JP3276490B2 - Vitamin D derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial applications]

The present invention relates to an active vitamin D compound, and more particularly to a compound (V) or a compound (VI) and a method for producing the same, and further relates to a method for producing a compound (XII) using the compound (VI). Things.
The compounds obtained here are various active vitamin D, namely 1α.
-It is important as a raw material compound for producing a hydroxyvitamin D compound.

[0002]

2. Description of the Related Art Active vitamin D compounds such as 1α, 2
And 5-dihydroxyvitamin D _3, l [alpha], 25-in the production of such dihydroxy vitamin D _2, (1) and allowed to bind the corresponding side chain Me ordinal position 17 of the steroid skeleton, steroid skeleton thereby obtaining a release Is disclosed in Japanese Patent Application Laid-Open No. 2-36166, Tetrahedron.
Letters 4147 (1972)).

(2) A method of reacting a 1α-alkylsilyloxyvitamin D ₃ -22-tosylate compound with a hydroxy-substituted alkylphenylsulfone derivative to reductively desulfonate (Japanese Patent Publication No. 2-504154).

(3) A selenium compound is reacted with a vitamin D compound having a desired side chain bonded to position 17 and then oxidized to give 5,6-trans-1.
Methods such as a method of obtaining an α-hydroxy form and its 1β-hydroxy form, further removing the 1β-hydroxy form, and then performing photoisomerization (JP-A-55-2686) are known. In these known methods, there is a problem in the preparation of a raw material used for bonding a required side chain to the 17-position. For example, 1α-alkylsilyloxyvitamin D ₃ used in Japanese Patent Publication No. 2-504154.
22-tosylated product is 3β-acetoxy-22,23
-Bisnor-5-cholenic acid is used as a starting material and is produced through many steps.

Further, a sulfur dioxide adduct is produced using vitamin D ₂ as a starting material, and this is ozonolyzed to give 20-
A method for obtaining a formyl-9,10-secopregnane derivative is known (Japanese Patent Publication No. 2-24268). Here 1
To obtain α- hydroxy body, but were allowed to leave the SO ₂ is carried out an oxidation reaction due to selenium dioxide, SO ₂
In the elimination reaction, a compound having a 5,6-trans structure is produced. Thus, after obtaining a 5,6-trans-1α-hydroxy form, photoisomerization is performed to obtain 1α having a 5,6-cis structure. -It is necessary to convert to a hydroxy form.

[0006]

The present invention is based on the formula (XV)
I)

[Formula 16] The present invention further provides a method for synthesizing a 1α-hydroxyvitamin D derivative using these compounds as raw materials.

[0007]

The compound (XVI) provided by the present invention is synthesized as follows. That is, 6-hydroxycyclovitamin D ₂ (I) derived from vitamin D ₂ is used as a raw material and reacted with 1,3-benzodithiolylium tetrafluoroborate to give 6- (1,3-benzodithiol-2). -Yloxy)-
3,5-Cyclovitamin D ₂ (II) is obtained. Here, the reaction is carried out under cooling to room temperature using a solvent such as dichloromethane, chloroform, trichloroethane, dichloroethane, pyridine, hexane, heptane and the like.

The compound (II) thus obtained is oxidized using selenium dioxide and t-butyl hydroperoxide to give the 1α-hydroxyl compound (III) of the compound.
Get. This compound, heteropoly acid, p- toluenesulfonic acid, using acetic acid or the like, when the normal cyclic ring cleavage according to methods performed, giving a 1α- hydroxyvitamin D _2.

The compound (III) obtained is acylated using pyridine, triethylamine or the like as a solvent, for example, an acid anhydride (eg, acetic anhydride, propionic anhydride, benzoic anhydride, toluic anhydride, etc.), an acid halide ( For example, acetyl chloride, benzoyl chloride, etc.), halocarbonates (eg, methyl chlorocarbonate, ethyl chlorocarbonate, etc.), mixed acid anhydrides (eg, propionic anhydride acetic acid,
Benzoic acid acetic anhydride). Further, the compound (III) is subjected to an acetalizing agent (eg, 3, 4) using a catalyst (eg, hydrogen chloride, pyridine p-toluenesulfonate, H-type ion exchange resin, etc.) using chloroform, toluene, ethyl acetate or the like as a solvent. -Dihydro-2H-pyran, 2,3-dihydrofuran, etc.).

Further, the compound (III) is reacted with a silylating agent (for example, trimethylchlorosilane, t-butyldimethylchlorosilane, hexamethyldisilazane-trimethylchlorosilane, etc.) using pyridine, tetrahydrofuran or the like as a solvent. This makes it possible to protect the 1α-hydroxyl group with the corresponding protecting group so that it is not affected in subsequent reactions.

Compound (XVI) can be obtained by subjecting compound (IV) thus obtained to ozone oxidation, followed by reductive decomposition reaction. In the ozone oxidation of compound (IV), it is expected that the C7-C8 and C10-C19 double bonds in addition to the desired C22-C23 double bond will be oxidized. Compound (XVI) in which the C22-C23 double bond was oxidatively cleaved was obtained.

As the solvent in the ozone oxidation, petroleum hydrocarbons (eg, hexane, heptane, etc.), halogenated hydrocarbons (eg, chloromethane, dichloromethane,
Chloroethane, chloroform, carbon tetrachloride, dichloroethane, etc., fatty acid esters (eg, methyl acetate, butyl acetate, ethyl acetate, etc.), and alcohols (eg, methanol, ethanol, etc.) are used. Ozone oxidation is performed under cooling.

In the reductive decomposition of the produced ozonide, phosphines, phosphites, dimethyl sulfide,
When a reducing compound such as diethyl sulfide is used, a compound in which A is CHO in formula (XVI), that is, a C22-aldehyde compound represented by formula (V) can be obtained. On the other hand, when a reducing compound such as sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride or the like is used, a compound in which A is CH ₂ OH in the formula (XVI), that is, a compound represented by the formula (VI) C22-alcohol compound can be obtained. Further, the C22-aldehyde compound represented by the formula (V)
It is also possible to obtain a C22-alcohol compound represented by the following formula: In this case, the reaction is carried out by reacting the aldehyde compound (V) with the reducing compound as the hydrogenated compound.

The compound represented by the formula (VI) or (V) thus obtained is an important raw material for synthesizing various 1α-hydroxyvitamin D compounds as described below. That is, equation (VI)

The compound of the formula (VII) is reacted with a sulfonating agent such as methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like to give a compound of the formula (VII)

Wherein Y represents an alkyl group, an alkyl-substituted aryl group or an aryl group, or further halogenated to obtain a compound of the formula (VIII)

The compound is converted to a compound represented by the following formula:

(Wherein Z represents an alkyl group, a fluoro-substituted alkyl group, a protected hydroxy-substituted alkyl group or a hydroxy-substituted alkyl group; the same applies hereinafter).

The conversion of the compound of the formula (VI) into the C22-sulfonate compound (VII) is carried out by reacting a sulfonating agent in the presence of an amine such as pyridine, triethylamine and dimethylaniline.

In order to derive the compound of the formula (VI) into a C22-halogenated compound (VIII), an alkali halide such as sodium iodide, potassium iodide, sodium bromide or the like is added to the C22-sulfonate compound (VII).
It is preferable to react with lithium chloride or the like.

The compound of the formula (VIII) or the compound of the formula (VI)
The reaction of the compound of the formula (IX) with the compound of the formula (IX) is carried out, for example, by dissolving the compound of the formula (IX) in tetrahydrofuran, ethyl ether, ethylene glycol dimethyl ether or the like, and optionally hexamethylphosphoric triamide ( HMPA), and under cooling, an n-butyllithium hexane solution is added thereto, and the compound of the formula (VIII) or the compound of the formula (VII) is added thereto.

The resulting formula (X)

The reaction product represented by the following formula is desulfonated using a metal amalgam, for example, sodium, amalgam, aluminum amalgam or the like, to give a compound of the formula (XI)

A compound of the formula ## STR10 ## is obtained, which is cleaved from the cyclo ring and, if necessary, the hydroxy-protecting group is removed.
Formula (XII)

A 1α-hydroxyvitamin D derivative represented by the following formula can be obtained.

Equation (V)

[Formula 5] In order to react the C22-aldehyde compound represented by the formula (IX) with the compound represented by the formula (IX), the reaction may be carried out in the same manner as in the synthesis of the compound (X) described above.

Formula (XIII) obtained

[Formula 13] Is desulfonated in the same manner as described above to give a compound of the formula (XIV)

[Formula 14] Is obtained by cleaving the cyclo ring and, if necessary, removing the hydroxy protecting group, to obtain a compound of the formula (XV)

[Formula 15] Can be obtained.

The summary of the present invention has been described above, and a more specific example will be described below.

Example 1 I → II: (6R) -6- (1,3-benzodithiol-2-yloxy) -3,5-cyclovitamin D ₂ (I
Synthesis of I) (6R) -6-hydroxy-3,5-cyclovitamin D
₂ (I) 12.5 g was dissolved in 280 ml of dichloromethane, 25 g of pyridine was added, and the mixture was cooled to -10 ° C. 1,
3-benzodithiolylium tetrafluoroborate 1
5.4 g was added, and the mixture was further stirred at the same temperature for 9 hours. The reaction solution was returned to room temperature by adding triethylamine (6.5 g), and concentrated to dryness under reduced pressure. The residue was extracted with hexane, and the hexane layer was washed with water and concentrated to obtain 19.2 g of yellow crystals. The crystals were washed with acetone to obtain 10.4 g of the title compound.
mp 126.5-127 ° C. NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{2 (3H, s, 18-} H 3), 0.79 (1H, m, 4
-H), 0.82 and 0.84 (6H, dd, J
_{= 6.5Hz, 26-H 3 and} 27-H 3),
4.59 (1H, d, J = 9.5 Hz, 6-H);
83 (1H, m (sharp), 19-H), 5.09
(1H, m (sharp), 19-H), 5.19 (2
H, m, 22-H and 23-H), 6.55 (1
H, s, SCHS), 7.07 (2H, m, Ar-
_{H 2), 7.30 (2H,} m, Ar-H 2)

Example 2 II → III: (6R) -1α-hydroxy-6
(1,3-benzodithiol-2-yloxy) -3,
Synthesis of 5-cyclovitamin D ₂ (III) 1.15 g of selenium dioxide, 3.75 g of t-butyl hydroperoxide and 120 ml of dichloromethane were added at room temperature for 30 minutes.
Stirred for minutes. 11.5 g of cyclovitamin D ₂ (II)
Was added and the mixture was further stirred at the same temperature for 15 minutes. 11. Quench with aqueous sodium hydroxide solution, wash and concentrate the dichloromethane layer with water and concentrate to yellow crystals.
4 g were obtained. The crystals were washed with hexane to obtain 10.6 g of the title compound. mp 142-143 ° C. NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{3 (3H, s, 18-} H 3), 0.64 (1H, m, 4
-H), 0.82 and 0.84 (6H, dd, J
_{= 6.5Hz, 26-H 3 and} 27-H 3),
4.16 (1H, m, 1-H), 4.66 (1H, d,
J = 9.6 Hz, 6-H), 5.11 (1H, d, J =
2Hz, 19-H), 5.20 (2H, m, 22-H)
and 23-H), 5.27 (1H, d, J = 2H)
z, 19-H), 6.50 (1H, s, SCHS),
_{7.08 (2H, m, Ar-} H 2), 7.31 (2H,
m, _Ar-H 2)

Example 3 III → IV: (6R) -1α-acetoxy-6
(1,3-benzodithiol-2-yloxy) -3,
Synthesis of 5-cyclovitamin D ₂ (IV) 1.78 g of 1α-hydroxy form (III)
The solution was dissolved in 8 ml, 3.42 g of acetic anhydride was added, and the mixture was stirred at room temperature overnight. After adding ice chips and stirring for 1 hour, the mixture was extracted with ether. The ether layer was washed with an aqueous solution of copper sulfate, washed with water and concentrated to obtain 4.03 g of the title compound. NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{3 (3H, s, -18-} H 3), 0.71 (1H, m,
4-H), 0.82 and 0.84 (6H, dd,
_{J = 6.5Hz, 26-H 3} and 27-H 3),
_{2.07 (3H, s, -OCOCH 3} ), 4.65 (1
H, d, J = 9.6 Hz, 6-H), 4.93 (1H,
d, J = 2 Hz, 19-H), 5.20 (2H, m, 2)
2-Hand 23-H), 5.28 (1H, d, J =
2Hz, 19-H), 6.51 (1H, s, SCH)
_{S), 7.08 (2H, m} , Ar-H 2), 7.31
_{(2H, m, Ar-H} 2)

Example 4 IV → VI: (7E)-(1S, 3S, 5R, 6R)-
1-acetoxy-6- (1,3-benzodithiol-2
-Yloxy) -3,5-cyclo-9,10-seco-2
3,24-dinor-7,10 (19) -colladien-2
Synthesis of 2-ol (VI) (i) 1.00 g of the 1α-acetoxy compound (IV) was dissolved in 30 ml of dichloromethane, 0.25 g of pyridine was added, the mixture was cooled to -70 ° C, and ozone was blown therein. After completion of the reaction, nitrogen was purged, and 3.5 ml of an ethanol solution of 70 mg of sodium borohydride was added. The reaction solution was returned to room temperature, poured into cold diluted hydrochloric acid, and the dichloromethane layer was washed with an aqueous sodium hydrogen carbonate solution, washed with water and concentrated to obtain 1.05 g of a crude product. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 2) to give the title compound 0.1.
52 g were obtained. mp 159-160 ° C. NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{4 (3H, s, 18-} H 3), 0.71 (1H, m, 4
-H), 0.97 (1H, m, 4-H), 1.06 (3
_{H, d, J = 6.6Hz,} 21-H 3), 2.07 (3
_{H, s, -OCOCH 3),} 3.40 (1H, m, 22
-H), 3.65 (1H, m, 22-H), 4.66.
(1H, d, J = 9.6 Hz, 6-H), 4.94 (1
H, d, J = 2 Hz, 19-H), 5.09 (1H,
d, J = 9.6 Hz, 7-H), 5.17 (1H, m,
1-H), 5.27 (1H, d, J = 2 Hz, 19-
H), 6.51 (1H, s, SCHS), 7.08 (2
_{H, m, Ar-H 2} ), 7.31 (2H, m, Ar-H
₂ )

(Ii) 1α-acetoxy compound (IV)
24 g were reacted in the same manner as in (i). After completion of the reaction, nitrogen was purged and 1 ml of dimethyl sulfide was added. The reaction solution was returned to room temperature, washed with water, washed with cold diluted hydrochloric acid, washed with an aqueous solution of sodium hydrogen carbonate, washed with water, and concentrated to obtain 0.26 g of a crude product.
I got Purification by silica gel column chromatography (hexane: ethyl acetate = 5: 1), (7E)-(1
S, 3S, 5R, 6R) -1-acetoxy-6- (1,
3-benzodithiol-2-yloxy) -3,5-cyclo-9,10-seco-23,24-dinor-7,10
(19) -colladien-22-al (V) 0.13 g
I got NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{6 (3H, s, 18-} H 3), 0.72 (1H, m, 4
-H), 0.97 (1H, m, 4-H), 1.14 (3
_{H, d, J = 6.9Hz,} 21-H 3), 2.07 (3
_{H, s, OCOCH 3),} 4.64 (1H, d, J =
9.5 Hz, 6-H), 4.94 (1H, d, J = 2H)
z, 19-H), 5.13 (1H, d, J = 9.5H)
z, 7-H), 5.17 (1H, m, 1-H), 5.2
7 (1H, d, J = 2 Hz, 19-H), 6.52 (1
H, s, SCHS), 7.08 (2H, m, Ar-
_{H 2), 7.31 (2H,} m, Ar-H 2), 9.59
(1H, d, J = 3.1 Hz, CHO) The obtained aldehyde compound (V) was dissolved in a mixed solvent of dichloromethane and ethanol, and sodium borohydride was added at room temperature and stirred. After completion of the reaction, the reaction was quenched with cold dilute hydrochloric acid, and the dichloromethane layer was washed with an aqueous sodium hydrogen carbonate solution, washed with water, and concentrated to obtain the title compound.

Example 5 VI → VII: (7E)-(1S, 3S, 5R, 6R)
-1-acetoxy-6- (1,3-benzodithiol-
2-yloxy) -3,5-cyclo-9,10-seco-
23,24-dinor-7,10 (19) -colladiene-
Synthesis of 22-yl tosylate (VII)
Then, 0.45 g of tosyl chloride was added at 5 ° C, and the mixture was stirred at 0 to 5 ° C overnight. 2 g of ice chips were added, and the flask was kept at room temperature and stirred for 1 hour. After ether extraction, the ether layer was washed with an aqueous solution of copper sulfate, washed with water, and concentrated to 0.33
g of the title compound were obtained. NMR spectrum (CDCl ₃ ) δ (ppm): 0.4
_{8 (3H, s, 18-} H 3), 0.70 (1H, m, 4
-H), 0.95 (1H, m, 4-H), 1.00 (3
_{H, d, J = 6.6Hz,} 21-H 3), 2.06 (3
_{H, s, -OCOCH 3),} 2.45 (3H, s, -C
_{H 3 (tosyl)), 3.81} (1H, m, 22-
H), 3.98 (1H, m, 22-H), 4.63 (1
H, d, J = 9.5 Hz, 6-H), 4.93 (1H,
d, J = 2 Hz, 19-H), 5.08 (1H, d, J
= 9.5 Hz, 7-H), 5.16 (1H, m, 1-
H), 5.25 (1H, d, J = 2 Hz, 19-H),
6.50 (1H, s, SCHS), 7.08 (2H,
_{m, Ar-H 2),} 7.30 (2H, m, Ar-
_{H 2), 7.35 (2H,} m, Ar-H 2 (tosy
l)), 7.79 (2H, m, Ar-H 2 (tosy
l))

Example 6 VII → VIII: (7E)-(1S, 3S, 5R, 6
R) -1-acetoxy-6- (1,3-benzodithiol-2-yloxy) -3,5-cyclo-9,10-seco-22-iodo-23,24-dinor-7,10 (1
9) Synthesis of -colladiene (VIII) 0.30 g of 22-tosylate (VII) was mixed with 9 m of acetone.
and 0.32 g of sodium iodide was added, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated, and the residue was extracted with ether. The ether layer was washed with water, washed with an aqueous solution of sodium thiosulfate, washed with water, and concentrated to obtain 0.28 g of the title compound. NMR spectrum (CDCl ₃ ) δ (ppm): 0.
_{56 (3H, s, 18-} H 3), 0.71 (1H, m,
4-H), 0.97 (1H, m, 4-H) 1.04 (3
_{H, d, J = 6.3Hz,} 21-H 3), 2.07 (3
_{H, s, -OCOCH 3) 3.18} (1H, m, 22-
H), 3.33 (1H, m, 22-H), 4.64 (1
H, d, J = 9.5 Hz, 6-H), 4.94 (1H,
d, J = 2 Hz, 19-H), 5.10 (1H, d, J)
−9.5 Hz, 7-H), 5.17 (1H, m, 1−
H), 5.27 (1H, d, J = 2 Hz, 19-H),
6.51 (1H, s, SCHS), 7.08 (2H,
_{m, Ar-H 2),} 7.31 (2H, m, Ar-H 2)

Example 7 VIII + IX → X: (6R) -1α-hydroxy-6
-(1,3-benzodithiol-2-yloxy) -2
3-phenylsulfonyl-25-tetrahydropyranyloxy synthesis of oxy-3,5-cyclo vitamin _D 3 (X) 2- methyl-2-tetrahydropyranyloxy-4-phenyl sulfonyl butane (IX) 0.24g, HMPA
0.14 ml was dissolved in 4 ml of dry tetrahydrofuran, and 0.48 ml of a 15% n-butyllithium hexane solution was added at -50 ° C under a nitrogen atmosphere. After stirring at −20 ° C. for 20 minutes, 0.10 g of 22-iodine compound (VIII)
Was added, and the mixture was stirred at the same temperature for 1 hour, and further stirred at room temperature for 1 hour. 2 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 2) to obtain 90 mg of the title compound. NMR spectrum (CDCl ₃ ) δ (ppm): 0.4
6, 0.47, 0.48 and 0.50 (12H,
_{each s, 18-H 3)} , 6.48 (4H, s, S
CHS), 7.07 (8H, m , Ar-H 2), 7.3
_{1 (8H, m, Ar-} H 2), 7.55 (8H, m, A
_{r-H 2 (phenylsulfonyl))} , 7.6
2 (4H, m, Ar-H (phenylsulfony)
_{l)), 7.89 (8H,} m, Ar-H 2 (pheny
lsulfonyl))

Example 8 X → XI: (6R) -1α-hydroxy-6- (1,
3-benzodithiol-2-yloxy) -25-tetrahydropyranyloxy-3,5-cyclovitamin D ₃
Synthesis of (XI) 90 mg of the 23-phenylsulfonyl compound (X) was dissolved in 9 ml of methanol, and disodium hydrogen phosphate 0.19 was added.
g, 5% sodium amalgam 2.7 g,
For 30 minutes. The reaction solution was filtered and concentrated, and the residue was extracted with ether. The ether layer was washed with water and concentrated, and the residue was purified by preparative thin-layer chromatography (hexane: ethyl acetate = 9: 5) to obtain 52 mg of the title compound. NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{4 (3H, s, 18-} H 3), 0.64 (1H, m, 4
-H), 1.19 and 1.21 (6H, each
_{s, 26-H 3 and 27} -H 3), 3.44
and 3.95 (2H, each m, CH ₂ (TH
P)), 4.16 (1H, m, 1-H), 4.67 (1
H, d, J = 9.6 Hz, 6-H), 4.72 (1H,
m, CH (THP)), 5.06 (1H, d, J = 9.
6 Hz, 7-H), 5.11 (1 H, d, J = 2 Hz,
19-H), 5.27 (1H, d, J = 2 Hz, 19-
H), 6.50 (1H, s, SCHS), 7.08 (2
_{H, m, Ar-H 2} ), 7.31 (2H, m, Ar-H
₂ )

Example 9 XI → XII: 1α, 25-dihydroxyvitamin D ₃
Synthesis of (XII) 52 mg of cyclovitamin derivative (XI) was dissolved in 1.6 ml of 5% aqueous dioxane, heated to 30 ° C., added with 5 mg of phosphomolybdic acid, and stirred at the same temperature for 3 hours. The reaction solution was cooled, poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ether. The ether layer is washed with water and concentrated, and the residue is subjected to preparative thin-layer chromatography (chloroform: methanol =
10: 1) to give 11 mg of the title compound. NMR spectrum (CDCl ₃ ) δ (ppm): 0.5
_{5 (3H, s, 18-} H 3), 0.94 (3H, d, J
_{= 6.4Hz, 21-H 3)} , 1.21 (6H, s, 2
_{6-H 3 and 27-H} 3), 4.22 (1H,
m, 3-H) 4.43 (1H, m, 1-H), 5.00.
(1H, m (sharp), 19-H), 5.33 (1
H, m (sharp), 19-H), 6.02 (1H,
d, J = 11.2 Hz, 7-H), 6.38 (1H,
d, J = 11.2 Hz, 6-H)

[0032]

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──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Takashi Kono 5-41 Senmon, Itami-shi, Hyogo Prefecture, Itami Plant, Imperial Chemical Industry Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 339/06 C07C 401/00 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the formula (XVI) A compound represented by the formula: 2. The compound according to claim 1, wherein A is --CHO. 3. The compound according to claim 1, wherein A is --CH ₂ OH. 4. A compound of the formula (IV) Is oxidized with ozone and reacted with a reducing agent to give a compound of formula (VI) Is obtained, and the obtained compound (VI) is sulfonated to give a compound of the formula (VII). (Wherein Y represents an alkyl group, an alkyl-substituted aryl group or an aryl group), and the obtained compound (VII) is halogenated to obtain a compound of the formula (VIII). And the resulting compound (VIII) was converted to a compound of the formula (IX). (Wherein, Z represents an alkyl group, a fluoro-substituted alkyl group, a protected hydroxy-substituted alkyl group or a hydroxy-substituted alkyl group), and reacted with a phenylsulfone derivative represented by the formula (X): The compound (X) is subjected to reductive desulfonation to give a compound of the formula (XI) And the resulting compound (XI) is subjected to solvolysis and, in some cases, removal of a protecting group for a hydroxyl group, to obtain a compound of the formula (XII) A method for producing a vitamin D compound represented by the formula: