 19 nor vitamin D derivative (19b) It can be produced by the following method by coupling reaction of 20R form (31b) and A ring phosphine oxide form (54).

 [0059] [Chemical 22]

[0060] [Chemical 23]

 18b 19b

[0061] <Method for synthesizing 22oxy19-norvitamin D derivative>

 The 20S isomer (20a) (64a) and 20R isomer (64b) of the CD ring synthon were prepared by the following 9 steps including the 20S isomer (20a isomer (25a), 20R isomer (25b) force). Coupling reaction with A-ring phosphinoxide (40) gave (20S) -22-oxa-19 norvitamin D derivative (2 Oa), (20R) -22-oxa 19 norvitamin D derivative (20b) Manufacturing.

[0062] [Chemical 24]

[0063] [Chemical 25]

[0064] [drug]

 The vitamin D derivative of the present invention can be used as an osteoporosis therapeutic agent, an anticancer agent, an autoimmune disease therapeutic agent, a rickets therapeutic agent, or an osteomalacia therapeutic agent (hereinafter also referred to as “therapeutic agent”).

[0065] <Dosage form>

 In addition to containing the vitamin D of the present invention as an active ingredient, the therapeutic agent contains the necessary additives, and in accordance with conventional methods, solid oral preparations, oral liquid preparations, or parenteral preparations such as injections Can be prepared as Most preferred is a solid oral formulation.

[0066] 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, if necessary, hydroxypropyl Binders such as cellulose and hydroxypropylmethylcellulose (HPMC), lubricants such as magnesium stearate, polyethylene glycol, starch and talc, disintegrants such as calcium cellulose glycolate and carmellose calcium, stabilizers such as ratatose, It can be prepared by mixing 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. 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.

 [0067] When preparing an oral liquid preparation, an inert diluent taste-masking agent such as purified water or 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.

 [0068] The injection may be a sterile aqueous or non-aqueous solution, suspension, emulsion, etc., and may be a subcutaneous, intramuscular or 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. Further, if necessary, a pH adjuster, buffer, preservative, wetting agent, emulsifier, dispersant, stabilizer (eg, ratatose), isotonic agent, local anesthetic, solubilizing agent (eg, glutamic acid, Aspartic acid) may be added.

 [0069] <Effective dose>

 The effective dose of the vitamin D derivative of the present invention varies depending on the patient's body weight, age, sex, administration method, physical condition, symptom, dosage form, etc.In the case of oral administration to adults, 0.001 μg to 50 g or less per day More preferably, it is 0.01 g or more and 10 g or less, and it is preferable to take it once or in 2 to several times.

 Example

<0070><(20S) 2-hydroxyethoxy 19-norvitamin D derivative (11a), (12a), (20S) -2 hydroxyethylidene-one 19-norvitamin D derivative (13a), (14a) synthesis> The following scheme According to the procedure described above, synthesis was performed according to the following procedure. [0071] [Chemical 26]

[0072] [Chemical 27]

[0073] After bubbling oxygen gas into a solution of potassium t-butoxide (205. lmg, 1.83mmol, 1.25eq) in anhydrous t-butanol (2Oml) for 15 minutes, the aldehyde 23 (474.3mg, 1.4 6mmol) Anhydrous t-butanol (5 ml) solution was slowly added, and the mixture was further stirred for 15 minutes while bubbling oxygen gas. After the reaction check, argon gas was bubbled for 10 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (20 g), and 20-keto 24 (375.8 mg, 83%) was obtained from the eluate of 5% ethyl acetate Z-hexane.

 [0074] Compound 23: 11— NMR (CDC1) δ: — 0.01, 0.01 (each 3H, s, SiMe x 2)

 Three

 , 0.88 (9H, s, tBuSi), 0.96 (3H, s, H—18), 1.08 (3H, d, J = 6.6Hz, H-21), 2.35 (1H, ddd, J = ll.5, 6.8 , 3.2Hz, H-20), 4.02 (1H, m, H-8), 9.57 (1H, d, J = 3.2Hz, CHO).

 Compound 24: 11—NMR (CDC1) δ: 0.00, 0.01 (each 1H, s, SiMe x 2), 0

 Three

 .87 (9H, s, tBuSi), 0.85 (3H, s, H—18), 2.09 (3H, s, H—21), 4.04 (1 H, m, H—8).

Mass m / z (%): 310 (M ⁺ , 2), 253 (100), 161 (29), 145 (23), 119 (43), 75 (57).

 [Chemical 28]

 24 25a 25b

[0075] To a solution of 20-keto 24 (1.90 g, 6.131 mmol) cooled to 0 ° C in methanol (20 ml) Sodium borohydride (231.9 mg, 6.131 mmol) 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 (70 g), and 20-alcohol 25a (20S, 1.67 g) and 25b (20R, 208. Omg) were obtained from the eluate of 2% ethyl acetate Z hexane. (Total 98%)

[0076] The compound SSa ^ H— NMR (CDC1) δ: — 0.003, 0.01 (each 3H, s, SiMe x

 Three

 2), 0.89 (9H, s, tBuSi), 1.01 (3H, s, H—18), 1.12 (3H, d, J = 6.1Hz, H—21), 3.73 (1H, m, H—20), 4.01 (1H, m, H— 8).

Mass m / z (%): 312 (M ⁺ , 1), 255 (19), 237 (100), 161 (38), 75 (72). Compound SSb: ¹ !! — NMR (CDC1) δ: — 0.003, 0.01 (each 1H, s, SiMe x

 Three

 2), 0.88 (9H, s, tBuSi), 0.91 (3H, s, H—18), 1.20 (3H, d, J = 6.2Hz, H—21), 3.68 (1H, m, H—20), 4.02 (1H, m, H-8).

Mass m / z (%): 312 (M ⁺ , 1), 255 (5), 237 (100), 161 (45), 75 (94).

[0077] [Chemical 29]

[0078] Phosphorinorechloride (POC1, 800 μ1, 8.561 mmol, 2 eq) was added to an anhydrous pyridine (15 ml) solution of 20-anoleconole 25a (1.33 g, 4.281 mmol) cooled to 0 ° C. . 1 in C

 Three

 The mixture was stirred at room temperature for 21 hours. The reaction solution was transferred to ice water, 2NHC1 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 (30 g), and Compound 26 (975.6 mg, 77%) was obtained from the hexane eluate.

[0079] 匕 Compound Ζδ ^ Η—NMR (CDC1) δ: 0.01, 0.02 (each 3H, s, SiMe x 2), 0

 Three

.89 (9H, s, tBuSi), 1.11 (3H, s, H—18), 1.64 (3H, dt, J = 7.1, 2.0Hz, H-21), 4.07 (1H, m, H —18), 5.04 (1H, qt, J = 7.1, 2.0Hz, H— 20). Mass m / z (%): 294 (M ⁺ , 6), 237 (100), 161 (85), 75 (75).

 [0080] [Chemical 30]

[0081] Selenium dioxide (177.5 mg, 1.600 mmol, 0.5 eq) in dichloromethane cooled to 0 ° C

(5ml) solution [This _{^{70 0 / ο ΐΒιιΟΟΡί (552 /}} ζ1, 3.839mmol, 1.2eq) mosquitoes卩免1:00 f¾¾t frame was then Compound 26 (1. OOg, 3.199mmol) in dichloromethane (10ml) solution of It was dripped. After stirring at room temperature for 4 hours, the reaction solution was transferred to ice water, 10% NaOH 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 (30 g) to obtain Compound 27a (847. Omg, 85%) from the eluate of 5% ethyl acetate Z hexane.

[0082] Compound SYa: ¹ !! — NMR (CDC1) δ: 0.01, 0.02 (each 3H, s, SiMe x 2),

 Three

 0.88 (9H, s, tBuSi), 1.14 (3H, s, H—18), 1.71 (3H, dd, J = 7.2, 1.1Hz, H—21), 4.10 (1H, m, H—8) , 4.44 (1H, m, H--16), 5.51 (1H, qd, J = 7.1, 1.1Hz, H-20).

 Mass m / z (%): 310 (no M +), 235 (100), 160 (75), 75 (90).

[0083] [Chemical 31]

 28a

Compound 27a (630.2 mg, 2.029 mmol) cooled to 0 ° C in anhydrous pyridine (6 ml) was added to phenol chlorothionophonolemate (PhOC (S) Cl, 330 1, 2.435 mmol, 1.2 eq) The caro escaped. After 3.5 hours, the reagent (220 1, 1.623 mmol, 0.8 eq) was added and stirred for another 2.5 hours. Transfer the reaction solution to ice water, add 2NHC1, and extract with ethyl acetate. did. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (30 g) to obtain Compound 28a (772.5 mg, 85%) from the eluate of 3% ethyl acetate Z hexane.

[0085] Compound SSa ^ H— NMR (CDC1) δ: 0.026, 0.030 (each 3H, s, SiMe x 2

 Three

 ), 0.89 (9H, s, tBuSi), 1.19 (3H, s, H—18), 1.54 (3H, d, J = 7.1Hz, H-21), 2.31 (1H, m, H—15), 4.06 (1H, q, J = 7.1Hz, H-20), 4.10 (1H, m, H-8), 5.70 (1H, m, H-16), 7.16-7.39 (5H, m, arom H).

Mass m / z (%): 446 (M ⁺ , 1), 389 (2), 292 (10), 235 (100), 161 (80), 7 5 (85).

[0086] [Chemical 32]

[0087] Ethyl bromacetate (550 1, 4.978 mmol, 3 eq) was added to a solution of the compound 28a (740.5 mg, 1.659 mmol) in 10% KOHZMeOH (10 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was transferred to ice water, and 2NHC1 was collected 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 dissolved in dichloromethane (10 ml), cooled to 0 ° C., and a solution of diazomethane in jetyl ether (about 0.5 M, 10 ml) was added. After stirring at 0 ° C for 30 minutes, the solvent was distilled off. The residue was purified by silica gel column chromatography (20 g) to obtain Compound 29a (6 61. Omg, 99%) from the eluate of 3% ethyl acetate Z hexane.

[0088] The compound SSa: ¹ !! — NMR (CDC1) δ: 0.02 (6Η, s, SiMe x 2), 0.88 (9H, s

 Three

 , tBuSi), 1.12 (3H, s, H— 18), 1.36 (3H, d, J = 7.0Hz, H— 21), 2.28 (1 H, m), 3.16 (2H, s, H— 23 ), 3.57 (1H, q, J = 7.0Hz, H-20), 3.71 (3H, s, OMe), 4.07 (1H, m, H-8), 5.64 (1H, m, H-16).

Mass m / z (%): 398 (M ⁺ , 35), 383 (15), 341 (28), 256 (19), 235 (92), 161 (100), 75 (58).

[0089] [Chemical 33]

 29a 29a '29a'

[0090] Ethylmagnesium bromide (4.97 ml, 4.974 mmol, 3 eq, 1. OM THF solution) was added to an anhydrous THF (5 ml) solution of Compound 29a (661. Omg, 1.658 mmol) cooled to 0 ° C. added. After stirring for 3 hours, the reagent (1.66 ml, 1.66 mmol, leq) was added, and the mixture was further stirred for 2 hours. The reaction mixture was transferred to ice water, 2NHC1 was added, 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 the ketone body 29a, (154.2 mg, 23%) and alcohol 29a '(494. Omg, 70%) were eluted from the 2% ethyl acetate / hexane eluate. ) Was obtained.

[0091] SS compound "SSa": ¹ !! — NMR (CDC1) δ: 0.022, 0.024 (each 3H, s, SiMe x

 Three

 2), 0.89 (9H, s, tBuSi), 1.08 (3H, t, J = 7.3Hz, H-26), 1.12 (3H, s, H-18), 1.35 (3H, d, J = 7.0 Hz, H—21), 2.61 (2H, m, H—25), 3.18 (2H, m, H-23), 3.39 (1H, q, J = 7.0Hz, H—20), 4.08 (1H, m , H—8), 5.6 4 (1H, m, H—16).

Mass m / z (%): 396 (M ⁺ , 35), 324 (32), 267 (37), 235 (73), 161 (100), 75 (80).

 Compound 29a 'NMR (CDC1) δ: 0.03 (6H, s, SiMe x 2), 0.89 (9H, s

 Three

 , tBuSi), 0.87 (6H, t, J = 7.4Hz, H— 26a, 27a), 1. 15 (3H, s, H— 18), 1.37 (3H, d, J = 7.0Hz, H— 21), 2.56 (2H, s, H-23), 3.37 (1H, q, J = 7.0Hz, H-20), 4.08 (1H, m, H— 8), 5.63 (1H, m, H— 16).

Mass m / z (%): 426 (M ⁺ , 38), 408 (20), 235 (91), 161 (100), 75 (62).

[0092] [Chemical 34]

 29a '30a

[0093] p-Toluenesulfonic acid monohydrate (723.4 mg, 3.803 mmol, 3 eq) was added to a solution of compound 29a '(541. Omg, 1.268 mmol) in methanol (5 ml) cooled to 0 ° C. After stirring at room temperature for 5 hours, the reaction solution was transferred to ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (20 g) to obtain alcohol 30a (328.8 mg, 83%) from the eluate of 20% ethyl acetate Z hexane.

 [0094] Compound 30 &: — NMR (CDC1) δ: 0.87 (6Η, t, J = 7.4Hz, H— 26a, 27a)

 Three

 , 1.19 (3H, s, H-18), 1.39 (3H, d, J = 6.9Hz, H-21), 2.57 (2H, s, H -23), 3.38 (1H, q, J = 6.9Hz, H-20), 4.18 (1H, m, H-8), 5.67 (1H, m, H-16).

Mass m / z (%): 312 (M ⁺ , 1), 294 (6), 276 (16), 160 (73), 145 (100).

 [0095] [Chemical 35]

[0096] To a solution of oxalyl dichloride (187 1, 2.145 mmol, 2.2 eq) in anhydrous dichloromethane (2 ml) cooled to 78 ° C, dimethyl sulfoxide (303 ΐ, 4.29 mmol, 4.4 eq) in anhydrous dichloromethane (0.5 ml) After the solution was stirred for 10 minutes, a solution of compound 30a (304.7 mg, 0.9 75 mmol) in anhydrous dichloromethane (3 ml) was prepared. After stirring at 78 ° C. for 15 minutes, triethylamine (1.36 ml, 9.75 mmol, 10 eq) is added 78. 15 minutes at C, 0. Stir at C for 30 min. Ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. Silica gel column The product 30a ′ (251.2 mg, 83%) was obtained from the fraction eluted with 15% ethyl acetate / hexane.

[0097] Compound 30a,: One NMR (CDC1) δ: 0.87, 0.88 (each3H, t, J = 7.5Hz, H

 Three

-26a, 27a), 0.97 (3H, s, H— 18), 1.44 (3H, d, J = 7.0Hz, H— 21), 2.5 4, 2.58 (each 1H, d, J = 12.9Hz, H— 23), 2.87 (1H, dd, J = 10.5, 6.3 Hz, H-14), 3.46 (1H, q, J = 7.0Hz, H—20), 5.59 (1H, m, H—16). / z (%): 310 (M ⁺ , 13), 292 (49), 209 (29), 177 (100), 115 (49)

[0098] [Chemical 36]

To a solution of compound 30a cooled to 0 ° C, (98.9mg, 0.319mmol) in anhydrous dichloromethane (lml) (iso-Pro) NEt (278 ^ 1, 1.595mmol, 5eq) and ΜΟΜ. 1 (60 1, 0.796

 2

 mmol, 2.5 eq) was added and the mixture was stirred at room temperature for 19 hours at 0 ° C. The reaction mixture was transferred to ice water, 2 NHC1 was added, and the mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (7g), and the compound 31a (82. lmg, 73%) was obtained from the 10% ethyl acetate / hexane eluate, and further eluted with 30% ethyl acetate Z-hexane. The unreacted raw material 30a ′ (26.7 mg, 26%) was recovered from the portion.

[0099] Compound Sla ^ H—NMR (CDC1) δ: 0.86, 0.87 (each 3H, t, J = 7.4Hz, H

 Three

 -26a, 27a), 0.97 (3H, s, H— 18), 1.44 (3H, d, J = 7.0Hz, H— 21), 2.4 9 (1H, m, H-15), 2.58, 2.64 (each 1H, d, J = 12.2Hz, H—23), 2.86 (1H, m, H-14), 3.40 (3H, s, OMe, overlapped with H—20), 4.69 (2H, s, OCH O), 5.58 (1H, m, H-16).

 2

Mass m / z (%): 354 (M ⁺ , 1), 292 (8), 252 (13), 176 (100), 117 (92). [0100] [Chemical 37]

 33a

[0101] — A solution of ring A phosphinoxide (380.4mg, 0.577mmol, 1.5eq) cooled to 78 ° C in anhydrous THF (3ml): LHMDS (577; zl, 0.577mmol, 1.0 M THF solution, 1.5 eq) was added, and the mixture was stirred for 30 minutes, and a solution of ketone 31a (136.4 mg, 0.385 mmol) in anhydrous THF (1.5 ml) 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. 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 distilled off. The residue was purified by silica gel column chromatography (15 g) to obtain compound 33a (mixture of 116.5 mg, 38%, approx. 3: 2) from the eluate of 3% ethyl acetate Z hexane, and 10% ethyl acetate Z hexane. Unreacted raw material 31a (82.3 mg, 60%) was recovered from the eluate, and A ring phosphine oxide (254. Omg) was recovered from the eluate of 30% ethyl acetate Z hexane.

[0102] Compound SSa: ¹ !! — NMR (CD OD) δ: 0.04〜0.07 (12Η, s, SiMe χ 4), 0.

 Three

 12, 0.130 (2: 3) (9Η, s, SiMe χ 3), 0.82 ~ 0.90 (27Η, m, Η— 18, 26a, 27a, tBuSi χ 2), 1.42 (3Η, d, J = 7. OHz , H—21), 2.63 (2H, m, H—23), 2.79 (1H, m, H—9), 3.40 (3H, s, OMe, overlapped with H—20), 3.54, 3.61 (3 : 2) (1H, m, H- 2), 3.80 (1H, m), 3.88, 3.93 (3: 2) (1H, m), 4.69 (2H, s, OCH O), 5.61 (1H, m, H-16), 5.79 (1H, m, H-7), 6.

 2

 09 (1H, m, H-6).

Mass m / z (%): 794 (M ⁺ , 1), 732 (3), 616 (53), 484 (94), 427 (47), 30 9 (36), 73 (100).

[0103] [Chemical 38]

[0104] Compound 33a (122.5 mg, 0.154 mmol, mixture of about 3: 2) was dissolved in 1/7 7 acetic acid 7 water (8: 8: 1, 8.5 ml) and stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution and then with 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 (7 g) to obtain Compound 34a (a mixture of 102.3 mg, 92%, about 3: 2) from the eluate of 3% ethyl acetate Z-hexane.

[0105] Compound S a: ¹ !! — NMR (CD OD) δ: 0.06 to 0.10 (12Η, s, SiMe χ 4), 0.

 Three

 82〜0.90 (27Η, m, Η— 18, 26a, 27a, tBuSi χ 2), 1.42 (3Η, d, J = 7.0 Hz, H-21), 2.64 (2H, m, H— 23), 2.79 ( 1H, m, H— 9), 3.40 (3H, s, O Me, overlapped with H— 20), 3.51, 3.60 (3: 2) (1H, m, H— 2), 3.89 to 4.02 (2H, m , H— 1, 3), 4.69 (2H, s, OCH O), 5.62 (1H, m, H— 16), 5

 2

 .89 (1H, d, J = ll.2Hz,, H-7), 6.16 (1H, m, H-6).

 Mass m / z (%): 722 (no M +), 660 (2), 603 (2), 544 (10), 355 (35), 30 9 (32), 75 (100).

[0106] [Chemical 39]

[0107] —A solution of oxalyl dichloride (14 / zl, 0.156 mmol, 1.2 eq) in anhydrous dichloromethane (lml) cooled to 78 ° C and anhydrous dichloromethane (22 0.3, 0.312 mmol, 2.4 eq) in anhydrous dichloromethane (0.5 ml) The solution was stirred for 10 minutes, and then a solution of compound 34a (94. Omg, 0.13 Ommol, about 3: 2) in anhydrous dichloromethane (lml) was prepared. After holding at 78 ° C for 15 minutes, HJ ethenoreamine (91 1, 0.650 mmol, 5 eq) was calo-free, 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 dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (7 g) to obtain compound 35a (88. lmg, 94%) from the eluate of 3% ethyl acetate Z-hexane.

[0108] Compound SSa: ¹ !! — NMR (CDC1) δ: 0.059, 0.065, 0.070, 0.101 (each 3

 Three

 H, s, Si— Me x 4), 0.87, 0.90 (each 9H, s, Si— tBu x 2, overlapped with H-18, 26a, 27a), 1.43 (3H, d, J = 7.0Hz, H— 21), 2.60, 2.66 (each 1H, d, J = 12.3Hz, H— 23), 2.81 (1H, m, H— 9), 3.40 (3H, s, OM e, overlapped with H— 20), 4.35 (1H, dd, J = 6.2, 4.1Hz), 4.56 (1H, dd, J = 8.9, 5.6Hz), 4.69 (2H, s, OCH O), 5.62 (1H, m, H-16), 5.90

 2

 (1H, d, J = ll.2Hz, H-7), 6.35 (1H, d, J = ll.2Hz, H-6).

 Mass m / z (%): 720 (no M +), 601 (10), 485 (100), 353 (78).

[0109] [Chemical 40]

 35a 36a

— N-Butyllithium (150 ΐ, 0.238 mmol, 1.59M hexane solution, 2 eq) in an anhydrous THF (lml) solution of jetyl cyanomethylphosphonate (39 1, 0.238 mmol, 2 eq) cooled to 40 ° C After stirring for 15 minutes, compound 35a (86.lmg, 0.119mmol) Anhydrous THF (lml) solution was added slowly. — After stirring at 40 ° C for 2 hours, 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 distilled off. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 36a (8 0.9 mg, 91%, approximately 1: 1 mixture) from the eluate of 3% ethyl acetate Z hexane.

[0111] 匕 Compound Sea: ¹ !! — NMR (CDC1) δ: 0.06-0.13 (12H, Si -Me x 4), 0.8

 Three

 2, 0.84 (1: 1) (9H, s, Si-tBu, overlapped with H— 18, 26a, 27a), 0.9 26, 0.930 (9H, s, tBu— Si), 1.43 (3H, d, J = 7.0Hz, H— 21), 2.79 (1H, m, H-9), 3.00, 3.11 (1: 1) (1H, m, H— 10), 3.40 (3H, s, OMe, overlap ped with H— 20), 4.690, 4.694 (1: 1) (2H, s, OCH O), 4.47, 5.00 (1

 2

 : 1) (1H, m, Hl), 4.58, 5.05 (1: 1) (1H, m, H-3), 5.48 (1H, d, J = l. 7Hz, C = CHCN), 5.62 (1H, m, H- 16), 5.88, 5.91 (1: 1) (1H, d, J = ll .2Hz, H-7), 6.18, 6.31 (1: 1) (1H, d, J = ll.2Hz, H—6).

Mass m / z (%): 743 (M ⁺ , 1), 681 (2), 565 (60), 508 (79), 481 (60), 73 (100).

[0112] [Chemical 41]

— Diisobutylaluminum hydride (DIBAL—H) (152 μm) in an anhydrous toluene (lml) solution of Compound 36a (75.8 mg, 0.102 mmol, mixture of E: Z = 1: 1) cooled to 78 ° C 1, 0.150 mmol, 1.0 M toluene solution, 1.5 eq) was added. After 1.5 hours, the reaction mixture was diluted with hexane and purified by silica gel column chromatography (5 g). Compound 37a (61.6 mg, 81%, approx. 1: 1). [0114] Compound 37a (E form): H—NMR (CDC1) δ: 0.02, 0.07, 0.09, 0. 10 (each

 Three

 3Η, s, Si— Me x 4), 0.83, 0.92 (each 9H, s, Si— tBu x 2, overlapped with H-18, 26a, 27a), 1.42 (3H, d, J = 7.0Hz, H— 21), 2.82 (1H, m, H-9), 3.05 (1H, m, H—10), 3.37 (3H, s, OMe, overlapped with H -20), 4.69 (2H, s, OCH O), 4.58 (1H, m, H—l), 5.46 (1H, m, H— 3)

 2

 , 5.62 (1H, m, H-16), 5.93 (1H, d, J = ll.4Hz, H-7), 6.16 (1H, m, C = CH), 6.19 (1H, d, J = ll. 4Hz, H—6), 10.19 (1H, d, J = 7.8Hz, CH

0).

 Compound 37a (Z form) ^ H-NMRCCDCl) δ: 0.02, 0.07, 0.10, 0.11 (each

 Three

 3H, s, Si— Me x 4), 0.84, 0.93 (each 9H, s, Si -tBu x 2, overlapped with H-18, 26a, 27a), 1.42 (3H, d, J = 7.0Hz, H— 21), 2.82 (1H, m, H-9), 3.02 (1H, m, H-10), 3.37 (3H, s, OMe, overlapped with H -20), 4.69 (2H, s, OCH O, overlapped with H— 3), 5.54 (1H, m, H—

 2

 1), 5.62 (1H, m, H− 16), 5.89 (1H, d, J = ll.4Hz, H− 7), 6.16 (1H, m, C = CH), 6.31 (1H, d, J = ll. 4Hz, H— 6), 10. 16 (1H, d, J = 7.7Hz, C HO).

 [0115] [Chemical 42]

0 ° C [Cooled Panolaldehyde 37a (60. lmg, 0.080mmol, about 1: 1 mixture) in ethanol (lml) solution with sodium borohydride (3. Omg, 0.080mmol, leq) 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 column chromatography (5 g) gave compound 38a (59.3 mg, 98%, approximately 1: 1 mixture) from the eluate of 15% ethyl acetate Z-hexane.

[0117] Compound 38a (E form) ^ H— NMR (CDC1) δ: 0.01 to 0.10 (12H, Si-Me x 4)

 Three

 , 0.85, 0.91 (each 9H, s, Si— tBu x 2, overlapped with H— 18, 26a, 27a), 1.42 (3H, d, J = 7.0Hz, H— 21), 3.40 (3H, s, OMe , overlapped w ith H-20), 4.69 (2H, s, OCH O), 4.17 to 4.34 (2H, m, CH OH), 4.3

 twenty two

 8 (1H, m, Hl), 4.82 (1H, m, H-3), 5.61 (1H, m, H-16), 5.72 (1H, m, C = CH), 5.94 (1H, d, J = ll.0Hz, H—7), 6.14 (1H, d, J = ll.0Hz, H-6).

Compound 38a (Z form): ¹ H—NMR (CDC1) δ: 0.01 to 0.10 (12H, Si-Me x 4)

 Three

 , 0.82, 0.93 (each 9H, s, Si -tBu x 2, overlapped with H— 18, 26a, 27a), 1.42 (3H, d, J = 7.0Hz, H— 21), 3.40 (3H, s, OMe , overlapped w ith H-20), 4.69 (2H, s, OCH O), 4.17 to 4.34 (2H, m, CH OH), 4.4

 twenty two

 8 (1H, m, H-3), 4.88 (1H, m, Hl), 5.61 (1H, m, H—16), 5.72 (1H, m, C = CH), 5.90 (1H, d, J = ll.0Hz, H—7), 6.25 (1H, d, J = ll.0Hz, H-6).

[0118] [Chemical 43]

 38a 13a 14a b

[0119] A solution of Compound 38a (55.3 mg, 0.074 mmol, approx. 1: 1 mixture) in methanol (lml) [Camphors norephonic acid (102.9 mg, 0.443 mmol, 6 eq) Stir 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 (3 g), and the mixture of compound 13a and compound 14a (28.3 mg, 80%, approx. 1: 1 mixture) from the eluate of 2% methanol Z acetate Product). The mixture was further purified by HPLC [YMC—Pack ODS—AM SH—342—5, 20% HO / MeOH, 8 ml Zmin] to obtain 11.8 mg of Compound 13a (E form)

 2

 11.5 mg of Compound 14a (Z form) was obtained.

[0120] Compound 13a (E-form): — NMR (CDC1) δ: 0.83 (3Η, s, H—18), 0.866, 0.

 Three

 874 (each 3H, t, J = 7.4Hz, H— 26a, 27a), 1.42 (3H, d, J = 6.9Hz, H— 21), 2.56, 2.57 (each 1H, d, J = 12.8Hz, H — 23), 2.79 (1H, m, H— 9), 3.16 (1H, dd, J = 12.6, 4.7Hz, H— 10), 3.43 (1H, q, J = 6.9Hz, H— 2 0), 4.11 (1H, dd, J = 12.4, 5.3Hz, CH OH), 4.36 (2H, m, H— 1, CH O

 twenty two

H), 4.82 (1H, m, H-3), 5.64 (1H, m, H-16), 5.77 (1H, m, C = CH), 5.97 (1H, d, J = ll.2Hz, H- 7), 6.27 (1H, d, J = ll.2Hz, H-6).

 UV Imax (EtOH): 245 nm (ε = 31600), 254 nm (ε = 35800), 263 nm (ε = 24100).

 Compound 14a (Z form) ^ H-NMRCCDCl) δ: 0.85 (3H, s, H-18), 0.865, 0.

 Three

 873 (each 3H, t, J = 7.4Hz, H— 26a, 27a), 1.42 (3H, d, J = 7.0Hz, H— 21), 2.54, 2.57 (each 1H, d, J = 12.9Hz, H — 23), 2.69 (1H, dd, J = 12.7, 4.7Hz, H-4), 2.80 (1H, m, H-9), 2.88 (1H, dd, J = 14.2, 4.0Hz, H- 10), 3.43 (1H, q, J = 7.0Hz, H-20), 4.16 (1H, dd, J = 12.5, 5.7 Hz, CH OH), 4.36 (1H, dd, J = 12.5, 8.1Hz, CH OH), 4.45 (1H, m, H

 twenty two

 -3), 4.85 (1H, m, H-l), 5.63 (1H, m, H-16), 5.77 (1H, m, C = CH), 5.94 (1H, d, J = ll.2Hz, H — 7), 6.37 (1H, d, J = ll.2Hz, H— 6). UV Imax (EtOH): 245nm, 254nm, 263nm.

[0121] [Chemical 44]

 34a 34a '11a 12a

[0122] Compound 34a (72.4 mg, 0. lOOmmol, a mixture of about 3: 2) cooled to 0 ° C in anhydrous DMF (1. Oml) solution was added with sodium hydride (120. lmg, 3.003 mmol, 30eq , 60% oil disp.) And Br (CH) OTBS (104 ^ 1, 0.500mmol, 5eq) are added. C for 22 hours

 twenty two

 Stir. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate Z-hexane (1: 1). 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 (7 g) to obtain Compound 34a ′ (94.7 mg, containing reagents) from the eluate of 2% ethyl acetate Z-hexane.

Next, Compound 34a was dissolved in methanol (1.5 ml), and camphorsulfonic acid (139.4 mg, 0.600 mmol, 6 eq) was stirred at room temperature 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 evaporated. The residue was purified by silica gel column chromatography (5g) to obtain a mixture of compound 11a and compound 12a (mixture of 35.2mg, 71%, approx 2: 1) from the eluate of 2% methanol Z ethyl acetate It was. The mixture was further analyzed by HPLC [YMC-Pack ODS-AM SH-342- 5, 25% H 2 O / MeOH, 8 mlZmin].

 2

 Purification was performed to obtain 14.6 mg of Compound lla form) and 6.7 mg of Compound 12a (| 8 form).

[0124] I compound lla (a form): ¹ H—NMR (CDC1) δ: 0.84 (3Η, s, H—18), 0.86, 0.8

 Three

7 (each 3H, t, J = 7.5Hz, H— 26a, 27a), 1.42 (3H, d, J = 7.0Hz, H— 21), 2.53, 2.58 (each 1H, d, J = 12.9Hz, H — 23), 2.62 (1H, m, H—4), 2.79 (1H, m, H-9), 2.87 (1H, dd, J = 14.4, 5.0Hz, H-10), 3.32 (1H, dd, J = 8.0, 2.8Hz, H-2), 3.43 (1H, q, J = 7.0Hz, H-20), 3.62-3.8 4 (4H, m, OCH CH O), 3.95 (1H, m, H-3), 4.16 (1H, m, H-l), 5.62 (1H, m, H-16), 5.91 (1H, d, J = ll.2Hz, H-7), 6.32 (1H, d, J = ll.2 Hz, H-6).

 UV λ max (EtOH): 243nm (ε = 28400), 251nm (ε = 33200), 261nm (ε = 22300).

 Compound 12a (j8 form): — NMR (CDC1) δ: 0.83 (3H, s, H—18), 0.856, 0.

 Three

 866 (each 3H, t, J = 7.5Hz, H— 26a, 27a), 1.42 (3H, d, J = 6.9Hz, H— 21), 2.49 (1H, m, H— 4), 2.56, 2.57 ( each 1H, d, J = 12.9Hz, H— 23), 2.78 (1H, m, H— 9), 3.09 (1H, dd, J = 13.5, 3.4Hz, H— 10), 3.30 (1 H, dd , J = 8.7, 2.8Hz, H-2), 3.43 (1H, q, J = 6.9Hz, H-20), 3.65-3.89 (5H, m, Hl, OCH CH O), 4.18 (1H, m, H— 3), 5.63 (1H, m, H—

 twenty two

 16), 5.94 (1H, d, J = ll.3Hz, H-7), 6.27 (1H, d, J = ll.3Hz, H-6) .UV λ max (EtOH): 243nm, 251nm, 261nm.

<Synthesis of (20R) 2-hydroxyethoxy 19-norvitamin D derivatives (lib), (12b), (20 R) — 2-hydroxyethylidene 19-norvitamin D derivatives (13b), (14b)>

 Synthesis was performed according to the following procedure according to the following scheme.

[Chemical 45]

[0126] [Chem 46]

[0127] — Dimethinolesnoreoxide (509 ΐ, 7. 193 mmol, 2.6 eq) in anhydrous dichloromethane (3 ml) in oxalyl dichloride (314 / zl, 3.596 mmol, 1.3 eq) cooled to 78 ° C After stirring for 10 minutes with an anhydrous dichloromethane (lml) solution, a solution of compound 27a (845.6 mg, 2.72 3 mmol) in anhydrous dichloromethane (7 ml) was prepared. After stirring at 78 ° C for 15 minutes, tritylamine (2.09 ml, 0. 150 mol, 5.5 eq) was added. 10 minutes at C, 0. Stir at C for 30 min. Ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (25 g) to obtain Compound 27a ′ (792.8 mg, 94%) from the eluate of 5% ethyl acetate / hexane.

 [0128] The compound 27a 'NMR—NMR (CDC1) δ: 0.02, 0.05 (each 3Η, s, SiMe x 2)

 Three

, 0.90 (9H, s, tBuSi), 1.25 (3H, s, H—18), 1.83 (3H, dd, J = 7.5, 1.1 Hz, H-21), 4.12 (1H, m, H—8), 6.43 (1H, q, J = 7.5Hz, H— 20) .Mass m / z (%): 308 (M ⁺ , 12), 293 (3), 251 (100), 159 (8), 75 (19 ).

[0129] [Chemical 47]

To a solution of Compound 27a, (144.7mg, 0.469mmol) cooled to 0 ° C in methanol (lml), CeCl · 7Η0 (17.5mg, 0.0469mmol, 0.leq) and sodium hydrogen borohydride (1

 3 2

7.7 mg, 0.469 mmol) was added. The mixture was stirred at 0 ° C for 30 minutes. 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 subjected to silica gel column chromatography (C—300, 5g) The compound 27b (126.4 mg) and the compound 27a (16.7 mg) were obtained from the eluate of 2% ethyl acetate Z hexane. (total 98%)

[0131] The compound SYb ^ H— NMR (CDC1) δ: 0.02 (6Η, s, SiMe x 2), 0.90 (9H, s

 Three

 , tBuSi), 1.27 (3H, s, H—18), 1.71 (3H, dd, J = 7.2, 1.4Hz, H—21), 4.04 (1H, m, H-8), 4.35 (1H, m, H— 16), 5.44 (1H, qd, J = 7.1, 1.7Hz, H-20).

Mass m / z (%): 310 (M ⁺ , 5), 292 (9), 253 (17), 235 (51), 161 (100), 7 5 (49).

[0132] [Chemical 48]

[0133] Compound 27b (385.5 mg, 1.241 mmol) cooled to 0 ° C in anhydrous pyridine (4 ml) was added to phenol-chlorothionophonolemate (PhOC (S) Cl, 336 1, 2.483 mmol, 2eq) was added. After stirring for 6 hours, the reaction solution was transferred to ice water, 2NHC1 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 (25 g), and compound 28b (361.4 mg, 65%) was obtained from the eluate of 3% dichloromethane Z hexane.

 [0134] The compound SSb ^ H— NMR (CDC1) δ: 0.026, 0.033 (each 3H, s, SiMe x 2

 Three

 ), 0.89 (9H, s, tBuSi), 1.07 (3H, s, H—18), 1.60 (3H, d, J = 6.9Hz, H -21), 2.27 (1H, m, H—15), 4.04 (1H, q, J = 6.9Hz, H-20), 4.10 (1H, m, H-8), 5.70 (1H, m, H-16), 7.16-7.39 (5H, m, arom H).

Mass m / z (%): 446 (M ⁺ , 3), 431 (1), 389 (4), 293 (17), 235 (13), 161 (100).

[Chemical 49]

[0135] To a solution of Compound 28b (345.3 mg, 0.773 mmol) in 10% KOHZMeOH (4 ml) was added bromoethyl acetate (258 1, 2.319 mmol, 3 eq), and the mixture was stirred at room temperature for 4 hours. The reaction solution was transferred to ice water, and 2NHC1 was collected 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 dissolved in dichloromethane (4 ml), cooled to 0 ° C., and a solution of diazomethane in jetyl ether (about 0.5 M, 4.6 ml) was added. After stirring at 0 ° C for 30 minutes, the solvent was distilled off. The residue was purified by silica gel column black Mato chromatography (12 g), I匕合product from hexane eluate to 5% acetic acid Echiru / 29b (296.3mg, 96%) was obtained _Q

[0136] Compound SSb: ¹ !! — NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, SiMe x 2),

 Three

 0.89 (9H, s, tBuSi), 1.05 (3H, s, H— 18), 1.46 (3H, d, J = 7.0Hz, H— 2 1), 2.26 (1H, m), 3. 16, 3.23 ( each 1 H, d, J = 14.7Hz, H— 23), 3.47 (1H, q, J = 7.0Hz, H— 20), 3.72 (3H, s, OMe), 4.07 (1H, m, H— 8 ), 5.59 (1H, m, H-16).

Mass m / z (%): 398 (M ⁺ , 37), 383 (16), 341 (24), 292 (7), 235 (62), 1 61 (100), 75 (48).

[0137] [Chemical 50]

[0138] Ethylmagnesium bromide (2.68ml, 2.68mmol, 3eq, 1.0M THF solution) was added to anhydrous THF (3ml) solution of Compound 29b (355.7mg, 0.892mmol) cooled to 0 ° C. Yeah. After stirring at 0 ° C for 4 hours, the mixture was further stirred at room temperature for 2 hours. The reaction mixture was transferred to ice water, 2NHC1 was added, 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). From the eluate of 1% ethyl acetate / hexane, ketone 29b "(97. Omg, 27%) and alcohol 29b, (264.9mg, 70%) were obtained. Obtained.

[0139] SS compound "SSb": ¹ !! — NMR (CDC1) δ: 0.018, 0.024 (each 3 H, s, SiMe x

 Three

 2), 0.88 (9H, s, tBuSi), 1.08 (3H, t, J = 7.4Hz, H-26), 1.03 (3H, s, H-18), 1.42 (3H, d, J = 6.9Hz, H— 21), 2.53— 2.74 (2H, m, H— 25), 3. 18, 3.23 (each 1H, d, J = 14. OHz, H— 23), 3.32 (1H, q, J = 6.9 Hz , H-20), 4.08 (1H, m, H-8), 5.58 (1H, m, H-16).

Mass m / z (%): 396 (M ⁺ , 5), 339 (1), 324 (4), 267 (6), 235 (60), 161 (69), 75 (100).

 Compound 29b, ^ H-NMRCCDCl) δ: 0.02, 0.03 (each 3H, s, SiMe x 2)

 Three

 , 0.89 (9H, s, tBuSi, overlapped with H— 26a, 27a), 1.04 (3H, s, H— 18), 1.45 (3H, d, J = 6.9Hz, H— 21), 2.57, 2.63 (each 1H, d, J = 12.7 Hz, H-23), 3.30 (1H, q, J = 7. OHz, H— 20), 4.09 (1H, m, H— 8), 5.5 5 (1H, m, H — 16).

Mass m / z (%): 426 (M ⁺ , 8), 408 (6), 235 (79), 161 (46), 75 (100).

[0140] [Chemical 51]

P-Toluenesulfonic acid monohydrate (255.3 mg, 1.342 mmol, 2 eq) was added to a solution of compound 29b ′ (286.4 mg, 0.671 mmol) in methanol (3 ml) cooled to 0 ° C. After stirring at room temperature for 5 hours, the reaction solution was transferred to ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and anhydrous magnesium sulfate Dried and evaporated. The residue was purified by silica gel column chromatography (10 g) to obtain alcohol 30b (181.5 mg, 87%) from the eluate of 15% ethyl acetate Z-hexane.

[0142] Compound SOb ^ H—NMR (CDC1) δ: 0.86, 0.88 (each 3H, t, J = 7.5Hz, H

 Three

 -26a, 27a), 1.07 (3H, s, H— 18), 1.46 (3H, d, J = 7.0Hz, H— 21), 2.5 7, 2.63 (each 1H, d, J = 12.7Hz, H— 23), 3.31 (1H, q, J = 7.0Hz, H--20), 4.18 (1H, m, H-8), 5.59 (1H, m, H-16).

Mass m / z (%): 312 (M ⁺ , 8), 294 (2), 276 (15), 160 (71), 145 (100).

[0143] [Chemical 52]

[0144] 78. Dissolved in C. Dissolved dichlorinated oxazinole (113 / zl, 1.298 mmol, 2.5 eq) in anhydrous dichloromethane (l ml) with dimethyl sulfoxide (184 ΐ, 2.595 mmol, 5 eq) in anhydrous dichloromethane (0.3 ml) After stirring the solution for 10 minutes, a solution of compound 30b (162.3 mg, 0.5 19 mmol) in anhydrous dichloromethane (2 ml) was prepared. After stirring at 78 ° C for 15 minutes, tritylamine (723 1, 5.19 mmol, 10 eq) was added, and 78. 15 minutes at C, 0. Stir with C for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (7 g), and the compound 30b ′ (125.6 mg, 78%) was obtained from the eluate of 15% ethyl acetate Z-hexane.

 [0145] Compound 30b,: One NMR (CDC1) δ: 0.88, 0.89 (each 3H, t, J = 7.5Hz,

 Three

 H-26a, 27a), 0.85 (3H, s, H—18), 1.48 (3H, d, J = 7.0Hz, H—21), 2.60, 2.63 (each 1H, d, J = 13.2Hz, H-23), 2.91 (1H, dd, J = 10.7, 6. 6Hz), 3.35 (1H, q, J = 7.0Hz, H-20), 5.55 (1H, m, H-16).

Mass m / z (%): 310 (M ⁺ , 16), 292 (24), 209 (29), 176 (100), 161 (63)

[0147] Compound 30b cooled to 0 ° C, (125.6mg, 0.405mmol) in anhydrous dichloromethane (lm 1) solution (iso- Pro) NEt (564 ^ 1, 3.236mmol, 8eq) and MOMCl (123 1, 1.6

 2

 18 mmol, 4 eq) was added, and the mixture was stirred at 0 ° C to room temperature for 15 hours. The reaction mixture was transferred to ice water, 2 NHC1 was added, and the mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 31b (127. Omg, 89%) from the 10% ethyl acetate / hexane eluate.

[0148] 匕 Compound Sib: ¹ !! — NMR (CDC1) δ: 0.88 (6Η, t, J = 7.5Hz, H-26a, 27a)

 Three

 , 0.85 (3H, s, H-18), 1.48 (3H, d, J = 7.0Hz, H— 21), 2.49 (1H, m, H -15), 2.65 (2H, s, H— 23), 2.90 (1H, dd, J = 10.7, 6.6Hz, H— 14), 3.31 (3H, q, J = 7.0Hz, H— 20), 3.41 (3H, s, OMe), 4.692.4.697 (each 1H, d, J = 7.3Hz, OCH O), 5.53 (1H, m, H--16).

 2

Mass m / z (%): 354 (M ⁺ , 6), 322 (6), 292 (19), 222 (16), 176 (100), 1 61 (61).

[0149] [Chemical 54]

 OTMS

 33b

[0150] A ^ A3 (454 1, 0.454mmol, 1. OM THF solution, 2e q in an anhydrous THF (2ml) solution of ring A phosphinoxide (299.3mg, 0.454mmol, 2eq) cooled to 78 ° C ) And stirred for 30 minutes, then a solution of 3 lb (80.5 mg, 0.227 mmol) of ketone body in anhydrous THF (1 ml) was slowly added. After stirring at 78 ° C for 2 hours, the temperature was gradually raised, and stirring was continued at 0 ° C for 1 hour. A saturated salt aqueous 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 33b (92.7 mg, 51%, approximately 3: 2 mixture) from the eluate of 3% ethyl acetate Z hexane, and 10% ethyl acetate. Unreacted raw material 17 (28.4 mg, 35%) was recovered from the eluate of ruthenium hexane, and A ring phosphine oxide (196.8 mg) was recovered from the eluate of 30% ethyl acetate Z hexane.

 [0151] Compound SSb ^ H— NMR (CD OD) δ: 0.04 to 0.07 (12H, s, SiMe x 4), 0.

 Three

 124, 0.127 (2: 3) (9H, s, SiMe x 3), 0.71, 0.72 (2: 3) (3H, s, H— 18), 0.85 to 0.90 (24H, m, H— 26a, 27a, tBuSi x 2), 1.45 (3H, d, J = 7.OH z, H-21), 2.65 (2H, s, H— 23), 2.79 (1H, m, H— 9), 3.32 (1H, q , J = 7.0 Hz, H-20), 3.41 (3H, s, OMe), 3.54, 3.60 (3: 2) (1H, m, H— 2), 3.80 (1H, m), 3.88, 3.93 (3: 2) (1H, m), 4.69 (2H, s, OCH O), 5.57 (1

 2

 H, m, H-16), 5.88, 5.90 (2: 3) (1H, d, J = ll.1Hz, H—7), 6.10, 6.13 (3: 2) (1H, d, J = ll.1Hz, H— 6).

Mass m / z (%): 794 (no M ⁺ ), 616 (18), 559 (4), 484 (36), 427 (18), 3 09 (53), 75 (10).

[0152] [Chemical 55]

[0153] A solution of Compound 33b (128.9 mg, 0.162 mmol, about 3: 2 mixture) cooled to 0 ° C. in Ding 11 Z acetic acid Z water (8: 8: 1, 4.25 ml) C force was also stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution and then with 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 (5 g), and unreacted raw material 20 (20. Omg, 16%, approximately 3: 2 mixture) was recovered from the eluate of 2% ethyl acetate Z hexane. Compound 34b (a mixture of 93.8 mg, 80%, about 2: 1) was obtained from the elution portion of ethyl acetate with hexane.

[0154] Compound S b: ¹ !! — NMR (CD OD) δ: 0.06 to 0.10 (12H, s, SiMe x 4), 0.

 Three

 71, 0.72 (1: 2) (3H, s, H— 18), 0.85 to 0.90 (24H, m, H— 26a, 27a, tBu Si x 2), 1.46 (3H, d, J = 7. OHz, H- 21), 2.65 (2H, s, H- 23), 2.78 (1 H, m, H-9), 3.32 (1H, q, J = 7. OHz, H-20), 3.41 (3H, s , OMe), 3.5 2, 3.60 (2: 1) (1H, m, H— 2), 3.90 to 4.02 (2H, m, H— 1, 3), 4.69 (2H, s, OCH O), 5.58 ( 1H, m, H—16), 5.89 (1H, d, J = ll.1Hz,, H—7), 6.

 2

 15, 6.18 (2: 1) (1H, d, J = ll. 1Hz, H— 6).

 Mass m / z (%): 722 (no M +), 660 (1), 544 (54), 487 (20), 412 (19), 3 55 (100).

[0155] [Chemical 56]

 34b 35b

[0156] A solution of oxalyl dichloride (15 1, 0.166mmol, 2eq) in anhydrous dichloromethane (0.5ml) cooled to 78 ° C was added to dimethylsulfoxide (24 1, 0.332mmol, 4eq) in anhydrous dichloromethane (0.2ml). ) After stirring the solution for 10 minutes, a solution of compound 34b (60.3 mg, 0.0831 mmol, about 3: 2) in anhydrous dichloromethane (lml) was prepared. After holding at 78 ° C for 15 minutes, HJ ethenoreamine (116 1, 0.831 mmol, 10 eq) was calo-free, and 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 dichloromethane. 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 35b (57.5 mg, 96%) from the eluate of 3% ethyl acetate Z-hexane.

[0157] The Compound SSb: ¹ !! — NMR (CDC1) δ: 0.058, 0.068, 0.069, 0.100 (each 3

 Three

 H, s, Si— Me x 4), 0.73 (3H, s, H— 18), 0.87, 0.90 (each 9H, s, Si— tBu x 2, overlapped with H— 26a, 27a), 1.46 (3H, d, J = 7.0Hz, H- 2 1), 2.65 (2H, s, H-23), 2.82 (1H, m, H-9), 3.32 (1H, q, J = 7.0Hz, H-20) , 3.41 (3H, s, OMe), 4.36 (1H, dd, J = 6.3, 4.1Hz), 4.56 (1H, dd, J = 8.7, 5.5Hz), 4.694, 4.496 (each 1 H, d, J = 7.4Hz, OCH O),

 2

5.58 (1H, m, H--16), 5.90 (1H, d, J = ll.2Hz, H-7), 6.35 (1H, d, J = 11.2Hz, H-6).

Mass m / z (%): 720 (M ⁺ , 1), 601 (13), 542 (8), 485 (100), 353 (38).

[0158] [Chemical 57]

[0159] — n-Butyllithium (100 ΐ, 0.159 mmol, 1.58M hexane solution) in an anhydrous THF (0.5 ml) solution of jetyl cyanomethylphosphonate (26 1, 0.159 mmol, 2 eq) cooled to 40 ° C , 2eq) and stirred for 15 minutes, then a solution of compound 35b (57.5 mg, 0.0795 mmol) in anhydrous THF (0.5 ml) was slowly added. — After stirring at 40 ° C for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated Japanese brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 36b (54.6 mg, 92%, approximately 1: 1 mixture) from the eluate of 3% ethyl acetate Z-hexane.

 [0160] Compound 36b (E form) ^ H-NMRCCDCl) δ: 0.06, 0.08, 0.11, 0.13 (each

 Three

 3H, s, Si— Me x 4), 0.72 (3H, s, H— 18), 0.84, 0.93 (each 9H, s, Si -tBu x 2), 0.87 (6H, t, J = 7.5Hz, H — 26a, 27a), 1.46 (3H, d, J = 6.9 Hz, H-21), 2.65 (2H, s, H— 23), 2.79 (1H, m, H— 9), 3.12 (1H, m, H-10), 3.32 (1H, q, J = 6.9Hz, H-20), 3.41 (3H, s, OMe), 4.69 (2H, s, OCH O), 4.47 (1H, m, H-1) , 5.00 (1H, m, H-3), 5.47 (1H, d, J = l

2

 .9Hz, C = CH), 5.58 (1H, m, H— 16), 5.91 (1H, d, J = ll. 2Hz, H— 7), 6. 18 (1H, d, J = ll. 2Hz, H—6).

 Compound 36b (Z form) ^ H-NMRCCDCl) δ: 0.06, 0.08, 0.11, 0.13 (each

 Three

3H, s, Si— Me x 4), 0.71 (3H, s, H— 18), 0.82, 0.93 (each 9H, s, Si -tBu x 2), 0.87 (6H, t, J = 7.5Hz, H — 26a, 27a), 1.47 (3H, d, J = 6.9 Hz, H-21), 2.65 (2H, s, H— 23), 2.79 (1H, m, H— 9), 3.00 (1H, m, H-10), 3.32 (1H, q, J = 6.9Hz, H--20), 3.41 (3H, s, OMe), 4.69 (2H, s , OCH O), 4.59 (1H, m H-3), 5.04 (1H, m, H-l), 5.47 (1H, d, J = l

2

 .9Hz, C = CH), 5.58 (1H, m, H—16), 5.88 (1H, d, J = ll.2Hz, H—7), 6.31 (1H, d, J = ll.2Hz, H— 6).

Mass m / z (%): 743 (no M ⁺ ), 681 (1), 565 (56), 508 (100), 481 (72), 433 (37), 376 (19).

 [0161] [Chemical 58]

[0162] — Diisobutylaluminum hydride (DIBAL-H) in anhydrous toluene (lml) solution of Compound 36b (51. lmg, 0.0685mmol, E: Z = 1: 1 mixture) cooled to 78 ° C (103 μ \, 0.13 mmol, 1.0 M toluene solution, 1.5 eq) was collected. After 2 hours, the reaction solution was diluted with hexane and purified by silica gel column chromatography (5 g). Compound 37b (45.6 mg, 89%, approx. 1: 1).

 [0163] Compound 37b (E form) ^ H-NMRCCDCl) δ: 0.02, 0.08, 0.09, 0.10 (each

 Three

 3H, s, Si— Me x 4), 0.73 (3H, s, H— 18), 0.85, 0.93 (each 9H, s, Si -tBu x 2), 0.89 (6H, t, J = 7.5Hz, H — 26a, 27a), 1.46 (3H, d, J = 7.0 Hz, H-21), 2.65 (2H, s, H— 23), 2.79 (1H, m, H— 9), 3.05 (1H, m, H-10), 3.32 (1H, q, J = 7.0Hz, H— 20), 3.41 (3H, s, OMe), 4.69 (2H, s, OCH O), 4.58 (1H, m, H—l) , 5.46 (1H, m, H— 3), 5.58 (1H, m, H—

2

 16), 5.94 (1H, d, J = ll.2Hz, H-7), 6.16 (1H, m, C = CH), 6.19 (1H, d, J = ll.2Hz, H-6), 10.19 ( 1H, d, J = 7.9Hz, CHO).

 Compound 37b (Z form) ^ H—NMR (CDC1) δ: 0.02, 0.08, 0.10, 0.11 (each

 Three

3H, s, Si— Me x 4), 0.72 (3H, s, H— 18), 0.83, 0.93 (each 9H, s, Si -tBu x 2), 0.89 (6H, t, J = 7.5Hz, H— 26a, 27a), 1.47 (3H, d, J = 7.0 Hz, H-21), 2.65 (2H, s, H— 23) , 2.79 (1H, m, H— 9), 3.00 (1H, m, H -10), 3.32 (1H, q, J = 7.0Hz, H— 20), 3.41 (3H, s, OMe), 4.69 ( 2H, s, OCH O, overlapped with H— 3), 5.54 (1H, m, H—l), 5.58 (1H, m,

2

 H-16), 5.89 (1H, d, J = ll.2Hz, H-7), 6.16 (1H, m, C = CH), 6.31 (1H, d, J = ll.2Hz, H-6), 10.16 (1H, d, J = 7.7Hz, CHO).

 [0164] [Chemical 59]

 37b

[0165] A solution of aldehyde 37b (45.6 mg, 0.0609 mmol, approximately 1: 1 mixture) cooled to 0 ° C in ethanol (lml) with CeCl · 7Η0 (2.3 mg, 0.0061 mmol, 0. leq) and hydrogen Conversion

 3 2

 Sodium boron (2.3 mg, 0.0609 mmol) was added 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 (5 g) to obtain compound 38b (38.8 mg, 85%, approximately 1: 1 mixture) from the eluate of 15% ethyl acetate Z-hexane.

 Compound 38b (E form) ^ H-NMRCCDCl) δ: 0.01 to 0.10 (12H, Si-Me x 4)

 Three

 , 0.73 (3H, s, H-18), 0.85, 0.92 (each 9H, s, Si -tBu x 2), 0.87 (6 H, t, J = 7.3Hz, H-26a, 27a), 1.46 (3H , d, J = 6.9Hz, H-21), 2.65 (2 H, s, H-23), 2.79 (1H, m, H-9), 2.88 (1H, dd, J = 12.8, 4.4Hz, H — 10), 3.32 (1H, q, J = 6.9Hz, H— 20), 3.41 (3H, s, OMe), 4.69 (2H, s, OCH O), 4.17 to 4.33 (2H, m, CH OH) , 4.38 (1H, m, H-l), 4.82 (1H

twenty two

, m, H--3), 5.58 (1H, m, H-16), 5.72 (1H, m, C = CH), 5.94 (1H, d, J = 11.1Hz, H-7), 6.14 (1H, d, J = ll.0Hz, H-6).

Compound 38b (Z form): ¹ H—NMR (CDC1) δ: 0.01 to 0.10 (12H, Si-Me x 4)

 Three

 , 0.72 (3H, s, H-18), 0.83, 0.93 (each 9H, s, Si— tBu x 2), 0.87 (6 H, t, J = 7.3Hz, H-26a, 27a), 1.46 (3H , d, J = 6.9Hz, H-21), 2.65 (2 H, s, H-23), 2.79 (1H, m, H-9), 3.32 (1H, q, J = 6.9Hz, H-20 ), 3.41 (3H, s, OMe), 4.69 (2H, s, OCH O), 4.17 to 4.33 (2H, m, CH OH),

 twenty two

4.48 (1H, m, H— 3), 4.86 (1H, m, H— 1), 5.58 (1H, m, H— 16), 5.72 (1H, m, C = CH), 5.90 (1H, d, J = ll.1Hz, H-7), 6.25 (1H, d, J = ll.1 Hz, H—6).

[0167] [Chemical 60]

 38b 13b 14b

[0168] Camphorsulfonic acid (72. Omg, 0.310mmol, 6eq) was added to methanol (lml) solution of Compound 38b (38.8mg, 0.0516mmol, mixture of about 1: 1) and stirred at room temperature for 2 hours. did. 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 (3 g) to obtain a mixture of Compound 13b and Compound 14b (24.3 mg, 98%, approximately 1: 1 mixture) from the 2% methanol / ethyl acetate eluate. It was. The mixture was further purified by HPLC [YMC—PackODS—AM SH—342—5, 25% H 2 O / MeOH, 8 ml Zmin], and 11.8 mg of Compound 13b (E form)

2

 9.4 mg of product 14b (Z form) was obtained.

[0169] Compound 13b (E form) ^ H-NMRCCDCl) δ: 0.72 (3Η, s, H-18), 0.87, 0.8

 Three

8 (each 3H, t, J = 7.4Hz, H— 26a, 27a), 1.46 (3H, d, J = 6.9Hz, H— 21 ), 2.59, 2.64 (each 1H, d, J = 12.8Hz, H— 23), 2.79 (1H, m, H— 9), 3.16 (1H, dd, J = 12.6, 4.6 Hz, H— 10 ), 3.35 (1H, q, J = 6.9Hz, H—20), 4.10 (1H, dd, J = 12.5, 5.3Hz, CH OH), 4.36 (2H, m, H— 1, CH OH

 twenty two

), 4.82 (1H, m, H-3), 5.61 (1H, m, H-16), 5.76 (1H, m, C = CH), 5.98 (1H, d, J = ll.2Hz, H — 7), 6.27 (1H, d, J = ll.2Hz, H— 6).

 UV Imax (EtOH): 245nm, 254nm, 263nm.

 Compound 14b (Z form) ^ H-NMRCCDCl) δ: 0.74 (3H, s, H-18), 0.87, 0.8

 Three

 8 (each 3H, t, J = 7.4Hz, H— 26a, 27a), 1.46 (3H, d, J = 6.9Hz, H— 21), 2.58, 2.63 (each 1H, d, J = 12.8Hz, H — 23), 2.68 (1H, dd, J = 12.8, 4.5Hz, H-4), 2.79 (1H, m, H-9), 2.88 (1H, m, H-10), 3.35 (1H, q, J = 6.9Hz, H-20), 4.15 (1H, dd, J = 12.4, 5.3Hz, CH OH), 4.36 (1

 2

 H, dd, J = 12.4, 8.3Hz, CH OH), 4.44 (1H, m, H-3), 4.85 (1H, m, H

 2

 -1), 5.60 (1H, m, H-16), 5.76 (1H, m, C = CH), 5.93 (1H, d, J = ll. 1Hz, H-7), 6.37 (1H, d, J = ll. 1Hz, H— 6).

 UV Imax (EtOH): 245nm, 254nm, 263nm.

[Chemical 61]

 34b 34b '

0. Compound 34b (25. Omg, 0.0483 mmol, mixture of about 3: 2) cooled to C was added to a solution of anhydrous DMF (1. Oml) in sodium hydride (57.9 mg, 1.448 mmol, 30 eq, Add 60% oil disp.) And Br (CH) OTBS (50 μ 1, 0.241 mmol, 5 eq). C for 22 hours

 twenty two

Stir. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate Z-hexane (1: 1). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue Purification by silica gel column chromatography (5 g) gave 34b ′ (30.6 mg, 72%) from the eluate of 2% ethyl acetate Z-hexane.

[0172] [Chemical 62]

 34b 11b 12b

[0173] A solution of compound 34b '(30.6 mg, 0.0346 mmol, approximately 2: 1) in methanol (lml) [camphors norephonic acid (48.3 mg, 0.208 mmol, 6eq) in room temperature Stir 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 (3 g), and a mixture of compound lib and compound 12b (13.5 mg, 79%, approximately 2: 1 mixture) was eluted from the eluate of 2% methanol Z ethyl acetate. Obtained. The mixture was further purified by HPLC [YMC—PackODS—AM SH—342 -5, 25% H 2 O / MeOH, 8 ml Zmin], and the compound llb (α form) was added to 6. Omg.

 2

 And 3.5 mg of Compound 12b (β form) was obtained.

[0174] y compound llb (a form): ¹ H—NMR (CDC1) δ: 0.73 (3Η, s, H—18), 0.87, 0.8

 Three

 8 (each 3H, t, J = 7.5Hz, H— 26a, 27a), 1.46 (3H, d, J = 7.0Hz, H— 21), 2.59, 2.63 (each 1H, d, J = 12.8Hz, H — 23, overlapped with H— 4), 2.78 (1H, m, H— 9), 2.87 (1H, dd, J = 14.4, 5.0Hz, H— 10), 3.35 (2 H, m, H-2, 20), 3.69-3.84 (4H, m, OCH CH O), 3.94 (1H, m, H-3

 twenty two

 ), 4.16 (1H, m, Hl), 5.60 (1H, m, H—16), 5.91 (1H, d, J = ll.2Hz, H-7), 6.33 (1H, d, J = ll.2Hz , H— 6).

 UV Imax (EtOH): 243nm, 251nm, 261nm.

Compound 12b (j8) ¹ H-NMR (CDC1) δ: 0.72 (3H, s, H-18), 0.87, 0.8 8 (each 3H, t, J = 7.5Hz, H— 26a, 27a), 1.46 (3H, d, J = 7. OHz, H— 21), 2.58, 2.63 (each IH, d, J = 12.8Hz, H— 23), 2.78 (IH, m, H— 9), 3.09 (IH, dd, J = 13.3, 3.4 Hz, H— 10), 3.31 (IH, dd, J = 8.8, 2.9 Hz, H -2), 3.35 (1H, q, J = 7. OHz, H— 20), 3.66-3.90 (5H, m, H— 1, OCH

 2

CH O), 4.18 (1H, m, H-3), 5.61 (1H, m, H-16), 5.93 (1H, d, J = ll

2

 .3Hz, H-7), 6.28 (IH, d, J = ll.3Hz, H—6).

 UV λ max (EtOH): 243nm, 251nm, 261nm.

[0175] <(20S) -22 Thia 19, 24 Synthesis of dinorvitamin D derivative (15a)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0176] [Chemical 63]

 28a 29a

[0177] Compound 29a: C NMR (CDC1) δ: — 4.95, —4.63, 18.1, 18.2, 19.3,

 Three

 21.9, 23.9, 26.0, 31.0, 33.1, 34.7, 35.7, 38.6, 46.8, 52.5, 55.5, 69.2, 125.9, 155.1, 171.6.

 [0178] [Chemical 64]

[0179] Compound 29a ': C NMR (CDC1) δ: — 4.95, —4.65, 8.22, 18.16, 18. 22, 19. 6, 22. 7, 26. 0, 31. 0, 34. 7, 35. 8, 39. 5, 41. 6, 46. 9, 55. 5, 6 9. 2, 74. 0 , 125. 3, 156. 3.

 [0180] [Chemical 65]

 29a '30a

[0181] Compound 30a: C NMR (CDCl) δ: 8. 20, 8. 22, 17. 9, 19. 0, 22. 6, 30.

 Three

 5, 31. 0, 31. 1, 34. 0, 35. 5, 39. 4, 41. 5, 46. 5, 54. 9, 69. 3, 74. 0, 12 5. 4, 156. 0 .

 [0182] [Chemical 66]

 30a 30a

[0183] Compound 30a ': C NMR (CDCl) δ: 8. 21, 18. 2, 21. 8, 24. 1, 27. 4, 31

 Three

 0, 34. 2, 39. 2, 40. 6, 41. 1, 74. 0, 125. 6, 153. 6, 210. 7.

 [0184] [Chemical 67]

30a '39a [0185] Compound 30a '(38.7 mg, 0.125 mmol) cooled to 0 ° C in anhydrous dimethylformamide (0.8 ml) solution with imidazole (50.9 mg, 0.745 mmol) and chlorotriethylsilane (TESC1, 62.8 ^ 1, 0.374 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Imidazole (6 equivalents) and chlorotriethylsilane (3 equivalents) were added, and the mixture was further stirred for 16 hours. The reaction solution was extracted with 50% ethyl acetate Z-hexane, 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 47a (35.4 mg, 67%) from the eluate of 5% ethyl acetate Z-hexane. Further, unreacted compound 39a (3.8 mg, 10%) was recovered from the elution portion of 20% ethyl acetate Z hexane.

[0186] Compound SSa: ¹ !! NMR (CDC1) δ: 0.58 (6Η, q, J = 7.9Hz, 3 x Si— CH

 3 2

CH), 0.85, 0.86 (each 3H, t, J = 7.3Hz, H— 26a, 27a), 0.95 (9H, t, J

Three

 = 8.0Hz, 3 x Si— CH CH), 0.97 (3H, s, H— 18), 1.42 (3H, d, J = 7.0

 twenty three

 Hz, H-21), 1.51 (4H, q, J = 7.0Hz, H— 26, 27), 2.51 (2H, m, H— 23), 3.43 (1H, q, J = 6.9Hz, H— 20 ), 5.57 (1H, m, H-16).

1 ³ C NMR (CDC1) δ: 7.20, 7.43, 8.28, 8.45, 18.0, 21.5, 23.9,

 Three

 24.1, 27.3, 31.9, 32.3, 34.4, 39.3, 40.1, 40.6, 53.4, 63.9, 125. 1, 153.8, 210.9.

 Mass m / z (%): 424 (M +, 1), 395 (3), 338 (8), 292 (10), 263 (1), 201 (100), 177 (14), 115 (20) , 75 (9).

[0187] [Chemical 68]

Compound 40 (85.2mg, 0.149mml) anhydrous tetrahydrofuran (0 After adding n-butynolethium (95.7 ^ 1, 0.149mmol, 1.56M hexane solution) to the solution and stirring for 15 minutes, compound 39a (31.7mg, 0. O75mmol) in anhydrous tetrahydrofuran (0.8ml) ) Solution was added and stirred at −78 ° C. for 1 hour. The reaction mixture was heated to -40 ° C over about 2.5 hours. The reaction mixture was washed with a saturated salt ammonium solution and 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), and the compound 41a (22.8 mg, 39%) was obtained from the eluate of 2% ethyl acetate Z hexane, and unreacted compound 39a (8.5 mg, 27%) Compound 40 (33.2 mg) was recovered from the eluate of 40% ethyl acetate Z-hexane.

[0189] Compound Ala: ¹ !! NMR (CDC1) δ: 0.04 to 0.06 (12Η, 4 x Si-Me), 0.

 Three

 60 (6H, q, J = 7.9Hz, 3 x Si— CH CH), 0.83 (3H, s, H— 18), 0.85 ~ 0

 twenty three

 .88 (18H, 2 x Si-t-Bu), 0.88 (6H, t, J = 7.3Hz, H— 26a, 27a), 0.95 (9H, t, J = 7.9Hz, 3 x Si— CH CH) , 1.40 (3H, d, J = 7.0Hz, H— 21),

 twenty three

 2.53 (2H, m, H— 23), 3.41 (1H, q, J = 6.8Hz, H— 20), 4.04 to 4.11 (2 H, m, Hl, 3), 5.60 (1H, m, H— 16 ), 5.91 (1H, d, J = ll.2Hz, H—7), 6.17 (1H, d, J = ll.2Hz, H—6).

1 ³ C NMR (CDC1) δ: -4.70, —4.62, —4.52, —4.43, 7.23, 7.47

 Three

 , 8.27, 8.43, 17.7, 18.3, 18.4, 21.7, 23.5, 26.0, 28.5, 29.6, 31. 9, 32.3, 35.4, 36.9, 39.5, 40.1, 43.9, 46.3, 49.6, 59. 1, 68.2, 68.3 , 78.5, 116.6, 121.8, 125.1, 134.3, 140.0, 155.8.

 Mass m / z (%): 776 (M +, 3), 747 (1), 719 (1), 644 (6), 615 (1), 560 (3), 528 (18), 471 (5) , 429 (2), 396 (31), 339 (15), 301 (6), 265 (9), 201 (100), 159 (7), 103 (15), 75 (28), 73 (23) .

[0190] [Chem 69]

[0191] Camphorsulfonic acid (39.8 mg, 0.171 mmol) was added to a solution of compound 41a (22.2 mg, 0.029 mmol) in methanol (l ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added an 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 chroma preparative chromatography (5 g), I from hexane eluate to 80% acetic acid Echiru /匕合product 15a (1 2.2mg, 98%) was obtained _Q

 [0192] Compound 15 &: NMR (CDC1) δ: 0.84 (3Η, s, H-18), 0.87, 0.88 (eac

 Three

 h 3H, t, J = 7.5Hz, H-26a, 27a), 1.43 (3H, d, J = 7.0Hz, H— 21), 2.5 6, (2H, d, J = 3.7Hz, H— 23) , 3.44 (1H, q, J = 6.9Hz, H— 20), 4.06, 4.13 (1H, m, Hl, 3), 5.63 (1H, m, H— 16), 5.95 (1H, d, J = ll.3Hz, H-7), 6.30 (1H, d, J = ll.3Hz, H-6).

1 ³ C NMR (CDC1) δ: 8.23, 17.7, 21.9, 23.6, 28.7, 29.7, 31.0, 3

 Three

 5.3, 37.4, 39.9, 41.1, 42.4, 44.8, 49.7, 59.0, 67.4, 67.6, 74.0,

115.8, 123.9, 125.6, 131.8, 141.9, 155.5.

[0193] <(20R) 22 thia 19, 24 Synthesis of dinorvitamin D derivative (15b)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0194] [Chemical 70]

[0195] Compound 29b: C NMR (CDCl) δ-5. 0, -4. 6, 18. 2, 19. 6, 22. 0, 26

 Three

 0, 31. 1, 32. 5, 34. 7, 35. 6, 37.-, 47. 0, 52. 5, 54. 8, 69. 1, 125. 4, 154. 7, 166. 5 .

 [0196] [Chemical 71]

[0197] Compound 29b ': C NMR (CDCl) δ: — 5. 0, —4. 6, 8. 2, 8. 3, 18. 2, 19.

 Three

 6, 22. 7, 26. 0, 31. 0, 34. 7, 35. 9, 37. 7, 40. 6, 47. 0, 54. 8, 69. 1, 73. 8, 124. 5, 155. 6.

 [0198] [Chemical 72]

[0199] Compound 30b: C NMR (CDCl) δ: 8. 20, 8. 25, 17. 9, 19. 0, 22. 6, 30. 6 , 31. 0, 31. 1, 34. 0, 35. 7, 37. 6, 40. 5, 46. 7, 54. 2, 69. 2, 73. 8, 124. 5, 155. 3.

 [0200] [Chemical 73]

[0201] Compound 30b ': C NMR (CDC1) δ: 8. 20, 8. 23, 17. 7, 22. 5, 24. 2, 27

 Three

 4, 31. 0, 31. 1, 34. 8, 38. 5, 40. 5, 40. 6, 53. 9, 62. 8, 74. 0, 124. 6, 153. 3, 210. 9 .

 [0202] [Chemical 74]

[0203] Compound 30b, cooled to 0 ° C, (21.3 mg, 0. 69 mmol) in anhydrous dimethylformamide (1 ml) with imidazole (56. Omg, 0.823 mmol) and chlorotriethylsilane (69. 1). ^ 1, 0.412 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Additional imidazole (28. Omg, 0.412 mmol) and black-mouthed triethylsilane (34.5 1, 0. 206 mmol) were added, and the mixture was further stirred at room temperature for 6 hours, and then with 50% ethyl acetate Z-hexane. Extracted. 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 (5g) to obtain compound 39b (17.7 mg, 60%) from the eluate of 3% ethyl acetate Z hexane and unreacted from the eluate of 30% ethyl acetate Z hexane Compound 30b ′ (2. Omg, 9%) was recovered. [0204] Compound 39b: H NMR (CDC1) δ: 0.60 (6H, q, J = 8.0Hz, 3 x Si— CH

 3 2

CH), 0.86 (3H, s, H-18), 0.867, 0.873 (each 3H, t, J = 7.3Hz, H—

Three

 26a, 27a), 0.96 (9H, t, J = 7.9Hz, 3 x Si— CH CH), 1.46 (3H, d, J = 7

 twenty three

 OHz, H-21), 2.56 (2H, m, H— 23), 3.32 (1H, q, J = 6.8 Hz, H— 20), 5.50 (1H, m, H— 16).

1 ³ C NMR (CDC1) δ: 7.2, 7.5, 8.3, 8.4, 17.8, 22.1, 24.3, 27.4,

 Three

 32.1, 34.7, 37.9, 39.3, 40.7, 54.0, 62.9, 78.4, 123.9, 153.5, 21 1.0.

 [0205] [Chemical 75]

 41b

[0206] n-butynolethium (77.9 1, 0.122mmol, 1.56M hexane solution) was added to a solution of Compound 40 (69.4mg, 0.122ml) cooled to 78 ° C in anhydrous tetrahydrofuran (0.3 ml). After stirring for 15 minutes, a solution of compound 39b (10.4 mg, 0.025 mmol) in anhydrous tetrahydrofuran (0.3 ml) was prepared and stirred at 78 ° C. for 1 hour. The temperature was raised to -30 ° C over about 2.5 hours. The reaction solution was entented with 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 (5 g) to obtain Compound 41b (1.8 mg, 17%) from the eluate of 1% ethyl acetate Z hexane, and unreacted compound 39b (5.5 mg, 53%). %), 70% ethyl acetate From the eluate of Z-hexane, Compound 40 (45.6 mg) was recovered.

 [0207] Compound 41b: Yeah! NMR (CDC1) δ: 0.05 to 0.07 (12Η, 4 x Si-Me), 0.5

 Three

9 (6H, q, J = 7.9Hz, 3 x Si— CH CH), 0.72 (3H, s, H— 18), 0.84 to 0. 88 (6H, t, J = 7.3Hz, H— 26a, 27a), 0.86, 0.88 (each 9H, 2 x Si— t— Bu), 0.96 (9H, t, J = 7.9Hz, 3 x Si-CH CH), 1.44 (3H, d, J = 7.0Hz

 twenty three

 , H-21), 2.56 (2H, s, H— 23), 3.33 (1H, q, J = 6.8Hz, H— 20), 4.05 to 4.10 (2H, m, Hl, 3), 5.56 ( 1H, m, H—16), 5.91 (1H, d, J = ll.2H z, H-7), 6.17 (1H, d, J = ll.2Hz, H—6).

 Mass m / z (%): 776 (M +, 7), 644 (7), 528 (38), 513 (9), 471 (13), 39 6 (65), 339 (34), 309 (18 ), 264 (23), 201 (100), 185 (20), 103 (35), 75 (77), 73 (52).

 [Chemical 76]

[0209] Camphorsulfonic acid (7.9 mg, 0.0340 mmol) was added to a solution of compound 41b (4.4 mg, 0.0057 mmol) in methanol (0.2 ml), and the mixture was stirred at room temperature for 1.5 hours. An aqueous sodium hydrogen carbonate 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 evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 15b (2.4 mg, 96%) from the eluate of 90% ethyl acetate / hexane.

[0210] i Compound lSb: ¹ !! NMR (CDC1) δ: 0.73 (3Η, s, H—18), 0.87, 0.88 (ea

 Three

ch 3H, t, J = 7.5Hz, H— 26a, 27a), 1.46 (3H, d, J = 7.0Hz, H-21), 2. 56 (2H, d, J = 6.3Hz, H— 23) , 3.35 (1H, q, J = 6.9Hz, H-20), 4.06, 4.13 (1H, m, Hl, 3), 5.60 (1H, m, H-16), 5.94 (1H, d, J = ll.3Hz, H-7), 6.30 (1H, d, J = ll.3Hz, H-6). C NMR (CDC1) δ: 8.3, 17.4, 22.6, 23.7, 23.9, 28.8, 31.1, 35

 Three

 .5, 37.4, 38.9, 40.8, 42.4, 44.8, 49.6, 50.2, 58.1, 67.5, 67.6, 7 3.9, 115.6, 123.9, 124.8, 131.6, 142.2, 155.4.

 Mass m / z (%): 434 (M +, 1), 398 (10), 380 (9), 300 (100), 282 (51), 264 (48), 159 (52), 145 (32) , 91 (57), 55 (50).

[0211] <(20S) — Synthesis of 22 thia 19 norvitamin D derivative (16a)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0212] [Chemical 77]

[0213] Compound 28a (331.9mg, 0.763mmol) in 10% potassium hydroxide Z methanol (7ml) The room temperature [trowel was stirred for 3.5 hours. The reaction solution was transferred to ice water, 2N hydrochloric acid 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 distilled off. The residue was dissolved in methylene chloride (7 ml), cooled to 0 ° C., and a solution of diazomethane in jetyl ether (about 0.5 M, 3 ml) was added. After stirring at 0 ° C for 30 minutes, the solvent was distilled off. Purification by silica gel chromatography (16 g) gave Compound 42a (262.4 mg, 86%) from the eluate of 2% ethyl acetate Z-hexane.

 [0214] Compound ASa ^ H NMR (CDC1) δ: 0.03 (6Η, s, 2 χ Si -Me), 0.89 (9H

 Three

 , s, Si-t-Bu), 1.13 (3H, s, H—18), 1.36 (3H, d, J = 7.0Hz, H—21), 2.29 (1H, m, H-15), 2.56 (2H, m, H— 24), 2.70 (2H, m, H— 23), 3.43 (1H, q, J = 6.8Hz, H— 20), 3.70 (3H, s, — OMe), 4.08 ( 1H, m, H—8), 5.62 (1H, m, H—16).

[0215] [Chemical 78]

[0216] To a solution of Compound 42a (262.4 mg, 0.636 mmol) in anhydrous tetrahydrofuran (2 ml) cooled to 78 ° C, ethyllithium (EtLi, 1.12 ml, 1.908 mmol, about 1.5 M ethyl ether solution) was added. The mixture was stirred at 78 ° C for 1 hour. The reaction solution was transferred to ice water, a saturated salt 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 evaporated. The residue was purified by silica gel chromatography (15 g) to obtain Compound 43a (274.9 mg, 98%) from the eluate of 8% ethyl acetate / hexane.

[0217] The compound ASa: ¹ !! NMR (CDC1) δ: 0.02 (6Η, s, 2 x Si— Me), 0.86 (each

 Three

 3H, t, J = 7.5Hz, H-26a, H— 27a), 0.89 (9H, s, Si— t— Bu), 1. 15 (3 H, s, H-18), 1.37 (3H, d , J = 7. OHz, H—21), 1.69 (4H, m, H—26, H -27), 2.30 (1H, m, H—15), 2.49 (2H, m, H—23), 3.43 (1H, q, J = 7. OHz, H-20), 4.08 (1H, m, H-8), 5.62 (1H, m, H-16).

[0218] [Chemical 79]

Compound 43a (366.9 mg, 0.832 mmol) cooled to 0 ° C in anhydrous methylene chloride (3 ml) was added to diisopropyl etheramine ((iso-Pro) 2NEt, 724.6 1, 4. 16 mmol) and chloro Add methyl methyl ether (MOMC, 158.0 ^ 1, 2.08mmol) And carried for 4 hours at room temperature. Diisopropino retinoreamine (362.3 ^ 1, 2.08 mmol) and chloromethyl methyl ether (79.0 1, 1.04 mmol) were added and stirred for another 2 hours. The reaction mixture was transferred to ice water, 2N hydrochloric acid solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (22 g) to obtain Compound 44a (309. lmg, 77%) from the eluate of 3% ethyl acetate Z hexane, and Compound 43a (309. lmg, 77%) from the eluate of 12% ethyl acetate Z hexane. 61.6 mg, 17%) was recovered.

[0220] Compound A a: ¹ !! NMR (CDC1) δ: 0.02 (6Η, s, 2 x Si -Me), 0.83 (6H

 Three

 , t, J = 7.5Hz, H-26a, H— 27a), 0.89 (9H, s, Si— t— Bu), 1.15 (3H, s, H-18), 1.36 (3H, d, J = 6.9 Hz, H— 21), 2.28 (1H, m, H— 15), 2.42 (2 H, m, H-23), 3.38 (3H, s, — OMe), 3.43 (1H, q, J = 6.9Hz , H—20), 4 • 08 (1H, m, H-8), 4.65 (2H, s, OCH O), 5.62 (1H, m, H—16).

 2

 [0221] [Chemical 80]

[0222] Compound 44a (309. lmg, 0.638 mmol) in anhydrous tetrahydrofuran (3. Oml) was added to triethylamine (Et3N, 100 1) and tetrabutylammonium fluoride (nBu NF, 1

 Four

.91 ml, 1.914 mmol, 1.0 M tetrahydrofuran solution). Stirred under C for 91 hours. Futeratetrabutyl ammonium (638.0 ^ 1, 0.638 mmol, 1.0 M tetrahydrofuran solution) was added, and the mixture was further stirred at 50 ° C for 24 hours. The reaction solution was transferred to ice water 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 chromatography (15 g), and the raw material (15.8 mg, 5%) was recovered from the eluate of 8 o / o ethyl acetate. 45a (207.9 mg, 88%) was obtained from the eluate of til Z hexane.

[0223] Compound ASa ^ H NMR (CDC1) δ: 0.83 (6Η, t, J = 7.5Hz, H— 26a, H— 2

 Three

 7a), 1.19 (3H, s, H—18), 1.38 (3H, d, J = 7.0Hz, H—21), 2.33 (1H, m, H-15), 2.42 (2H, m, H — 23), 3.38 (3H, s, — OMe), 3.41 (1H, q, J = 7.0Hz, H-20), 4.18 (1H, m, H— 8), 4.65 (2H, s, OCH O) , 5.66 (1H,

 2

 m, H— 16).

[0224] [Chemical 81]

[0225] Compound 45a (98.7mg, 0.2663mmol) in anhydrous methylene chloride (2.5ml) was mixed with cerite (400.8mg) and pyridinium dichromate (PDC, 200.4mg) and stirred for 3 hours. did . The reaction solution was directly purified by silica gel chromatography (15 g) to obtain Compound 46a (75.3 mg, 77%) from the fraction eluted with 50% ethyl acetate / hexane.

[0226] 匕 Compound ΑδΒ: ¹ !! NMR (CDC1) δ: 0.829, 0.832 (each 3Η, t, J = 7.5Hz

 Three

 , H-26a, H-27a), 0.97 (3H, s, H— 18), 1.44 (3H, d, J = 7.0Hz, H— 2 1), 1.54 (4H, m, H— 26, H— 27), 2.86 (1H, m, H-15), 3.38 (3H, s,-OMe), 3.46 (1H, q, J = 7.0Hz, H-20), 4.64 (2H, s, OCH O), 5.57 (1

 2

 H, m, H—16).

[0227] [Chemical 82]

[0228] A solution of phosphine oxide 40 (125.8 mg, 0.220 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (800 μ 1) was added to lithium bis (trimethylsilyl) amide (LHMDS, 209.0 ^ 1, 1.908 mmol). , 1. OM tetrahydrofuran solution) was stirred and stirred for 30 minutes, and then a solution of compound 46a (40.6 mg, 0. llmmol) in anhydrous tetrahydrofuran (500 1) was slowly added. After stirring at 78 ° C for 1 hour, a saturated 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 chromatography (5 g) to obtain compound 47a (33.5 mg, 42.2%) from the elution part of 7% ethyl acetate Z hexane, and the compound elution from the elution part of 3% ethyl acetate Z hexane. 40 (45.7 mg) was recovered.

[0229] Compound AYa: ¹ !! NMR (CDC1) δ: 0.046, 0.054, 0.062 (6Η, 3Η, 3Η, s

 Three

 , 3 χ Si -Me), 0.83 (3H, s, H— 18) 0.85, 0.88 (each 9H, s, 2 x Si— t-Bu), 1.19 (3H, s, H-18), 1.42 (3H , d, J = 6.9Hz, H—21), 1.52 (4H, m, H-26, H-27), 2.80 (1H, m, H—9), 3.38 (3H, s, — OMe), 3.46 (1H, q, J = 6.9Hz, H— 20), 4.08 (each 1H, m, H— 1, H— 3), 4.65 (2H, s, OCH O), 5.60 (1H, m, H— 16 ), 5.90 (1H, d, J = ll.1Hz, H-7), 6.17

2

 (1H, d, J = ll.1Hz, H-6).

[0230] [Chemical 83]

[0231] To a solution of Compound 47a (26.5 mg, 0.0367 mmol) in methanol (2.5 ml) was added camphorsulfonic acid (51.2 mg, 0.220 mmol), 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 distilled off. The residue was purified by silica gel chromatography (5 g) to obtain 16a (14.6 mg, 89%) from the eluate of 80% ethyl acetate Z-hexane.

[0232] Compound ^ a: ¹ !! NMR (CDC1) δ: 0.83 (3Η, s, H—18), 0.829, 0.832 (

 Three

 each 3H, t, J = 6.6Hz, H— 26a, H— 27a), 1.42 (3H, d, J = 7.0Hz, H— 2 1), 1.48 (4H, m, H— 26, H— 27) , 2.76 (1H, m, H— 9), 3.48 (1H, q, J = 7.0Hz, H-20), 4.07 (each 1H, m, H—l, H— 3), 5.62 (1H, m, H-16), 5.95 (1H, d, J = ll.3Hz, H-7), 6.31 1H, d, J = ll.3Hz, H-6).

 [0233] <Synthesis of (20R) 22 thia 19 norvitamin D derivative (16b)>

 Synthesis was performed according to the following procedure according to the following scheme.

 [0234] [Chemical 84]

28b 42b [0235] Compound 28b (207. 2 mg, 0.464 mmol) in 10% potassium hydroxide Z methanol (3 ml) was charged with ethyl bromopropionate (178 1, 1. 391 mmol) at room temperature. And stirred for 4 hours. The reaction mixture was transferred to ice water, 2N hydrochloric acid 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 evaporated. The residue was dissolved in methylene chloride (2 ml), cooled to 0 ° C., and a solution of diazomethane in jetyl ether (about 0.5 M, 3 ml) was added. After stirring at 0 ° C for 30 minutes, the solvent was distilled off. The residue was purified by silica gel column chromatography (10 g) to obtain Compound 42b (142.2 mg, 74%) from the eluate of 1% ethyl acetate Z-hexane.

 [0236] Compound 42b: Yeah! NMR (CDC1) δ: 0. 02, 0. 03 (each 3H, s, 2 x Si— M

 Three

 e), 0. 89 (9H, s, Si— t— Bu), 1. 04 (3H, s, H— 18), 1. 46 (3H, d, J = 6.9 Hz, H- 21) , 2. 24 (1H, m, H— 15), 2. 58 (2H, m, H— 24), 2. 72 (2H, m, H-23), 3. 32 (1H, q, J = 6.9Hz, H-20), 3.67 (3H, s, OMe), 4.08 (1H, m, H-8), 5.54 (1H, m, H-16).

[0237] [Chemical 85]

[0238] Ethyllithium (690 1, 1.034 mmol, approximately 1.5 M jetyl ether solution) was added to a solution of compound 42b (142.2 mg, 0.344 mmol) in anhydrous tetrahydrofuran (l ml) cooled to 78 ° C. After stirring for 1 hour, a saturated ammonium 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 distilled off. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 43b (141. lmg, 93%) from the eluate of 3% ethyl acetate Z-hexane.

[0239] Compound 43b: 丄! NMR (CDC1) δ: 0. 02, 0. 03 (each 3H, s, 2 x Si— M e), 0.89 (9H, s, Bu— t— Si), 0.86 (6H, t, J = 7.5 Hz, H— 26a, 27a), 1.0 5 (3H, s, H-18), 1.46 (3H, d, J = 6.9Hz, H— 21, overlapped with H— 26, 27), 2.25 (1H, m, H— 15), 2.51 (2H, m, H— 23), 3.34 (1H, q, J = 6.9Hz, H-20), 4.09 (1H, m, H—8), 5.54 (1H, m H—16).

 Mass m / z (%): 440 (M +, 15), 422 (11), 293 (4), 235 (42), 161 (100)

[0240] [Chemical 86]

[0241] Diisoptylethylamine (180 1, 1.032 mmol) and chloromethyl methyl ether were added to a solution of Compound 43b (113.7 mg, 0.258 mmol) cooled to 0 ° C in anhydrous methylene chloride (1.5 ml). (39 1, 0.516 mmol) was added and stirred from 0 ° C to room temperature for 24 hours. The reaction mixture was transferred to ice water, 2N hydrochloric acid solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 44b (124. Omg, 99%) from the eluate of 1% ethyl acetate Z-hexane.

 [0242] My Compound 44b: Yeah! NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, 2 x Si— M

 Three

 e), 0.89 (9H, s, Si— t— Bu), 0.84 (6H, t, J = 7.5 Hz, H— 26a, 27a), 1.0 5 (3H, s, H-18), 1.44 (3H, d, J = 7.0Hz, H— 21), 2.25 (1H, m, H— 15), 2.47 (2H, m, H— 23), 3.32 (1H, q, J = 7.0Hz, H-20), 3.39 (3H, s, O Me), 4.09 (1H, m, H—8), 4.65 (2H, s, OCH O), 5.53 (1H, m, H—16)

Mass m / z (%): 484 (M +, 7), 422 (11), 292 (15), 235 (100), 160 (86 ).

 [0243] [Chemical 87]

 44b 45b

[0244] Tetrabutylammonium fluoride (742 1, 0.742 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of the compound 44b (120. Omg, 0.247 mmol) in anhydrous tetrahydrofuran (l ml) at 60 ° C. For 48 hours. 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 45b (87.5 mg, 95%) from the 20% ethyl acetate / hexane eluate.

[0245] B Compound ASb: ¹ !! NMR (CDC1) δ: 0.84 (6Η, t, J = 7.5Hz, H-26a, 27a)

 Three

 , 1.09 (3H, s, H-18), 1.47 (3H, d, J = 7. OHz, H— 21), 2.29 (1H, m, H -15), 2.44 (2H, m, H— 23) , 3.32 (1H, q, J = 7. OHz, H— 20), 3.39 (3H, s, OMe), 4.17 (1H, m, H— 8), 4.65 (2H, s, OCH O), 5.56 ( 1H, m, H

 2

 16).

[0246] [Chemical 88]

[0247] Celite and pyridinium chromate (98.9 mg, 0.263 mmol) were added to a solution of the compound 45b (48.7 mg, 0.131 mmol) in anhydrous methylene chloride (1.5 ml), and the mixture was stirred at room temperature for 2 hours. Stirred. The reaction solution was directly purified by silica gel column chromatography (10 g) to obtain Compound 46b (39. Omg, 81%) from a fraction eluted with 50% ethyl acetate Z-hexane.

 [0248] Compound 461): NMR (CDC1) δ: 0.84 (6Η, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 0.86 (3H, s, H— 18), 1.48 (3H, d, J = 7. OHz, H— 21), 2.90 (1H, m, H — 14), 3.39 (3H, s, OMe, overlapped with H-20), 4.66 (2H, s, OC HO), 5.53 (1H, m, H-16).

 2

 Mass m / z (%): 368 (M +, 4), 336 (3), 306 (18), 176 (84), 161 (78), 1 31 (100).

[0249] [Chemical 89]

[0250] Compound 40 (25.8 mg, 0.140 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (0.5 ml) was added to lithium bis (trimethinoresylinole) amide (140 1, 0.140 mmol, 1.0 M tetrahydrofuran). Solution) and stirred for 20 minutes, and then a solution of compound 46b (25.8 mg, 0.070 mmol) in anhydrous tetrahydrofuran (0.5 ml) was slowly added. After stirring for 2 hours, a saturated 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 (5g) to obtain the compound 47b (25.6mg, 50%) from the elution part of 3% ethyl acetate Z hexane, from the elution part of 8% ethyl acetate Z hexane. Unreacted compound 4 6b (9. Omg, 35%) was recovered, and further compound 40 (35 mg) was recovered from the eluate of 30% ethyl acetate Z-hexane. [0251] Compound 47b: H NMR (CDC1) δ: 0.048, 0.052, 0.062 (3H, 6H, 3H, s

 Three

 , 4 x Si -Me), 0.73 (3H, s, H— 18), 0.84 (6H, t, J = 7.5Hz, H— 26a, 2 7a), 0.86, 0.88 (each 9H, s, 2 x Si — T— Bu), 1.46 (3H, d, J = 7.0Hz, H-21), 2.80 (1H, m, H— 9), 3.39 (3H, s, OMe, overlapped with H— 20), 4.09 ( 2H, m, H— 1, 3), 4.65 (2H, s, OCH O), 5.58 (1H, m, H— 1

 2

 6), 5.91 (1H, d, J = ll.2Hz, H-7), 6.17 (1H, d, J = ll.2Hz, H-6).

Massm / z (%): 720 (no M +), 528 (19), 471 (5), 396 (30), 339 (17), 264 (13), 75 (100).

[0252] [Chemical 90]

Camphorsulfonic acid (49.5 mg, 0.213 mmol) was added to a methanol (lml) solution of the compound 47b (25.6 mg, 0.0035 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was transferred to ice water, 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated Japanese brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (3 g) to obtain Compound 16b (15.2 mg, 96%) from the 70% ethyl acetate / hexane eluate.

 [0254] Compound 16b: NMR (CDC1) δ: 0.74 (3H, s, H—18), 0.86 (6H, t, J =

 Three

7.5Hz, H-26a, 27a), 1.47 (3H, d, J = 6.9Hz, H-21), 1.48 (4H, q, J = 7.5Hz, H-26, 27), 2.75 (1H, m, H-10), 2.79 (1H, m, H-9), 3.39 (1H, q, J = 6.9Hz, H-20), 4.05 (1H, m, H-l), 4.10 (1H, m, H — 3), 5. 60 (1H, m, H-16), 5.95 (1H, d, J = ll.2Hz, H—7), 6.30 (1H, d, J = ll .2Hz, H-6) . Mass m / z (%): 448 (M +, 1), 430 (9), 412 (7), 394 (5), 300 (100), 28 2 (33), 249 (23).

 UV max (EtOH): 244nm, 252nm (ε = 28, 650), 262nm.

[0255] <(20S) — Synthesis of 22 thia 24 homo 19 norvitamin D derivative (17a)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0256] [Chemical 91]

[0257] To compound mixture 28a (124.5 mg, 0.279 mmol) in 10% potassium hydroxide Z methanol mixed solution (lml) was added 4 bromobutyric acid ethyl ester (127 1, 0.836 mmol) and stirred at room temperature for 4 hours. did. The reaction mixture was transferred to ice water, 2N hydrochloric acid 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 evaporated. The residue was dissolved in methylene chloride (2 ml), cooled to 0 ° C., and a solution of diazomethane in jetyl ether (about 0.5 M, 3 ml) was added. After stirring at 0 ° C for 30 minutes, the solvent was distilled off. The residue was purified by silica gel column chromatography (6 g) to obtain Compound 48a (118.5 mg, 99%) from the eluate of 2% ethyl acetate Z-hexane.

 [0258] Compound ASa ^ H NMR (CDC1) δ: 0.03 (6Η, s, 2 x Si -Me), 0.89 (9H

 Three

 , s, Si-t-Bu), 1.13 (3H, s, H—18), 1.37 (3H, d, J = 7.0Hz, H—21), 1.89 (2H, t, J = 7.2Hz, H— 24), 2.28 (1H, m, H— 15), 2.43, 2.46 (each

2H, t, J = 7.2Hz, H-23, 24a), 3.38 (1H, q, J = 7.0Hz, H— 20), 3.67 (3H, s, OMe), 4.08 (1H, m, H— 8 ), 5.61 (1H, m, H-16).

 Mass m / z (%): 426 (M +, 20), 369 (10), 292 (9), 235 (100), 161 (86

). [0259] [Chem 92]

[0260] Ethyllithium (2.2 ml, 3.306 mmol, about 1.5 M solution of jetyl ether) was added to a solution of compound 48a (470.3 mg, 1.102 mmol) in anhydrous tetrahydrofuran (4 ml) cooled to 78 ° C. . After stirring for 1 hour, a saturated salt 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 (12 g) to obtain Compound 49a (498.3 mg, 99%) from the eluate of 5% ethyl acetate Z-hexane.

 [0261] Compound ΑΘΒ Η NMR (CDCl) δ: 0.03 (6Η, s, 2 χ Si -Me), 0.89 (9H

 Three

 , s, Si-t-Bu), 0.86 (6H, t, J = 7.5Hz, H— 26a, 27a), 1.15 (3H, s, H— 18), 1.35 (3H, d, J = 6.9Hz, H— 21), 1.45 (4H, q, J = 7.5Hz, H— 26, 2 7), 2.29 (1H, m, H— 15), 2.44 (2H, t, J = 7. OHz, H— 23 ), 3.39 (1H, q, J = 6.9Hz, H-20), 4.08 (1H, m, H—8), 5.62 (1H, m, H—16).

 Mass m / z (%): 454 (M +, 6), 436 (4), 292 (5), 235 (76), 161 (86), 14 3 (100).

[0262] [Chemical 93]

[0263] Compound 49a (469.4mg, 1. O32mmol) cooled to 0 ° C in anhydrous methylene chloride (5ml) was added to diisopropyl etheramine (1.08ml, 6.192mmol) and chloromethyl methyl etherol ( 235 1, 3. O96mmol) 0. C force was applied at room temperature for 17:00. The reaction mixture was transferred to ice water, 2N hydrochloric acid solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (20 g) to obtain Compound 50a (492. lmg, 96%) from the eluate of 1% ethyl acetate Z-hexane.

[0264] Compound SOa: ¹ !! NMR (CDC1) δ: 0.03 (6Η, s, 2 x Si -Me), 0.89 (9H

 Three

 , s, Si-t-Bu), 0.83 (6H, t, J = 7.5Hz, H— 26a, 27a), 1.13 (3H, s, H— 18), 1.35 (3H, d, J = 7.0Hz, H-21), 1.49 (4H, q, J = 7.5Hz, H- 26, 2 7), 2.28 (1H, m, H-15), 2.41 (2H, m, H-23), 3.39 (3H, s, OMe, ove rlapped with H— 20), 4.08 (1H, m, H— 8), 4.65 (2H, s, OCH O), 5.6

 2

 1 (1H, m, H-16).

 Mass m / z (%): 498 (M +, 4), 436 (7), 292 (5), 235 (100), 161 (61).

[0265] [Chemical 94]

 50a 51a

[0266] Compound 50a (476.3 mg, 0.955 mmol) in anhydrous tetrahydrofuran (4 ml) was added tetrabutylammonium fluoride (2.86 1, 2.864 mmol, 1.0 M tetrahydrofuran solution) to 50 ° C. And stirred for 48 hours. 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 (15 g) to obtain compound 5 la (360. Omg, 98%) from the eluate of 25% ethyl acetate Z-hexane. [0267] Compound 51a: H NMR (CDC1) δ: 0.83 (6H, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 1.18 (3H, s, H-18), 1.37 (3H, d, J = 7.0Hz, H-21), 1.51 (4H, q, J = 7.5Hz, H-26, 27), 2.33 (1H, m, H—15), 2.41 (2H, m, H—23), 3.3 9 (3H, s, OMe, overlapped with H—20), 4.17 (1H, m, H—8), 4.65 (2 H, s, OCH O), 5.61 (1H, m, H--16).

 2

 Mass m / z (%): 384 (M +, 2), 322 (2), 252 (21), 145 (100).

[0268] [Chemical 95]

[0269] — A solution of dimethyl sulfoxide (134 1, 1.891 mmol) in anhydrous methylene chloride (lm 1) was added to a solution of oxalyl dichloride (82 / zl, 0.945 mmol) in anhydrous methylene chloride (2 ml) cooled to 78 ° C. After stirring for 10 minutes, a solution of compound 51a (303. Omg, 0.788 mmol) in anhydrous methylene chloride (3 ml) was added. — After stirring at 78 ° C. for 15 minutes, triethylamine (549 1, 3.94 mmol) was added and stirred at −78 ° C. for 15 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 (12 g), and Compound 52a (287.4 mg, 95%) was obtained from the eluate of 10% ethyl acetate Z-hexane.

[0270] Compound SSa: ¹ !! NMR (CDC1) δ: 0.83 (6Η, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 0.96 (3H, s, H-18), 1.43 (3H, d, J = 7.0Hz, H-21), 1.51 (4H, q, J = 7.5Hz, H-26, 27), 2.87 (1H, dd, J = 10.6, 6.4Hz, H-14), 3.38 (3 H, s, OMe), 3.45 (1H, q, J = 7.0Hz, H-20), 4.65 (2H, s, OCH O), Five.

 2

56 (1H, m, H-16).

 Mass m / z (%): 382 (M +, 15), 320 (50), 236 (16), 177 (100).

[0271] [Chemical 96]

[0272] Lithium bis (trimethinosyllinole) amide (157 1, 0.157 mmol, 1.0 M tetrahydrofuran) was added to a solution of the compound 40 (89.5 mg, 0.157 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (0.8 ml). After stirring for 20 minutes, a solution of compound 52a (40. Omg, 0.104 mmol) in anhydrous tetrahydrofuran (1.5 ml) was slowly added. The reaction mixture was stirred at −78 ° C. for 1 hour and then gradually warmed. After 2 hours (1-40 ° C), a saturated salt-ammonium solution 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 (5 g), and the compound 53a (33.6 mg, 44%) was obtained from the eluate of 3% ethyl acetate Z hexane, and unreacted from the eluate of 7% ethyl acetate Z hexane. Reaction compound 52a (22. Omg, 55%) was recovered, and compound 40 (48.2 mg) was further recovered from the eluate of 30% ethyl acetate Z-hexane.

[0273] The compound SSa ^ H NMR (CD OD) δ: 0.048, 0.052, 0.061 (3Η, 6Η, 3Η,

 Three

 s, 4 χ Si— Me), 0.82 (6H, t, J = 7.5Hz, H— 26a, 27a, overlapped with H-18), 0.86, 0.88 (each 9H, s, 2 x Si— t— Bu) , 1.41 (3H, d, J = 7.0 Hz, H-21), 1.51 (4H, q, J = 7.5 Hz, H— 26, 27), 2.80 (1H, m, H— 9), 3.38 (3H , s, OMe), 3.45 (1H, m, H— 20), 4.08 (2H, m, H— 1, 3), 4.65 (2H, s, OCH O), 5.59 (1H, m, H— 16), 5.90 (1H, d, J = ll.2Hz, H

 2

 -7), 6.17 (1H, d, J = ll.2Hz, H-6).

 Mass m / z (%): 734 (no M +), 528 (28), 471 (8), 396 (50), 339 (26), 264 (16), 75 (100).

[0274] [Chemical 97]

[0275] Compound 53a (30.3 mg, 0.0412 mmol) cooled to 0 ° C was added to a solution of camphorsulfonic acid (57.4 mg, 0.247 mmol) in methanol (lml) and stirred at room temperature for 1 hour. . The reaction mixture was transferred to ice water, 5% aqueous sodium hydrogen carbonate 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 evaporated. The residue was purified by silica gel column chromatography (3 g) to obtain Compound 17a (18.6 mg, 98%) from the eluate of 80% ethyl acetate Z-hexane.

[0276] Compound! Ta: ¹ !! NMR (CD OD) δ: 0.83 (3H, s, H—18), 0.85 (6H, t, J

 Three

 = 7.5Hz, H-26a, 27a), 1.41 (3H, d, J = 6.9Hz, H--21), 1.47 (4H, q, J = 7.5Hz, H-26, 27), 2.75 (1H, m , H-10), 2.79 (1H, m, H-9), 3.45 (1H, q, J = 6.9Hz, H-20), 4.05 (1H, m, H-l), 4.12 (1H, m, H-3), 5.60 (1H, m, H-16), 5.95 (1H, d, J = ll.2Hz, H-7), 6.30 (1H, d, J = l 1.2Hz, H-6 ).

 Mass m / z (%): 462 (no M +), 444 (3), 426 (3), 408 (3), 300 (46), 28 2 (28), 264 (33), 249 (31) , 143 (100).

 UV max (EtOH): 244nm, 252nm (ε = 29, 660), 262nm.

[0277] <(20R) — Synthesis of 22 thia 24 homo 19 norvitamin D derivative (17b)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0278] [Chemical 98]

[0279] To a solution of Compound 28b (331.2 mg, 0.741 mmol) in 10% potassium hydroxide Z methanol (3 ml) was added 4-ethyl bromobutyrate (338 / zl, 2.224 mmol) and stirred at room temperature for 4 hours. did. The reaction mixture was transferred to ice water, 2N hydrochloric acid 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 evaporated. The residue was dissolved in methylene chloride (2 ml), cooled to 0 ° C., and a diethyl methane solution in ethyl ether (about 0.5 M, 3 ml) was prepared. After stirring at 0 ° C for 30 minutes, the solvent was distilled off. The residue was purified by silica gel column chromatography (log) to obtain Compound 48b (292.3 mg, 92%) from the eluate of 1% ethyl acetate Z-hexane.

[0280] The Compound 48b: Yeah! NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, 2 x Si— M

 Three

 e), 0.89 (9H, s, Si— t— Bu), 1.04 (3H, s, H— 18), 1.44 (3H, d, J = 7.0 Hz, H-21), 2.28 (1H, m, H — 15), 2.41 ~ 2.53 (4H, m, H— 23, 24a), 3.30 (1H, q, J = 7.0Hz, H— 20), 3.67 (3H, s, OMe), 4.09 (1H, m, H—8), 5.53 (1H, m, H—16).

 Mass m / z (%): 426 (M +, 24), 369 (9), 292 (5), 235 (70), 161 (100).

[0281] [Chemical 99]

Compound 48b (292.3mg, 0.685mmol) anhydrous tetrahydrofurane cooled to 78 ° C Ethyllithium (1.37 ml, 2.055 mmol, about 1.5 M jetyl ether solution) was added to the solution (3 ml). After stirring for 1 hour, saturated saline 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 (10 g) to obtain Compound 49b (306. lmg, 98%) from the eluate of 5% ethyl acetate Z-hexane.

[0283] Compound 49b: 丄! NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, 2 x Si— M

 Three

 e), 0.89 (9H, s, Si— t— Bu), 0.86 (6H, t, J = 7.5 Hz, H— 26a, 27a), 1.0 5 (3H, s, H-18), 1.44 (3H, d, J = 7.0Hz, H— 21), 1.45 (4H, q, J = 7.5 Hz, H-26, 27), 2.25 (1H, m, H— 15), 2.47 (2H, m, H— 23 ), 3.30 (1H, q, J = 7.0Hz, H-20), 4.09 (1H, m, H-8), 5.53 (1H, m, H-16).

Mass m / z (%): 454 (M +, 7), 436 (3), 292 (5), 235 (98), 161 (73), 75 (100).

[0284] [Chemical 100]

[0285] Diethyl ether ammonium (556 1, 3.190 mmol) and chloromethyl methyl ether were added to a solution of compound 49b (290. lmg, 0.638 mmol) cooled to 0 ° C in anhydrous methylene chloride (3 ml). (121 kg, 1.595 mmol) was added and stirred from 0 ° C to room temperature for 17 hours. The reaction solution was transferred to ice water, 2N hydrochloric acid solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (10 g) to obtain Compound 50b (294.8 mg, 93%) from the eluate of 2% ethyl acetate Z-hexane.

[0286] The Compound 50b: Yeah! NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, 2 x Si— M e), 0.89 (9H, s, Si— t— Bu), 0.83 (6H, t, J = 7.5 Hz, H— 26a, 27a), 1.0 5 (3H, s, H-18), 1.44 (3H, d, J = 7.0Hz, H— 21), 1.51 (4H, q, J = 7.5 Hz, H-26, 27), 2.24 (1H, m, H— 15), 2.45 (2H, m, H— 23 ), 3.30 (1H, q, J = 7.0Hz, H-20), 3.39 (3H, s, OMe), 4.08 (1H, m, H— 8), 4.65 (2H, s, OCH O), 5.53 ( 1H, m, H—16).

 2

 Mass m / z (%): 498 (M +, 4), 436 (9), 292 (4), 235 (74), 161 (73), 75 (100).

[0287] [Chemical 101]

[0288] To a solution of Compound 50b (294.8 mg, 0.59 lmmol) in anhydrous tetrahydrofuran (2 ml) was added tetrabutylammonium fluoride (1.77 ml, 1.773 mmol, 1.0 M tetrahydrofuran solution) to 50 ° C. And stirred for 66 hours. 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), and Compound 51b (222.5 mg, 98%) was obtained from the fraction eluted with 15% ethyl acetate / hexane.

[0289] Compound Sib: ¹ !! NMR (CDC1) δ: 0.83 (6Η, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 1.08 (3H, s, H-18), 1.46 (3H, d, J = 6.9Hz, H-21), 1.53 (4H, q, J = 7.5Hz, H-26, 27), 2.29 (1H, m, H— 15), 2.45 (2H, m, H— 23), 3.3 0 (1H, q, J = 6.9Hz, H-20), 3.39 (3H, s, OMe), 4.18 (1H, m, H-8), 4.65 (2H, s, OCH O), 5.56 (1H, m, H-16).

 2

 Mass m / z (%): 384 (M +, 1), 322 (2), 252 (13), 160 (58), 145 (100).

[0290] [Chemical 102]

 51b

[0291] — A solution of oxalyl dichloride (57 1, 0.656 mmol) in anhydrous methylene chloride (2 ml) cooled to 78 ° C in dimethyl sulfoxide (93 1, 1.313 mmol) in anhydrous methylene chloride (0.5 ml) After stirring for 10 minutes, a solution of compound 51b (210.4 mg, 0.547 mmol) in anhydrous methylene chloride (2 ml) was added. — After stirring at 78 ° C. for 15 minutes, triethylamine (38 1 ^ 1, 2.735 mmol) was added and stirred at −78 ° C. for 15 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 (10 g) to obtain Compound 52b (178.5 mg, 85%) from the eluate of 10% ethyl acetate Z-hexane.

 [0292] Compound 521): NMR (CDC1) δ: 0.84 (6Η, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 0.86 (3H, s, H-18), 1.47 (3H, d, J = 7.0Hz, H-21), 1.52 (4H, q, J = 7.5Hz, H-26, 27), 2.91 (1H, dd, J = 10.7, 6.5Hz, H-14), 3.39 (3 H, s, OMe), 3.34 (1H, q, J = 7.0Hz, H-20), 4.66 (2H, s, OCH O), Five.

 2

53 (1H, m, H-16).

 Mass m / z (%): 382 (M +, 10), 320 (30), 236 (10), 177 (100).

[0293] [Chemical 103]

 53b

[0294] Lithium bis (trimethylsilyl) amide (162 1, 0.162 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of the compound 40 (92.4 mg, 0.162 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (0.8 ml). After stirring for 20 minutes, a solution of compound 52b (41.3 mg, 0.108 mmol) in anhydrous tetrahydrofuran (1.5 ml) was slowly added. After stirring for 2 hours, a saturated salt-ammonium solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, 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 5 3b (22.5 mg, 28%) from the eluate of 3% ethyl acetate / hexane, and unreacted from the eluate of 7% ethyl acetate Z-hexane. Compound 52b (26.8 mg, 65%) was recovered, and further compound 40 (60 mg) was recovered from the eluate of 30% ethyl acetate Z-hexane.

 [0295] Compound 53b: NMR (CDC1) δ: 0.05, 0.06 (9H, 3H, s, 4 x Si -Me)

 Three

 , 0.72 (3H, s, H-18), 0.83 (6H, t, J = 7.5Hz, H— 26a, 27a), 0.86, 0. 88 (each 9H, s, 2 x Si— t— Bu), 1.45 (3H, d, J = 7.0Hz, H— 21), 1.51 (4H, q, J = 7.5Hz, H— 26, 27), 2.80 (1H, m, H— 9), 3.39 (3H, s , OMe), 3.36 (1H, q, J = 7.0Hz, H— 20), 4.09 (2H, m, H— 1, 3), 4.65 (2H, s, OCH O), 5.58 (1H, m, H — 16), 5.91 (1H, d, J = ll.2Hz, H— 7), 6.17 (

2

 1H, d, J = ll. 2Hz, H-6).

 Mass m / z (%): 734 (no M +), 528 (57), 471 (16), 396 (86), 339 (38), 264 (20), 75 (100).

[0296] [Chemical 104]

Camphorsulfonic acid (42.6 mg, 0.184 mmol) was added to a solution of compound 53b (22.5 mg, 0.0031 mmol) in methanol (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was transferred to ice water, 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated Japanese brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (3 g) to obtain Compound 17b (13.7 mg, 97%) from the 70% ethyl acetate / hexane eluate.

[0298] Compound Tb: ¹ !! NMR (CDC1) δ: 0.73 (3Η, s, H-18), 0.86 (6H, t, J =

 Three

 7.5Hz, H-26a, 27a), 1.45 (3H, d, J = 6.9Hz, H-21), 1.46 (4H, q, J = 7.5Hz, H-26, 27), 2.75 (1H, m, H-10), 2.79 (1H, m, H-9), 3.36 (1H, q, J = 6.9Hz, H-20), 4.06 (1H, m, H-1), 4.13 (1H, m, H — 3), 5.58 (1H, m, H-16), 5.95 (1H, d, J = ll.3Hz, H—7), 6.30 (1H, d, J = ll .3Hz, H-6) .

 Mass m / z (%): 462 (M +, 1), 444 (2), 426 (3), 408 (2), 300 (36), 282 (22), 264 (22), 249 (22) , 143 (100).

 UV max (EtOH): 244nm, 252nm (ε = 28, 260), 262nm.

[0299] <Synthesis of (20S) -2 α-methyl-2 j8-hydroxy 19 norvitamin D derivative (18a), (20 S) -2j8 -methyl 2a hydroxy-19 norvitamin D derivative (19a)> According to the following scheme Was synthesized by the following procedure.

[0300] [Chemical 105]

[0301] Compound 54 (312.5 mg, 0.464 mmol) anhydrous tetrahydrofuran cooled to 78 ° C

 (1.5 ml) To the solution was added lithium bis (卜 limethinoresylinole) amide (464 1, 0.464 mmol, 1.0 M tetrahydrofuran solution), stirred for 20 minutes, and then compound 31a (82.3 mg, 0.232 mmol) in anhydrous tetrahydrofuran. (Lml) solution was added slowly. 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 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 (15 g), and compound 55a (mixture of 59.2 mg, 32%, approx. 3: 2) was obtained from the eluate of 3% ethyl acetate Z hexane, and converted to 15% ethyl acetate Z. Unreacted compound 31a (43.6 mg, 53%) was recovered from the eluate of xanthane, and compound 54 (220. Omg) was recovered from the eluate of 50% ethyl acetate-hexane.

 [0302] Compound δδΒ ^ Η NMR (CD OD) δ: 0.03 ~ 0.09 (12H, 4 x Si-Me), 0.

 Three

 11, 0.12 (3: 2) (9H, s, 3 x Si— Me), 0.82 to 0.93 (27H, m, H— 18, 26a, 27a, 2 x Si-t-Bu), 1.23, 1.24 (2 : 3) (3H, s, 2—Me), 1.42 (3H, d, J = 7. OHz, H-21), 2.60, 2.66 (each 1H, d, J = 12.3Hz, H— 23), 3.39 9, 3.403 (3H, s, OMe), 3.57 to 3.73 (2H, m, H—1, 3), 4.69 (2H, s, OC HO), 5.61 (1H, m, H—16), 5.87, 5.92 (3: 2) (1H, d, J = ll.2Hz, H— 7

2

 ), 6.09, 6.14 (2: 3) (1H, d, J = ll.2Hz, H-6).

[0303] [Chem 106]

[0304] Camphorsulfonic acid (101.9 mg, 0.439 mmol) was added to a methanol (lml) solution of the compound 55a (a mixture of 59.2 mg, 0.073 mmol, approximately 2: 3) and stirred at room temperature for 4 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 (5 g), and a mixture of compound 18a and compound 19a (31.6 mg, 93%, approx 2: 3 mixture) from the eluate of 80% ethyl acetate / hexane. Got. The mixture was further mixed with HPLC [LiChrosorb Si 60 (7 m), hexane: CHC1: MeO

 Three

 H: THF = 80: 20: 3: 1, 2.5 mlZmin] to obtain 1.8 mg of compound 18a and 1.9 mg of compound 19a.

[0305] The compound ISa: ¹ !! NMR (CDC1) δ: 0.83 (3Η, s, H—18), 0.87, 0.88 (eac

 Three

 h 3H, t, J = 7.4Hz, H-26a, 27a), 1.28 (3H, s, 2—Me), 1.42 (3H, d, J = 7.0Hz, H-21), 2.54, 2.58 (each 1H , d, J = 12.9Hz, H—23), 2.78 (1H, m, H-9), 2.95 (1H, dd, J = 13.6, 4.7Hz, H—10), 3.44 (1H, q, J = 7.0Hz, H-20), 3.76 (2H, m, H— 1, 3), 5.64 (1H, m, H— 16), 5.94 (1 H, d, J = ll. 2Hz, H-7), 6.29 (1H, d, J = ll.2Hz, H-6).

[0306] Compound 19 &: NMR (CDC1) δ: 0.84 (3H, s, H—18), 0.87, 0.88 (eac

 Three

h 3H, t, J = 7.5Hz, H-26a, 27a), 1.31 (3H, s, 2—Me), 1.42 (3H, d, J = 7.0Hz, H-21), 2.79 (1H, m, H-9), 3.44 (1H, q, J = 7.0Hz, H-20), 3.74, 3.79 (each 1H, m, H— 3, 1), 5.63 (1H, m, H— 16), 5.91 ( 1H, d, J = ll.3Hz, H-7), 6.33 (1H, d, J = ll.3Hz, H-6). [0307] <Synthesis of (20R)-2α-methyl-2 j8-hydroxy 19 norvitamin D derivative (18b), (20 R) -2 j8-methyl-2α hydroxy-19 norvitamin D derivative (19b)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0308] [Chemical 107]

 55b

[0309] Lithium bis (trimethylsilyl) amide (116 1, 0.116 mmol, 1. OM tetrahydrofuran solution) was added to a solution of compound 54 (78.2 mg, 0.116 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (1 ml). After stirring for 20 minutes, a solution of compound 31b (20.6 mg, 0.058 mmol) in anhydrous tetrahydrofuran (0.5 ml) 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 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 (15 g), and compound 55b (a mixture of 19. Omg, 40%, approximately 1: 5) was obtained from the eluate of 3% ethyl acetate Z hexane, and 7% ethyl acetate Z Unreacted compound 31b (12. Omg) was recovered from the hexane eluate, and Compound 54 (47. Omg) was further recovered from the 50% ethyl acetate Z hexane eluate.

[0310] Compound δδΐ): ¹ !! NMR (CD OD) δ: 0.03 ~ 0.09 (12Η, 4 x Si-Me), 0

 Three

11, 0.12 (5: 1) (9H, s, 3 x Si— Me), 0.71, 0.72 (5: 1) (3H, s, H— 18), 0.82 to 0.93 (24H, m, H— 26a , 27a, 2 x Si-t-Bu), 1.23, 1.24 (1: 5 (3H, s, 2— Me), 1.46 (3H, d, J = 7. OHz, H— 21), 2.65 (2H, s, H—23), 3.34 (1H, q, J = 7.0Hz, H-20), 3.41 (3H, s, OMe), 3.61 (1H, m), 3.7 0 (1H, dd, J = ll.3, 4.6Hz), 4.69 (2H, s, OCH O), 5.58 (1H, m, H— 1

 2

 6), 5.87, 5.93 (5: 1) (1H, d, J = ll.1Hz, H-7), 6.02, 6.13 (1: 5) (1H, d, J = ll. 1Hz, H-6) .

 [Chemical 108]

[0312] Compound 55b (19. Omg, 0.0235mmol, mixture of about 1: 5) in methanol (0.5ml) was added camphorsulfonic acid (43.6mg, 0.188mmol) and stirred at room temperature for 6 hours. did. 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 (3 g), and the mixture of compound 18b and compound 19b from the 70% ethyl acetate / hexane eluate (9. lmg, 83%, approximately 1: 5 mixture) Got. The mixture is HPLC [LiChrosorb Si 60, hexane: CHC1: MeOH = 20: 8

 Three

 0: 2.5, lmlZmin] to obtain 5. Omg of compound 18b and 1. lmg of compound 19b.

[0313] I compound lSb: ¹ !! NMR (CDC1) δ: 0.72 (3Η, s, H— 18), 0.87, 0.88 (each

 Three

3H, t, J = 7.4Hz, H-26a, 27a), 1.27 (3H, s, 2—Me), 1.46 (3H, d, J = 7.0Hz, H-21), 2.78 (1H, m, H — 9), 2.95 (1H, dd, J = 13.5, 4.4Hz, H -10), 3.35 (1H, q, J = 7.0Hz, H— 20), 3.74 (2H, m, H— 1, 3) , 5.61 (1 H, m, H-16), 5.94 (1H, d, J = ll.3Hz, H-7), 6.29 (1H, d, J = ll.3Hz, H-6). [0314] Compound 19b: H NMR (CDC1) δ: 0.73 (3H, s, H—18), 0.87, 0.88 (each

 Three

 3H, t, J = 7.5Hz, H-26a, 27a), 1.31 (3H, s, 2—Me), 1.46 (3H, d, J = 7. OHz, H-21), 2.79 (1H, m, H— 9), 3.35 (1H, q, J = 7. OHz, H— 20), 3.72, 3.78 (each 1H, m, H— 3, 1), 5.61 (1H, m, H— 16), 5.91 (1H, d, J = ll.2Hz, H-7), 6.33 (1H, d, J = ll.2Hz, H-6).

[0315] <Synthesis of (20S) 22 oxa 19 norvitamin D derivative (20a)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0316] [Chem 109]

[0317] Hydrogenated sodium (437.9mg, 10.948mmol, 60% dispersion in mineral oil) was added to a solution of Compound 25a (170. Omg, 0.547mmol) in anhydrous dimethylformamide (4ml) and stirred for 30 minutes. TsOCH CH OTBS (723.2mg, 2.188mmol) anhydrous

 twenty two

 A dimethylformamide (5 ml) solution was prepared. After 17 hours, ice water was added to the reaction solution to stop the reaction, followed by extraction with 50% ethyl acetate Z-hexane. 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), and the compound 56a (148.5 mg, 58%) was obtained from the eluate of 1% ethyl acetate and hexane, and unreacted from the eluate of 10% ethyl acetate and hexane. The reaction compound 25a (20. Omg, 6%) was recovered.

[0318] The compound δδΒ: ¹ !! NMR (CDC1) δ: 0.03, 0.06 (each 6Η, s, 4 χ Si— Me

 Three

 ), 0.89 (18H, s, Si-t-Bu), 1.11 (3H, s, H—18), 1.25 (3H, d, J = 6.5 Hz, H-21), 3.31, 3.50, 3.74 (1H, 1H, 2H, m, H- 23, 24), 3.88 (1H, m, H-20), 4.09 (1H, m, H-8), 5.56 (1H, m, H-16).

[0319] [Chemical 110]

[0320] Compound 56a (220. Omg, 0.469mmol) cooled to 0 ° C was added to a solution of tetrabutylammonium fluoride (704 1, 0.704mmol, 1.0M tetrahydride) in anhydrous tetrahydrofuran (1 ml). Furan solution) was added 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), and Compound 57a (146.4 mg, 88%) was obtained from the fraction eluted with 15% ethyl acetate / hexane.

[0321] Compound SYa: ¹ !! NMR (CDC1) δ: 0.03 (6Η, s, 2 x Si—Me), 0.89 (9H,

 Three

 s, Si-t-Bu), 1.12 (3H, s, H— 18), 1.28 (3H, d, J = 6.4Hz, H— 21), 2. 27 (1H, m, H-15), 3.36 , 3.57, 3.71 (1H, 1H, 2H, m, H— 23, 24), 3. 89 (1H, q, J = 6.4Hz, H— 20), 4.09 (1H, m, H— 8), 5.56 (1H, m, H— 1 6).

 [0322] [Chem 111]

To a solution of oxalyl dichloride (7 1, 0.080 mmol) in anhydrous methylene chloride (0.2 ml) cooled to 78 ° C, add a solution of dimethyl sulfoxide (11 1, 0.160 mmol) in anhydrous methylene chloride (0.1 ml). After stirring for 10 minutes, a solution of compound 57a (23.7 mg, 0.067 mmol) in anhydrous methylene chloride (0.3 ml) was prepared. After stirring at 78 ° C for 15 minutes, triethylamine (47 µΐ, 0.334 mmol) was added, and the mixture was stirred at 78 ° C for 10 minutes and at 0 ° C for 15 minutes. Ice in reaction mixture Water was added and 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 (3 g) to obtain Compound 58a (22.4 mg, 95%) from the eluate of 10% ethyl acetate Z hexane.

 [0324] Compound δδΒ ^ Η NMR (CDC1) δ: 0.03 (6Η, s, 2 x Si -Me), 0.89 (9H

 Three

 , s, Si-t-Bu), 1.10 (3H, s, H—18), 1.35 (3H, d, J = 6.5Hz, H—21), 2.27 (1H, m, H-15), 3.91, 4.07 (each 1H, d, J = 8.0Hz, H— 23), 3.95 (1H, q, J = 6.5Hz, H— 20), 4. 10 (1H, m, H— 8), 5.58 ( 1H, m, H-16).

[0325] [Chem 112]

[0326] Compound 58a (117. Omg, 0.332 mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (1 ml) was added ethylmagnesium bromide (498 1, 0.498 mmol, 1. OM tetrahydrofuran solution) Was added. After stirring at 0 ° C for 1 hour, the mixture was further stirred at room temperature for 3 hours. A 2N hydrochloric acid 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 evaporated. The residue was purified by silica gel column chromatography (6 g) to obtain Compound 59a (a mixture of 115.3 mg, 91%, approximately 1: 1) from the eluate of 10% ethyl acetate Z-hexane.

 [0327] Compound δθΒ ^ Η NMR (CDC1) δ: 0.03 (6 Η, s, 2 χ Si -Me), 0.89 (9H

 Three

, s, Si-t-Bu), 0.96 (3H, t, J = 7.5Hz, H—26), 1.11 (3H, s, H—18), 1.27 (3H, d, J = 6.5Hz, H--21), 2.27 (1H, m, H-15), 2.38 (1H, dd, J = 12.5, 3.2Hz), 3.06, 3.29 (1: 1) (1H, m, H-23), 3.48, 3.29 (1: 1) (1 H, m, H-23), 3.67 (1H, m, H-24), 3.87 (1H, m, H-20), 4.09 (1H, m, H-8), 5.55 (1H, m, H

[0328] [Chem 113]

[0329] — A solution of dimethylsulfoxide (51 1, 0.724 mmol) in anhydrous methylene chloride (0.3 ml) was added to a solution of oxalyl dichloride (32 / zl, 0.362 mmol) in anhydrous methylene chloride (1 ml) cooled to 78 ° C. After stirring for 10 minutes, a solution of compound 59a (115.3 mg, 0.301 mmol) in anhydrous methylene chloride (1.5 ml) was prepared. — After stirring at 78 ° C. for 15 minutes, triethylamine (21 0 ^ 1, 1.505 mmol) was added and stirred at −78 ° C. for 10 minutes and at 0 ° C. for 15 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 (6 g), and the compound 60a (103. Omg, 90%) was obtained from the elution part of 2% ethyl acetate Z hexane, and from the elution part of 10% ethyl acetate Z hexane. Unreacted compound 659a (11.5 mg, 10%) was recovered.

[0330] Compound eOa: ¹ !! NMR (CDC1) δ: 0.03 (6Η, s, 2 x Si -Me), 0.89 (9H

 Three

 , s, Si-t-Bu), 1.06 (3H, t, J = 7.3Hz, H— 26), 1.08 (3H, s, H— 18), 1.32 (3H, d, J = 6.5Hz, H— 21), 2.27 (1H, m, H— 15), 2.52 (2H, q, J = 7.3Hz, H-25), 3.91 (1H, m, H— 20), 3.86, 4.03 (each 1H , d, J = 17.0 Hz, H-23), 4.10 (1H, m, H-8), 5.55 (1H, m, H-16).

[0331] [Chemical 114]

[0332] Ethyllithium (271 1, 0.406 mmol, about 1.5 M jetyl ether solution) was added to a solution of the compound 60a (103. Omg, 0.271 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (lml). After 1 hour, ethyl lithium (1.5 equivalents) was added, and the reaction temperature was gradually raised to room temperature. After 4 hours, 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 distilled off. The residue was purified by silica gel column chromatography (5 g) to obtain Compound 61a (111. Omg, 99%) from the eluate of 2% ethyl acetate Z-hexane.

 [0333] 匕 Compound eia ^ H NMR (CDC1) δ: 0.03 (6Η, s, 2 x Si -Me), 0.858, 0

 Three

 .863 (each 3H, t, J = 7.6Hz, H— 26a, 27a), 0.89 (9H, s, Si— t— Bu), 1.11 (3H, s, H-18), 1.25 (3H, d, J = 6.5Hz, H— 21), 2.27 (1H, m, H— 15), 3.08, 3.31 (each 1H, d, J = 9. OHz, H— 23), 3.83 (1H, q, J = 6.5 Hz, H-20), 4.09 (1H, m, H—8), 5.53 (1H, m, H—16).

[0334] [Chem 115]

To a solution of 6 la (20.5 mg, 0.050 mmol) in anhydrous tetrahydrofuran (l ml) was added tetrabutylammonium fluoride (150 1, 0.150 mmol, 1.0 M tetrahydrofuran solution) and refluxed. After 11 hours, ice water was added to the reaction solution and extracted with ethyl acetate. Organic The 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 62a (10. Omg, 68%) from the eluate of 20% ethyl acetate / hexane.

[0336] i Compound eSa: ¹ !! NMR (CDC1) δ; 0.857, 0.863 (each 3H, t, J = 7.5Hz

 Three

 , H-26a, 27a), 1.15 (3H, s, H—18), 1.27 (3H, d, J = 6.4Hz, H—21), 2.32 (1H, m, H—15), 3.09, 3.31 (each 1H, d, J = 9. OHz, H— 23), 3.8 3 (1H, q, J = 6.4Hz, H— 20), 4. 18 (1H, m, H— 8), 5.58 ( 1H, m, H— 16)

[0337] [Chem 116]

[0338] —A solution of oxalyl dichloride (37 1, 0.419 mmol) in anhydrous methylene chloride (0.4 ml) cooled to 78 ° C. A solution of dimethyl sulfoxide (59 1, 0.836 mmol) in anhydrous methylene chloride (0.1 ml) After stirring for 10 minutes, a solution of 62a (56.4 mg, 0.190 mmol) in anhydrous sodium chloride (0.5 ml) was obtained. — After stirring at 78 ° C. for 15 minutes, triethylamine (265 1, 190 mmol) was added and stirred at −78 ° C. for 20 minutes and at 0 ° C. for 10 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 (3 g) to obtain 63a (45. Omg, 80%) from the eluate of 10% ethyl acetate Z-hexane.

[0339] Compound eSa: ¹ !! NMR (CDC1) δ; 0.87 (6Η, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 0.91 (3H, s, H-18), 1.33 (3H, d, J = 6.5Hz, H-21), 2.49 (1H, m), 2.88 (1H, dd, J = 10.7, 6.4Hz), 3.13 , 3.29 (each 1H, d, J = 8.9Hz, H -23), 3.93 (1H, q, J = 6.5Hz, H-20), 5.56 (1H, m, H-16).

[0340] [Chemical 117]

[0341] A solution of Compound 63a (45. Omg, 0.153 mmol) cooled to 0 ° C in anhydrous methylene chloride (0.5 ml) was mixed with isopropylpyrutamine (133 1, 0.764 mmol) and chloromethyl methyl ether. (29 1, 0.383 mmol) was calorie-free, and at 0 ^o C force, was framed at 21 hours at room temperature. To the reaction solution was added 2N hydrochloric acid solution, and the mixture was extracted with methylene chloride. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (3 g) to obtain compound 64a (44.8 mg, 87%) from the 10% ethyl acetate / hexane eluate and further from the 15% ethyl acetate Z-hexane eluate. The reaction compound 63a (3.7 mg, 8%) was recovered.

 [0342] Compound 64 &: NMR (CDC1) δ; 0.86 (6Η, t, J = 7.5Hz, H— 26a, 27a)

 Three

 , 0.91 (3H, s, H-18), 1.30 (3H, d, J = 6.5Hz, H-21), 2.49 (1H, m), 2.87 (1H, dd, J = 10.6, 6.5Hz), 3.23 , 3.36 (each 1H, d, J = 9.7Hz, H -23), 3.39 (3H, s, OMe), 3.86 (1H, q, J = 6.5Hz, H— 20), 4.73, 4.76 (each 1H, d, J = 7.1Hz, OCH O), 5.56 (1H, m, H—16).

 2

 [0343] [Chemical 118]

65a [0344] Lithium bis (trimethylsilyl) amide (250 1, 0.250 mmol, 1. OM tetrahydrofuran solution) was added to a solution of compound 40 (142.8 mg, 0.250 mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (l ml). After stirring for 20 minutes, a solution of compound 64a (43. Img, 0.127 mmol) in anhydrous tetrahydrofuran (0.5 ml) was slowly added. After stirring at 78 ° C for 1 hour, the temperature was gradually raised. Two hours later (40 ° C), 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 distilled off. The residue was purified by silica gel column chromatography (10 g) to obtain compound 65a (44.2 mg, 50%) from the eluate of 3% ethyl acetate Z hexane, and the unreacted compound from the eluate of 7% ethyl acetate Z hexane 64a (5.5 mg, 13%) was recovered, and further Compound 40 (70 mg) was recovered from the eluate of 40% ethyl acetate Z-hexane.

[0345] The compound δδΒ: ¹ !! NMR (CDC1) δ; 0.053, 0.054, 0.061 (3Η, 6Η, 3Η,

 Three

 m, 4 χ Si -Me), 0.76 (3H, s, H— 18), 0.86, 0.88 (each 9H, s, 2 x S it-Bu, overlapped with H— 26a, 27a), 1.28 (3H, d , J = 6.5Hz, H— 2 1), 2.80 (1H, m, H— 9), 3.20, 3.37 (each 1H, d, J = 9.8Hz, H— 23), 3.39 (3H, s, OMe), 3.83 (1H, q, J = 6.5Hz, H— 20), 4.06 (2H, m, H— 1, 3), 4.74, 4.77 (each 1H, d, J = 7.0Hz, OCH O), 5.57 (1H, m, H— 16

 2

 ), 5.91 (1H, d, J = ll.2Hz, H-7), 6.16 (1H, d, J = ll.2Hz, H-6).

Mass m / z (%): no M +, 528 (50), 471 (20), 396 (100), 339 (46), 264 (24).

[0346] [Chemical 119]

Camphorsulfonic acid (86.7 mg, 0.373 mmol) was stirred in a methanol (lml) solution of Compound 65a (43. Omg, 0.0622 mmol) at room temperature for 1 hour. 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 (3g), and the compound 20a (2

Obtained 5.5mg, 98%)

 [0348] Compound 20a: NMR (CDC1) δ; 0.78 (3H, s, H—18), 0.86 (6H, t, J =

 Three

 7.5Hz, H-26a, 27a), 1.30 (3H, d, J = 6.5Hz, H-21), 2.77 (2H, m, H -9, 10), 3.11, 3.30 (each 1H, d, J = 9. OHz, H— 23), 3.90 (1H, q, J =

6.5Hz, H-20), 4.06 (1H, m, H−3), 4.12 (1H, m, H−l), 5.58 (1H, m, H-16), 5.95 (1H, d, J = ll .3Hz, H—7), 6.30 (1H, d, J = ll.3Hz, H 6).

 Mass m / z (%): 418 (M +, 5), 400 (3), 300 (100), 282 (42).

[0349] <Synthesis of (20R) 22 oxa 19 norvitamin D derivative (20b)>

 Synthesis was performed according to the following procedure according to the following scheme.

[0350] [Chemical 120]

[0351] A mixture of 25b (686. Omg, 2.21mmol) in anhydrous dimethylformamide (10ml) with sodium hydrogen carbonate (1.77g, 44.2mmol, 60% dispersion in mineral oil) and stirred for 30 minutes did. To this solution was added anhydrous TsOCH CH OTBS (2.92 g, 8.84 mmol).

 twenty two

Methylformamide (4 ml) solution was added and stirred at room temperature for 15 hours. Taentied with ice water and extracted with 50% AcOEtZhexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (35 The compound 56b (632.4 mg, 61%) was obtained from the eluate of 1% ethyl acetate Z hexane, and the unreacted compound 25b (122.4 mg, 61%) was obtained from the eluate of 10% ethyl acetate Z hexane. 18%) was recovered.

[0352] The compound δδΐ): ¹ !! NMR (CDC1) δ: 0.021, 0.024, 0.058, 0.064 (each

 Three

 3H, s, Si— Me), 0.888, 0.892 (each 9H, s, Si— t— Bu), 1.08 (3H, s, H -18), 1.30 (3H, d, J = 6.5 Hz, H— 21 ), 3.43, 3.44 (each 1H, t, J = 5. 9Hz, H-24), 3.72 (2H, t, J = 5.9Hz, H— 23), 3.98 (1H, J = 6.4Hz, H -20 ), 4.09 (1H, m, H-8), 5.60 (1H, m, H-16).

[0353] [Chemical 121]

[0354] To a solution of 56b (742.3 mg, 1.58 mmol) in anhydrous tetrahydrofuran (6 ml) cooled to 0 ° C was added tetrabutylammonium fluoride (2.37 ml, 2.37 mmol, 1.0 M tetrahydrofuran solution), and the mixture was added for 1 hour. Stir. The reaction solution 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 (15 g) to obtain alcohol 57b (451.2 mg, 80%) from the eluate of 25% ethyl acetate / hexane.

 [0355] Compound 57b: 丄! NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, Si-Me), 0.

 Three

 89 (9H, s, Si— t— Bu), 1.08 (3H, s, H— 18), 1.33 (3H, d, J = 6.5Hz, H -21), 3.50, 3.70 (each 2H, m, H — 23, 24), 3.98 (1H, q, J = 6.4Hz, H -20), 4.10 (1H, m, H—8), 5.63 (1H, m, H—16).

[0356] [Chemical 122]

[0357] Oxalyl dichloride (121.2 / zl, 1.39 mmol) anhydrous methylene chloride cooled to 78 ° C

 A solution of dimethyl sulfoxide (197.2 / zl, 2.78 mmol) in anhydrous methylene chloride (0.5 ml) was added to the (1.5 ml) solution and stirred for 10 minutes. Compound 57b (411.2 mg, 1.32 mmol) in anhydrous methylene chloride (4 ml) was added, and after 15 minutes, triethylamine (806.8 1, 5.7 9 mmol) was added slowly—at 78 ° C for 15 minutes. The mixture was stirred at 0 ° C for 30 minutes and 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 (16 g), and aldehyde 58b (360.2 mg, 88%) was obtained from the eluate of 7% ethyl acetate Z hexane.

 [0358] The Compound 58b: Yeah! NMR (CDC1) δ: 0.025, 0.030 (each 3H, s, Si—Me),

 Three

 0.89 (9H, s, Si-t-Bu), 1.09 (3H, s, H—18), 1.37 (3H, d, J = 6.6Hz, H-21), 3.98 (2H, dd, J = 4.5, 0.9Hz, H- 23), 4.09 (1H, m, H-20), 4.10 (1H, m, H-8), 5.67 (1H, m, H-16), 9.73 (1H, t, J = 0.9Hz, —C HO).

[0359] [Chemical 123]

 58b 59b

Ethylmagnesium bromide (2.04 ml, 2.04 mmol) was added to a solution of compound 58b (360.2 mg, 1.02 mmol) cooled to 0 ° C. in anhydrous tetrahydrofuran (2 ml) and stirred for 1 hour. A 2N hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Organic layer in saturated saline After washing with anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (10 g), and the compound 59b (398.2 mg) was quantitatively obtained from the elution part of 5% ethyl acetate / hexane.

[0361] Compound 59b: 丄! NMR (CDC1) δ: 0: 02, 0. 03 (each 3H, s, Si— Me), 0.

 Three

 89 (9H, s, Si-t-Bu), 0. 96 (3H, t, J = 7.5 Hz, H— 27), 1. 07 (3H, s, H— 18), 1. 32 (3H , dd, J = 6. 5, 2. 7Hz, H— 21), 3. 19, 3.44, 3. 66 (each 1 H, m, H-23, 24), 3. 97 (1H, m, H — 20), 4. 09 (1H, m, H— 8), 5. 62 (1 H, m, H— 16).

[0362] [Chemical 124]

[0363] To a solution of oxalyl dichloride (99.2 µ \, 1.14 mmol) in anhydrous methylene chloride (1 ml) cooled to 78 ° C, dimethyl sulfoxide (161.4 ^ 1, 2.27 mmol) in anhydrous methylene chloride (0. 5 ml) was added and the solution was stirred for 10 minutes. A mixture of 59b (362. 6 mg, 0.948 mmol) in anhydrous salt and methylene (3 ml) was prepared, and after 15 minutes, triethylenoamine (660.4 1, 4.74 mmol) was added. After stirring at 78 ° C for 15 minutes and at 0 ° C for 1 hour, 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 (10 g) to obtain Compound 60b (349. Omg, 97%) from the eluate of 2.5% ethyl acetate Z-hexane.

 [0364] Yi Compound 60b: Yeah! NMR (CDC1) δ: 0: 02, 0. 03 (each 3H, s, Si— Me), 0.

 Three

89 (9H, s, Si-t-Bu), 1. 04 (3H, t, J = 7. 3Hz, H— 26), 1. 09 (3H, s, H— 18), 1. 35 (3H , d, J = 6.5 Hz, H—21), 2.52 (1H, q, J = 7.3 Hz, H—26), 3.91, 3.98 (each 1H, d, J = 16. 8Hz, H-23), 4.03 (1H, q, J = 6.4Hz, H 20), 4.09 (1H, m, H-8), 5.63 (1H, m, H

 [0365] [Chemical 125]

 60b 61b

[0366] Compound 60b (347.3 mg, 0.912 mmol) anhydrous tetrahydrofuran cooled to 78 ° C

 Ethyllithium (817.1 μ \, 1.37 mmol, about 1.7 M jetyl ether solution) was added to the (3 ml) solution and stirred for 1 hour. The reaction solution was entented with 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 evaporated. The residue was purified by silica gel column chromatography (12 g) to obtain 6 lb (364. lmg, 97%) of a compound from an eluate of 2% ethyl acetate Z hexane.

 [0367] Compound 61b: 丄! NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, Si-Me), 0.

 Three

 85 (6H, t, J = 7.5Hz, H— 27, 27a), 0.89 (9H, s, Si— t— Bu), 1.08 (3H, s, H-18), 1.30 (3H, d, J = 6.4Hz, H—21), 3.23 (2H, s, H—23), 3.95 (1H, q, J = 6.4Hz, H—20), 4.09 (1H, m, H—8), 5.60 (1H, m, H— 16).

[0368] [Chemical 126]

[0369] Cooled to 0 ° C, dissolved Compound 61b (343. Omg, 0.835mmol) in anhydrous methylene chloride (4ml) Diisopropylethylamine (872.8 ^ 1, 5. Olmmol) and chloromethylmethyl tellurium (190.3 ^ 1, 2.51 mmol) were added to the liquid and stirred at room temperature for 20 hours. To the reaction solution was added 2N hydrochloric acid solution, and the mixture was extracted with methylene chloride. The organic layer was washed with aqueous sodium hydrogen carbonate solution and 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 62b (304.6 mg, 80%) from the eluate of 1% ethyl acetate / hexane.

[0370] Compound 62b: NMR (CDC1) δ: 0.02, 0.03 (each 3H, s, Si—Me), 0.

 Three

 85 (6H, t, J = 7.5Hz, H— 27, 27a), 0.89 (9H, s, Si— t— Bu), 1.08 (3H, s, H-18), 1.28 (3H, d, J = 6.4Hz, H— 21), 3.27, 3.31 (each 1H, d, J = 9.7Hz, H-23), 3.39 (3H, s, — OMe), 3.89 (1H, q, J = 6.4Hz, H— 20), 4.09 (1H, m, H-8), 4.74 (2H, s, — OCH O— 5.60 (1H, m, H— 16)

[0371] [Chemical 127]

[0372] Compound 62b: Tetrabutylammonium fluoride (2.01 ml, 2. Olmmol, 1.0 M in tetrahydrofuran) was added to a solution of (304.6 mg, 0.670 mmol) in anhydrous tetrahydrofuran (2.5 ml). The mixture was stirred at 50 ° C for 30 hours. Tetrabutylammonium fluoride (1.34 ml, 1.34 mmol) was added, and the mixture was stirred at 50 ° C. for 24 hours, followed by extraction with acetyl chloride. The organic layer was washed with saturated Japanese salt water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (10 g) to obtain the compound 63b (221.5 mg, 97%) from the eluate of 20% ethyl acetate Z-hexane.

 [0373] Compound 63b: NMR (CDC1) δ: 0.85 (6Η, t, J = 7.5Hz, H— 27, 27a),

 Three

1.11 (3H, s, H-18), 1.29 (3H, d, J = 6.5Hz, H—21), 3.30 (2H, d, J = l .7Hz, H-23), 3.39 (3H, s, — OMe), 3.90 (1H, q, J = 6.4Hz, H— 20), 4. 18 (1H, m, H-8), 4.74 (2H , s, — OCH O—), 5.62 (1H, m, H— 16).

 2

 [0374] [Chemical 128]

 63b 64b

[0375] Oxalyl dichloride (123.8 ^ 1, 1.42mmol) anhydrous methylene chloride cooled to 78 ° C

 A solution of dimethyl sulfoxide (201.5 ^ 1, 2.84 mmol) in anhydrous methylene chloride (0.5 ml) was added to the (lml) solution and stirred for 10 minutes. A solution of compound 63b (219.7 mg, 0.645 mmol) in anhydrous methylene chloride (3.5 ml) was added, and after 15 minutes, triethylamine (899.3 1, 6.45 mmol) was added. After stirring at 78 ° C for 15 minutes and at 0 ° C for 30 minutes, 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 (6 g) to obtain Compound 64b (216.6 mg, 99%) from the eluate of 30% ethyl acetate Z-hexane.

[0376] Compound eb: ¹ !! NMR (CDC1) δ: 0.86, 0.87 (each 3H, t, J = 7.5Hz,

 Three

 H-27, 27a), 0.87 (3H, s, H— 18), 1.31 (3H, d, J = 6.5Hz, H— 21), 1. 59, 1.61 (each 2H, q, J = 7.4Hz, H- 26, 26a), 3.34 (2H, d, J = l.5Hz, H-23), 3.39 (3H, s, -OMe), 3.96 (1H, q, J = 6.4Hz, H-20), 4.74 (2 H, s, -OCH O—), 5.57 (1H, m, H—16).

 2

[0377] [Chemical 129]

[0378] Compound 40 (61. Omg, 0.107mmol) cooled to 78 ° C in anhydrous tetrahydrofuran (0.3ml) solution with n-butyllithium (67.6 ^ 1, 0.107mmol, 1.58M hexane solution) After stirring for 15 minutes, a solution of compound 64b (8.9 mg, 0.0263 mmol) in anhydrous tetrahydrofuran (0.3 ml) was added and stirred at 78 ° C. for 1 hour. The temperature was raised to −20 ° C. over about 2 hours, and the reaction solution was entented with 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 (5 g) to obtain compound 65b (7.3 mg, 40%) from the eluate of 2% ethyl acetate Z hexane, and the unreacted compound 64b (from the eluate of 30 ethyl acetate Z hexane) The compound 40 (27.3 mg) was recovered from the eluate of 2.9 mg, 33%) and 60% ethyl acetate Z-hexane.

[0379] The compound δδ!): ¹ !! NMR (CDC1) δ: 0.047, 0.050, 0.052, 0.061 (each

 Three

 3H, s, Si— Me), 0.73 (3H, s, H— 18), 0.86, 0.88 (each 9H, s, Si— t— Bu), 0.86 (6H, t, J = 7.4 Hz, H— 27 , 27a), 1.29 (3H, d, J = 6.5Hz, H— 2 1), 1.59, 1.61 (each 2H, q, J = 7.4Hz, H— 26, 26a), 3.31, 3.37 (each

1H, d, J = 9.8Hz, H-23), 3.39 (3H, s, — OMe), 3.92 (1H, q, J = 6.3 Hz, H-20), 4.04 to 4.11 (2H, m, H— 1, 3), 4.75 (2H, s, — OCH O—),

 2

5.60 (1H, m, H-16), 5.91 (1H, d, J = ll.3Hz, H-7), 6.17 (1H, d, J = 11.2Hz, H-6).

[0380] [Chemical 130]

[0381] To a solution of compound 65b (7.3 mg, 0.0106 mmol) in methanol (0.5 ml) was added camphorsulfonic acid (14.7 mg, 0.0634 mmol), and the mixture was stirred at room temperature for 1.5 hours. A sodium hydrogen carbonate aqueous 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 evaporated. The residue was purified by silica gel column chromatography (5 g), and the compound 20b (4.2 mg, 95%) was obtained from the eluate of ethyl acetate.

 [0382] Compound 20b: NMR (CDC1) δ: 0.74 (3H, s, H— 18), 0.86 (6H, t, J = 7

 Three

 .4Hz, H-27, 27a), 1.31 (3H, d, J = 7. OHz, H—21), 3.26 (2H, d, J = 6.9Hz, H-23), 3.97 (1H, q, J = 6.4Hz, H— 20), 4.06, 4.13 (each 1H, m, Hl, 3), 5.63 (1H, m, H— 16), 5.95 (1H, d, J = ll. 3Hz, H— 7 ), 6. 31 (1H, d, J = ll.3Hz, H— 6).

[0383] <Evaluation>

 [Evaluation of transcription activation ability]

 Vitamin D derivatives represented by the structural formulas (11a), (12a), (lib) ゝ (12b), (15a), (15b), (16a), (16b), (17a), (17b) As a comparative example, 1, 25— (OH) D, 2

 twenty three

The following evaluation was performed for MD.

[0384] COS-7 cells derived from monkey kidney were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 5% urine fetal serum. Spread lml in a 24-well plate to contain 2X104 cells per lwell, in a 37 ° C, 5% CO humidified incubator

 2

Left at rest. 24 hours later, a reporter plasmid (0.28 μg / well) containing 3 copies of mouse osteopontin VDRE (5,-GGTTCAcgaGGTT CA, Spp—TK—Luc), Trans-IT was used to transfer an endogenous control plasmid (0.02 μg / well) containing wild-type human VDR expression plasmid [pCMX—hVDR] (0.20 μg / well) and seapansy luciferase expression gene (pCMV—Luc). — Transfected into COS-7 cells by the lipofusion method using LT-1 reagent. After culturing for 4 hours, the culture medium was replaced with fresh DMEM medium containing 5% activated carbon-treated serum. On the next day, 1, 25- (OH) D dissolved in 101, sample or ethanol (control) was added to the cells transfected with the plasmid at 16:00.

 twenty three

 Intercultured. Each cell was treated based on a luciferase assay kit (Toyo Ink Inc.), and luciferase activity was measured by Luminous CT-9000D (Dia-intron). Transcriptional activity was corrected by an internal standard control. The experiment was performed three times for each sample.

[0385] Fig. 1 shows the results of vitamin D derivatives represented by structural formulas (l la) and (12a), and Fig. 2 shows the results of vitamin D derivatives represented by structural formulas (l ib) and (12b). Figure 11 shows the results of the vitamin D derivatives represented by structural formulas (15a) and (15b), Figure 12 shows the results of the vitamin D derivatives represented by structural formulas (16a) and (16b), and structural formulas (17a ), The results of vitamin D derivatives represented by (17b) are shown in FIG.

[0386] 丫 1-6908 (12 &), which has a 2β-hydroxyethoxy group, was 250 times more potent than the natural ligand. In addition, 2I form YI-690B (11a) was more than 10 times stronger. The 20R form was weaker than the 20S form, but the 2α- and 2j8-hydroxyethoxy derivatives showed 5 to 50 times stronger activity than 1,25- (OH) D.

 twenty three

 [0387] In addition, the vitamin D derivative represented by the structural formula (15a) is approximately 7.5 times the natural ligand, and the vitamin D derivative represented by the structural formula (15b) has the same activity as the natural ligand. Indicated. The vitamin D derivatives represented by the structural formulas (16a), (16b), (17a), and (17b) are less active than natural ligands in the 20R form (16b) and (17b). The 20S bodies (16a) and (17a) showed 20 times stronger activity than the natural ligand.

 [0388] [Evaluation for osteoclast differentiation]

Vitamin D derivatives represented by structural formulas (l la), (12a), (l ib), (12b), using 1, 25-(OH) D and 2MD as controls, 10 ^{_ 12} to 10 ^_8 M The activity was compared at each concentration. 1, 25

 twenty three

The results of one (OH) D and 2MD (structural formula (c)) are shown in Fig. 3 and are expressed by structural formulas (l la) and (12a). The results for vitamin D derivatives are shown in Fig. 4, and the results for vitamin D derivatives represented by structural formulas (l ib) and (12b) are shown in Fig. 5. 2MD has about 100 osteoclast differentiation compared to 1,25- (OH) D.

 twenty three

 It was twice as strong in promoting activity. YI-690A (12a) showed stronger osteoclast differentiation promoting activity than 2MD. YI-690B (l la) was as active as 2MD. YI—725A (l lb), 7 25B (12b) also had a strong activity of inducing categorization compared to 1, 25- (OH) D.

 twenty three

 [0389] [Effects on differentiation into mature rod cells]

 The effect on the differentiation of mature rod cells is that LPS (ribopolysaccharide) is not stimulated or stimulated using macrophages derived from mouse bone marrow, in the presence of GM-CSF (granulocyte 'macrophage colony stimulating factor) and vitamin D derivatives. The expression level of CD86 was measured with a fluorescent antibody and measured by FACS (fluorescent antibody method) for evaluation. The result is shown in FIG.

 [0390] YI—690A (12a) is more than 100 times stronger than 1,25— (OH) D

 twenty three

 The other isomers were 10 to 40 times more active.

[0391] [Evaluation of VDR binding activity (VDR affinity)]

 Rat vitamin D receptor ligand binding domain was synthesized in large quantities in LB medium using E. coli protein expression system. Bacteria cells that strongly expressed the protein were collected, and after sonication, the supernatant was obtained by ultracentrifugation (17, OOOrpm, 20min, 6.C). The supernatant containing approximately 0.025 g of radvitamin D receptor ligand binding domain was added to 600 1 50 mM Tris buffer [5 OmM Tris, lOOmM KC1, 5 mM DTT (dithiothreitol), 0.5% CHAPS, BS A (Bovine Serum albumin) 100 μg / mU, pH 7.5] was used as a receptor solution. Place this solution 570 1 in a culture tube and dissolve 1, 25- (OH) D (final concentration: 0. OlnM ~: M) or each sample dissolved in pharmacopeia ethanol (15 1).

 twenty three

After lutex, it was incubated at room temperature. 30 minutes later, [ ³ H] — 1, 25- (OH) D (2,000) dissolved in pharmacopeia ethanol (15 1)

(2 3 to 3, OOOcpm) was added to each tube and vortexed and incubated at 4 ° C in the dark. After 20 hours, 200 1 DCC (dextran-coated Tyacol, purchased from Yamasa Shoyu Co., Ltd.) was added to each tube, and after vortexing, incubated at room temperature for 30 minutes. [ ³ H] — 1, 25- (OH) D and free [ ³ H] — 1, 25— (OH) bound to the receptor by centrifugation (3 OOOrpm, 10 min, 0 ° C)

 2 3 2

After separating D, remove 500 1 from each tube and prepare a liquid scintillator (ACS-II, 9.5 ml) was added and the radioactivity was measured. The experiment was performed twice for each sample.

[0392] The results of vitamin D derivatives represented by structural formulas (15a) and (15b) are shown in Fig. 8, structural formulas (16a), (1

The results for the vitamin D derivative represented by 6b) are shown in FIG. 9, and the results for the vitamin D derivative represented by structural formulas (17a) and (17b) are shown in FIG.

[0393] Regarding the VDR binding activity, structural formulas (15a), (16a) and (17a) which are 20S isomers were comparable to or slightly weaker than natural ligands. Structural formula (15b) in 20R form

As for (16b) and (17b), the activity was less than that of the natural ligand and showed weak activity. .

 [0394] FIG. 7 shows the results of the vitamin D derivatives represented by the structural formulas (11a), (12a), (l ib) and (12b). 1, 25- (OH) The relative value when the activity of D is 1, and a new 2-substituted 19-nor

 twenty three

 A comparison of the biological activity of vitamin D derivatives and 2MD is shown. In all of the actions, 20S-2-hydroxyethoxy YI-690A showed an activity exceeding 2MD, and was the most active among 19-norvitamin D analogs.

 FIG. 14 shows the results of the vitamin D derivative represented by the structural formulas (15a), (15b), (16a), (16b), (17a), and (17b). Figures are relative values when 1, 25- (OH) D activity is 1.

 twenty three

 It shows with. Vitamin D derivatives represented by structural formulas (15a), (16a), and (17a), which are 20S forms, showed VDR affinity equivalent to that of natural ligands and transcription activity equivalent to or better than natural ligands. However, the vitamin D derivatives represented by the structural formulas (15b), (16b), and (17b), which are 20R forms, showed weak VDR affinity and transcriptional activity.

 [0396] The numerical values in Figs. 7 and 14 were calculated by the following method.

 [0397] (VDR affinity calculation method)

 The following formula was used for calculation. In addition, it shows that activity is so strong that a value is large.

 X = y / x

 X: Relative binding of each sample to VDR (VDR affinity)

y: l, 25- (OH) D force [ ³ H] — 1, 25— (OH) Inhibits binding of D and VDR by 50%

 2 3 2 3

 Concentration

X: each sample ^{[3 H] - 1, 25-} (OH) concentration which inhibits ^50% of the binding of D and VDR

 twenty three

[0398] (Phases in transcriptional activity, inhibitory activity of rod-shaped cells and inducible activity of osteoclasts Counteractivity calculation method)

Create a dose response curve (measured at different concentrations) and determine the ED value (concentration that represents 50% of the maximum activity of each sample). 1, 25- (OH) D E

50 2 3

The value is relative to the ED of each sample, with a D value of 1. The higher the value, the stronger the activity

50 50

It shows.

It is.

Claims

The scope of the claims

 A 19-norvitamin D derivative represented by the following general formula (1) or (2), having a substituent at the 2-position, a heteroatom at the 22-position, and a double bond at the 16-17-position of the D ring part .

 [Chemical 1]

(However, R represents a hydroxyalkoxyl group, a hydroxyalkylidene group, X represents a heteroatom, and n represents an integer of 1 to 4.)

The 19 norbitamid according to claim 1, wherein the heteroatom is a sulfur atom or an oxygen atom. D derivative.

 [3] The 19 norvitamin D derivative according to claim 1 or 2, wherein 1 ^ in the general formula (1) or (2) is a hydroxyethoxy group or a hydroxyethylidene group.

[4] The 19 norvitamin D derivative according to any one of claims 1 to 3, represented by the following structural formula (12a):

 [Chemical 3]

[5] Any one of claims 1 to 4, wherein a CD ring synthon and an A ring phosphine oxide are synthesized, and a 19-norvitamin D skeleton is produced by a coupling reaction, followed by structural modification at the 2-position. The manufacturing method of 19 norvitamin D derivative of description.

 [6] Osteoporosis therapeutic agent, anticancer agent, autoimmune disease therapeutic agent, rickets therapeutic agent, or osteomalacia therapeutic agent, comprising 19 norvitamin D derivative according to any one of claims 1 to 4 as an active ingredient

[7] A 19-norvitamin D derivative represented by the following general formula (3) having a heteroatom at the 22-position and a double bond at the 16-17-position of the D ring portion.

[Chemical 4]

(However, X is a heteroatom, and n is an integer from 1 to 4.)

 A 19-norvitamin D derivative represented by the following general formula (4) having a substituent at the 2-position, a heteroatom at the 22-position, and a double bond at the 16-17-position of the D ring portion.

[Chemical 5]

(Where R is a linear or branched alkyl group having 1 to 4 carbon atoms, X is a heteroatom, n

2

Indicates an integer from 1 to 4. )

The 19-nor vitamin D derivative according to claim 7 or 8, wherein the hetero atom is a sulfur atom or an oxygen atom. A therapeutic agent for osteoporosis, an anticancer agent, a therapeutic agent for autoimmune diseases, a therapeutic agent for rickets, or a therapeutic agent for osteomalacia, comprising the 19-nor vitamin D derivative according to claim 7 to 91 as an active ingredient