JPH05339230A - Activated type vitamin d2 and the production of its derivative - Google Patents

Abstract

PURPOSE:To enable high-yield production of activated-type vitamin D2 or its derivatives having good differentiation-inducing action and bone mass-improving action through simple process steps. CONSTITUTION:An adduct of ergosterol of formula I (X is protecting group for the OH in the 3-position; Ph is phenyl) to 4-phenyl-1,2,4-triazoline-3,5-dione is oxidized with ozone to give an aldehyde, which is subjected to condensation reaction with a sulfone derivative of formula II to give a compound of formula III. The sulfonyl group of the compound is eliminated reductively, then the hydroxyl-protecting groups in the 3 and 25 position to give a compound of formula IV. Then, the 5,7-diene-protecting group is removed from the product, then the resultant compound is subjected to light irradiation and thermal isomerization to give vitamin D2 and its derivatives. The product is tosylated, treated with an alkali in methanol to effect selective hydroxylation of 1alpha-position to give a compound of formula VI. The product is treated with acetic acid to form a 3-acetate compound which is hydrolyzed to eliminate 3beta-acetyl group to give an activated type vitamin D2 of formula VII and its derivative.

Description

Detailed Description of the Invention

[0001]

The present invention relates to (24R) -1α, 25-dihydroxyvitamin D ₂ (I) and (24S) -1α, 25-dihydroxyvitamin D ₂ having excellent differentiation-inducing action and bone mass-improving action. It relates to a method for producing (II) and (24S) -1α-hydroxyvitamin D ₂ (III).

[0002]

2. Description of the Related Art 1 is a natural vitamin D-inducing hormone
α, 25-dihydroxyvitamin D ₃ and its synthetic analog 1α-hydroxyvitamin D ₃ are known to be effective promoters of intestinal absorption of calcium, bone calcification, etc.
It is used as a therapeutic drug for osteoporosis. However, excessive intake of these compounds may cause side effects such as hypercalcemia due to their strong physiological activity. Currently, elucidation of an active vitamin D derivative that has a bone mass improving effect comparable to or higher than that of active vitamin D ₃ but lower side effects and toxicity and development of a synthetic method thereof are being actively conducted.

So far, active vitamin D ₂ has a so-called vitamin D activity comparable to that of active vitamin D ₃ , but its toxicity is reported to be 1/5 to 1/10 of that.
(DeLuca, Proc. Soc. Exp. Biol. Med., 178 , 432
(1985)).

DeLuc is a method for producing active vitamin D _2.
Method by a et al. (Bioorganic Chemistry, 13 , 158)
(1985); Tokushusho Sho-5015011, JP-A-3-
504508, etc., the method by Baggiolini et al. (J. Org. Chem., 51 , 3098 (1986))
It has been known. However, either method produces many isomers, making it difficult to separate the desired product,
It has the disadvantages of low yield and long reaction steps.

The present inventors have previously conducted 1α-hydroxyvitamin D ₂ , 1α, 25- by the method shown in the following scheme I.
Although a method for synthesizing dihydroxyvitamin D ₂ and its 24-epimer has been clarified, this method requires a long process and is not industrially satisfactory (Y. Ta.
chibana, Bull. Chem. Soc. Jpn., 61 , 3915 (1
988) and 62 , 3132 (1989)).

[0006]

[Chemical 27]

[0007]

DISCLOSURE OF THE INVENTION The present invention was devised to solve the above-mentioned drawbacks of the prior art,
It is an object of the present invention to provide a simpler method with a smaller number of steps.

[0008]

[Means for Solving the Problems] In order to achieve the above object, the inventors of the present invention have conducted extensive studies, and as a result, have used ergosterol as a starting material and undergoing a synthetic process (24R)- A method for producing 1α, 25-dihydroxyvitamin D ₂ (I), (24S) -1α, 25-dihydroxyvitamin D ₂ (II) and (24S) -1α-hydroxyvitamin D ₂ (III) was newly developed. The present invention has been completed.

That is, according to the present invention, the formula (IV)

[Chemical 28] (Wherein X represents a protective group for the hydroxyl group at the 3-position and Ph represents a phenyl group), and the 5,7-diene moiety of (22E) -5,7,22-ergostattrien-3β-ol 4-
The compound protected with phenyl-1,2,4-triazoline-3,5-dione (hereinafter abbreviated as "PTAD") is ozone-oxidized to obtain the compound of formula (V)

[Chemical 29] A compound of the aldehyde at the 22-position is represented by the formula (VI), (VII) or (VIII)

[Chemical 30] Sulfone derivative represented by [Y. Tachibana, Bull. Che
m. Soc. Jpn., 62 , 3132 (1989)] to give a compound of formula (IX), (X) or (XI)

[Chemical 31] The sulfonyl group at the 23-position of this compound is reductively eliminated with Na-Hg or the like to give a compound of formula (XI
I), (XIII) or (XIV)

[0010]

[Chemical 32] A compound represented by the formula (XV), (XVI) or (XVII) by removing the protecting groups for the hydroxyl groups at the 3- and 25-positions of the compound under acidic conditions using, for example, p-toluenesulfonic acid.

[Chemical 33] And the diene protecting group of this compound is L
The compound of formula (XVIII), (XIX) or (XX) can be desorbed by using iAlH ₄ or Me ₂ SO—K ₂ CO _3.

[Chemical 34] 5,7-diene compound represented by formula (XX)
I), (XXII) or (XXIII)

[Chemical 35] A vitamin D ₂ derivative represented by formula (XXI) is prepared by tosylating this compound and treating with methanol in the presence of heavy sodium chloride.
V), (XXV) or (XXVI)

[0011]

[Chemical 36] In the cyclovitamin _{D 2} compound represented, the 1α-position of the cyclo vitamin _{D 2} compound SeO ₂ -t-BuOO
It is selectively hydroxylated with H to give formulas (XXVII), (XXVI
II) or (XXIX)

[Chemical 37] And a compound represented by the formula
(XXX), (XXXI) or (XXXII)

[Chemical 38] And a compound of formula (I), (II) or (III)

[Chemical Formula 39] (24R) -1α, 25-dihydroxyvitamin D ₂ (I), (24S) -1α, 25-of the desired product represented by
Dihydroxyvitamin D ₂ (II) or (24S) -1α
-Hydroxyvitamin D ₂ (III) can be produced.

Of the above compounds, the compounds of formulas (IV), (V) and (I
X), (X), (XI), (XII), (XIII) and (XIV), the protecting group for the hydroxyl group at the 3-position is t-butyldimethyl which is commonly used in the technical field of the present invention. A silyl group is preferably used, but other silyl groups such as a triethylsilyl group, an isopropyldimethylsilyl group and a triphenylsilyl group can also be used, and further protected as an ester derivative by an acyl group such as an acetyl group or a benzoyl group. can do.

As an alternative to the above-mentioned production method of the present invention,
For the compounds (XXIV) and (XXV), that is, the compounds in which the 25-position is substituted with a hydroxyl group, the hydroxyl group is protected and the subsequent steps are carried out, and the hydroxyl-protecting group is eliminated at the final stage of the reaction step. It is also possible to do so.

That is, with respect to the cyclovitamin D ₂ compounds of formulas (XXIV) and (XXV) obtained by the above reaction step, the hydroxyl group at the 25th position is protected to formula (XXXIII) or (XXXI).
V)

[Chemical 40] (Wherein, R ₄ represents a protecting group of hydroxyl group) and cycloalkyl vitamin D ₂ compound represented by the 1α-position of the cyclo vitamin D ₂ compounds selectively hydroxylated formula (XXXV) or
(XXXVI)

[Chemical 41] And a compound represented by the formula
(XXXVII) or (XXXVIII)

[Chemical 42] (In the formula, Ac represents an acetyl group), a 3-acetate compound represented by the formula (XXX) or (XXXI)

[Chemical 43] (In the formula, Ac represents an acetyl group), a 3β-acetyl compound represented by the following formula is obtained, and the compound is alkali-hydrolyzed to obtain the desired product of the formula (I) or (II)
R) -1α, 25-dihydroxyvitamin D ₂ (I) and (24S) -1α, 25-dihydroxyvitamin D ₂ (II)
The method of obtaining is also included in the present invention.

In the above-mentioned alternative method of the production method of the present invention, the protective group for the 25-hydroxyl group of the compound represented by the formula (XXIV) or (XXV) can be stably and easily removed in the subsequent reaction step. A protecting group such as a triethylsilyl group is preferred. Of course, as described above, the compound (XXIV) or (X
XV) can be converted to the target compound (I) or (II) without protecting the hydroxyl group at the 25-position. However, by protecting the hydroxyl group at the 25-position, the compound (XXXIII) or (XXXIV) is treated with acetic acid in a later step to open the bicyclo ring, and the 1β- and trans isomers of the by-product produced. 1α-form (compound (XXXVII)
Alternatively, the operation of separating (XXXVIII)) by column chromatography becomes very easy. Such a step of protecting the hydroxyl group at the 25-position is also useful in the synthesis of other active vitamin D, such as 1α, 25-dihydroxyvitamin D ₃ .

The triethylsilyl group introduced at the 25-position can be easily removed by a conventional method using, for example, tetrabutylammonium fluoride.

From the PTAD adduct of ergosterol (IV) in the above-mentioned production method of the present invention, (24R) -1α,
25-dihydroxyvitamin D ₂ (I), (24S) -1
α, 25-dihydroxyvitamin D ₂ (II) and (24S)
A synthetic route to obtain -1α-hydroxyvitamin D ₂ (III) is exemplarily shown in Scheme II below. In this scheme II, the hydroxyl groups at the 3-position of compounds (IV), (V), (IX) to (XIV) are protected by t-butyldimethylsilyl group.

Further, the hydroxyl group at the 25-position of the compounds (XXIV) and (XXV) is protected to carry out the reaction to give (24R) -1α, 25
-Dihydroxyvitamin D ₂ (I) and (24S) -1α,
A synthetic route to obtain 25-hydroxyvitamin D ₂ (II) is exemplarily shown in Scheme III below.

[0019]

[Chemical 44]

[0020]

[Chemical 45]

[0021]

[Chemical 46]

[0022]

[Chemical 47]

[0023]

[Chemical 48]

[0024]

As described above, according to the present invention, (24R)-and (24S) -1 are more efficient than the conventional method.
α, 25-dihydroxyvitamin D ₂ (I, II) and (2
A method for producing 4S) -1α-hydroxyvitamin D ₂ (III) is provided.

That is, according to the present invention, active vitamin D ₂ and its derivatives having excellent differentiation-inducing action and bone mass-improving action can be easily produced with relatively few steps.

[0026]

EXAMPLES The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention.

Example 1 3β-t-butyldimethylsilyloxy-5α, 8α-
Synthesis of (4-phenyl-1,2-urazolo) -23,24-dinor-6-cholen-22-ar (V) i) Starting compound 5α, 8α- (4-phenyl-1,2-urazolo)- Synthesis of 6-ergosten-3β-ol 3-t-butyldimethylsilyl ether (IV): 50 g of ergosterol was dissolved in 500 ml of methylene chloride, and 4-phenyl-1,2,4-triazoline-3,5-dione 21
The reaction solution containing g was concentrated and the residue was crystallized from acetone to give 5α, 8α- (4-phenyl-1,2-urazolo)-.
45 g of 6-ergosten-3β-ol was obtained. This was dissolved in 200 ml of DMF, 24 g of imidazole and 24 g of t-butyldimethylsilyl chloride were added, and the mixture was heated and stirred at 50 ° C. for 1 hour. The reaction solution was extracted with chloroform, washed with water, and crystallized from ethanol to obtain 51 g of (IV) (X = t-butyldimethylsilyl).

Melting point 190 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.06 (3H, s), 0.11 (3H, s), 0.88 (9
H, s), 0.96 (3H, s), 1.02 (3H, d, J = 6.8Hz), 4.40 (1H,
m), 5.20 (2H, m), 6.07, 6.20 (2H, ABq, J = 8.0Hz), 7.
30 to 7.45 (5H, m).

Ii) Synthesis of Compound (V): Compound (IV)
100 g of (X = t-butyldimethylsilyl) was dissolved in 1 liter of methylene chloride containing 1% pyridine. -65
After cooling to .about.-70.degree. C. and ozone bubbling at 1.5 g / h for 5 hours, 40 ml of dimethyl sulfide was added and the temperature was gradually returned to room temperature and left overnight. The reaction solution was washed with a dilute aqueous solution of NaHCO ₃ hydrochloric acid, dried and the solvent was distilled off. The residue was purified by silica gel chromatography, and 50 g of recovered raw material and (V) (X = t-butyldimethylsilyl) 3
And 8.1 g were obtained.

Melting point 202-203 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.08 (3H, s), 0.10 (3H, s), 0.82 (3
H, s), 0.88 (9H, s), 0.96 (3H, s), 1.14 (3H, d, J = 6.8
Hz), 4.41 (1H, m), 6.22, 6.36 (2H, ABq, J = 8.3Hz), 7.
26 to 7.51 (5H, m, Ph), 9.55 (1H, d, J = 3.4Hz).

Example 2 (24R) -5,7,22-ergostatriene-3β,
Synthesis of 25-diol (XVIII) (S) -2,3-dimethyl-4-phenylsulfonyl-2
-Butanol tetrahydropyranyl ether (VI) 20.
Dissolve 0 g in 100 ml of tetrahydrofuran, and
Cooled to -70 ° C. 40.0 ml of a 1.6 M n-BuLi hexane solution was added dropwise at the same temperature, and the mixture was stirred for 30 minutes. 1,
After adding 10 ml of 3-dimethyl-2-imidazolidinone, 25.0 g of (V) (X = t-butyldimethylsilyl)
100 ml of a tetrahydrofuran solution of was added dropwise and reacted for 1 hour. A saturated NH ₄ Cl aqueous solution was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with brine, and the solvent was evaporated. (IX)
41.5 g of (X = t-butyldimethylsilyl) was obtained.
(IX) 41.5 g was dissolved in 400 ml of methanol and Na ₂ was added.
HPO ₄ 10.0 g, and 5% Na-Hg 100g was added, and stirred at room temperature overnight. After removing mercury, the methanol solution was concentrated and extracted with ethyl acetate. After washing with brine, the solvent was distilled off. The residue was purified by silica gel chromatography, and (XII) (X = t-butyldimethylsilyl) was added to 31.7.
g was obtained.

(XII) (31.7 g) was dissolved in methanol (300 ml), p-toluenesulfonic acid (0.4 g) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with brine and then concentrated. The residue was purified by silica gel chromatography to obtain 20.1 g of (XV).

(XV) 20.1 g of tetrahydrofuran 5
It was dissolved in 00 ml, LiAlH _{4 (} 4.0 g) was added, and the mixture was heated under reflux for 4 hours. Add a small amount of water to decompose excess LiAlH ₄ ,
The insoluble material was filtered and extracted with chloroform. After washing with brine, the solvent was distilled off. The residue was purified by silica gel chromatography, and the distillate was crystallized using ethanol to obtain (XVIII) (10.4 g).

Melting point 192-193 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H, s), 0.95 (3H, s), 1.00 (3
H, d, J = 7.0Hz), 1.06 (3H, d, J = 6.6Hz), 1.13, 1.17
(Each 3H, s), 3.67 (1H, s), 5.21 (2H, m), 5.39, 5.69 (each
1H, m).

Alternatively, the following structural formula:

[Chemical 49] A compound of formula (IV) represented by formula (IV), that is, a compound of formula (IV) (X = acetyl) in which the hydroxyl group at the 3-position is protected with an acetyl group is treated in the same manner as in the reaction procedure of Example 1 ii) to give 3β- Acetoxy-5α, 8α- (4-phenyl-1,2-urazolo) -23,24-dinor-6-cholen-22-al, ie the following structural formula:

[Chemical 50] The compound of the formula (V) (X = acetyl) represented by the formula (10) and compound (VI) (7.0 g) were treated in the same manner as in the latter step of this example to obtain the compound (XVIII) (2.1 g). It was

Example 3 (24S) -5,7,22-ergostatriene-3β,
25-diol (XIX) compound (V) (X = t-butyldimethylsilyl) 25.0
g and 20.0 g of the sulfone derivative (VII) are treated in the same manner as in Example 2 to give the compound (X) (X = t-butyldimethylsilyl), which is followed by reductive removal of the sulfonyl group from this compound. Removal of the protective groups for the hydroxyl groups at the 3rd and 25th positions was carried out in the same manner as in Example 2 to obtain 9.7 g of compound (XIX).

Melting point 197-198 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.66 (3H, s), 0.92 (3H, s), 0.98 (3
H, d, J = 7.1Hz), 1.04 (3H, d, J = 6.9Hz), 1.14, 1.17
(Each 3H, s), 3.68 (1H, m), 5.20 (2H, m), 5.40, 5.65 (each
1H, m).

Alternatively, the expression obtained by the alternative method of the second embodiment
Compound (V) (X = acetyl) (8.0 g) and compound (VII)
6.5 g was treated in the same manner as in the latter step of Example 2 to obtain 1.7 g of compound (XIX).

Example 4 (24S) -5,7,22-ergostatriene-3β-
All (XX) Compound (V) (X = t-butyldimethylsilyl) 20.0
g and 15.0 g of the sulfone derivative (VIII) were treated in the same manner as in Example 2 to give the compound (XI) (X = t-butyldimethylsilyl), and the reductive removal of the sulfonyl group from this compound and subsequent 3 The protective groups for the hydroxyl groups at positions 25 and 25 were removed in the same manner as in Example 2 to obtain 4.2 g of compound (XX).

Melting point 150-152 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.62 (3H, s), 0.82 (3H, d, J = 6.8H
z), 0.84 (3H, d, J = 6.8Hz), 0.91 (3H, d, J = 6.9Hz), 0.
95 (3H, s), 1.03 (3H, d, J = 6.3Hz), 3.67 (1H, m), 5.21
(2H, m), 5.41, 5.66 (1H, m each).

Example 5 2 g of (24R) -25-hydroxyvitamin D ₂ (XXI) 5,7-diene (XVIII) was dissolved in 500 ml of THF, and a high pressure mercury lamp (450 W) was used using 1.5% potassium nitrate as a filter. It was irradiated with light for 1 hour. A total of 5 g of (XVIII) was treated in the same manner. The reaction solution was concentrated, ethanol was added, and (XVIII) was recovered. The mother liquor was heated to reflux for 1 hour (under nitrogen stream). Ethanol was distilled off, and the residue was purified by silica gel to obtain (XXI) 3.2 g.

¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 0.97 (3H,
d, J = 6.6Hz), 1.04 (3H, d, J = 6.6Hz), 1.13, 1.17 (3 each)
H, s), 3.95 (1H, m), 4.82 (1H, s), 5.05 (1H, s), 5.29
(2H, m), 6.03, 6.23 (2H, ABq, J = 11.2Hz).

Example 6 5.0 g of (24S) -25-hydroxyvitamin D ₂ (XXII) compound (XIX) was treated in the same manner as in Example 5 (XX
II) 3.1 g was obtained.

¹ H NMR (CDCl ₃ ) δ: 0.54 (3H, s), 0.88 (3H,
d, J = 6.5Hz), 0.93 (3H, d, J = 6.5Hz), 1.15, 1.17 (3 each
H, s), 3.96 (1H, m), 4.82 (1H, s), 5.05 (1H, s), 5.28
(2H, m), 6.04, 6.23 (2H, ABq, J = 11.2Hz).

Example 7 (24S) -Vitamin D ₂ (XXIII) 4.0 g of the compound (XX) was treated in the same manner as in Example 5 (XXI
II) 2.2 g was obtained.

¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s), 0.83 (3H,
d, J = 6.8Hz), 0.86 (3H, d, J = 6.8Hz), 0.91 (3H, d, J =
6.9Hz), 1.03 (3H, d, J = 6.3Hz), 3.97 (1H, m), 4.81 (1
H, s), 5.04 (1H, s), 5.29 (2H, m), 6.02, 6.22 (2H, A
Bq, J = 11.2Hz).

Example 8 (24R) -1α, 25-dihydroxy-3,5-cyclovitamin D ₂ (XXVII) (24R) -25-hydroxyvitamin D ₂ (XXI) 3.0
g was dissolved in 30 ml of pyridine, 6.5 g of p-toluenesulfonyl chloride was added, and the mixture was stirred for 18 hours. The crude tosyl compound (3.1 g) was obtained by the conventional method. Methanol 1
3.1 g of this crude tosyl compound was dissolved in 00 ml, and NaHCO ₃ was added.
10 g was added and the mixture was heated under reflux for 3 hours. Water was added and the mixture was extracted with ethyl acetate. After washing with brine, the solvent was evaporated and the residue was purified by silica gel chromatography (XXIV) 2.
5 g was obtained.

¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s), 1.00 (3H,
d, J = 6.8Hz), 1.05 (3H, d, J = 6.6Hz), 1.13, 1.17 (3 each)
H, s), 3.22 (3H, s), 4.20 (1H, m), 4.91 (1H, s), 5.00
(1H, m), 5.04 (1H, s), 5.20 (2H, m).

(XXIV) 2.5 g methylene chloride 400 ml
Was dissolved in water, 0.4 g of SeO ₂ was added, and the mixture was stirred at room temperature for 1 hour. At 12 to 15 ° C, 4.0 ml of 2,2,4-trimethylpentane solution of 3M t-butyl hydroperoxide was added and stirred for 1 hour, and then 100 ml of 10% NaOH aqueous solution.
Was added, the methylene chloride layer was separated, washed with brine and then concentrated, and the residue was purified by silica gel chromatography to obtain 960 mg of (XXVII).

¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s), 0.90 (3H,
d, J = 6.1Hz), 0.94 (3H, d, J = 6.5Hz), 1.15, 1.17 (3 each)
H, s), 3.21 (3H, s), 4.20 (2H, m), 4.94 (1H, d, J = 9.4
Hz), 5.21 (4H, m).

Example 9 (24S) -1α, 25-dihydroxy-3,5-cyclovitamin D ₂ (XXVIII) (24S) -25-hydroxyvitamin D ₂ (XXII) 3.
0 g was treated as in Example 8 to give (XXV).

¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 1.00 (3H,
d, J = 6.8Hz), 1.04 (3H, d, J = 6.6Hz), 1.13, 1.16 (3 each)
H, s), 3.23 (3H, s), 4.19 (1H, m), 4.91 (1H, s), 4.99
(1H, m), 5.04 (1H, s), 5.21 (2H, m).

This compound (XXV) was treated in the latter stage of Example 8 to give 910 mg of (XXVIII).

¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 0.90 (3H,
d, J = 6.2Hz), 0.95 (3H, d, J = 6.5Hz), 1.13, 1.18 (3 each)
H, s), 3.22 (3H, s), 4.23 (2H, m), 4.94 (1H, d, J = 9.4
Hz), 5.22 (4H, m).

Example 10 (24S) -1α-hydroxy-3,5-cyclovitamin D ₂ (XXIX) (24S) -vitamin D ₂ (XXIII) 2.0 g Example 8
The same treatment as in (XXVI) was obtained.

¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s), 0.83 (3H,
d, J = 6.8Hz), 0.86 (3H, d, J = 6.8Hz), 0.91 (3H, d, J =
6.9Hz), 1.02 (3H, d, J = 6.3Hz), 3.21 (3H, s), 4.21 (1
H, m), 4.91 (1H, s), 5.00 (1H, m), 5.03 (1H, s), 5.20
(2H, m).

This compound (XXVI) was treated in the latter stage of Example 8 to obtain 720 mg of (XXIX).

¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 0.83 (3H, s)
d, J = 6.8Hz), 0.86 (3H, d, J = 6.8Hz), 0.91 (3H, d, J =
6.9Hz), 1.03 (3H, d, J = 6.3Hz), 3.22 (3H, s), 4.22 (2
H, m), 4.93 (1H, d, J = 9.4Hz), 5.21 (4H, m).

Example 11 (24R) -1α, 25-dihydroxyvitamin D
₂ (I) Compound (XXVII) (960 mg) was dissolved in acetic acid (5 ml) and the temperature was raised to 55 ° C.
And reacted for 20 minutes. The reaction solution was added to an aqueous NaHCO ₃ solution, extracted with ethyl acetate, washed with brine, and the solvent was evaporated. The residue was purified by silica gel chromatography to separate β-form and trans-form, and (24R) -1α,
25-dihydroxyvitamin D ₂ 3β-acetate (XX
X) 360 mg was obtained. To 360 mg of this acetate (XXX), 3 ml of 10% ethanolic KOH was added and stirred for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with brine, and the solvent was evaporated. The residue is purified by silica gel column chromatography and then crystallized (I).
250 mg was obtained.

Melting point 156-158 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 0.97 (3H, d, J = 6.6H
z), 1.01 (3H, d, J = 6.5Hz), 1.15, 1.18 (each 3H, s), 4.2
3 (1H, m), 4.43 (1H, m), 4.99 (1H, s), 5.28 (2H, m), 5.
33 (1H, s), 6.02, 6.34 (2H, ABq, J = 11.2Hz).

Example 12 (24S) -1α, 25-dihydroxyvitamin D ₂ (I
I) The compound (XXVIII) (910 mg) was treated in the same manner as in Example 11 to obtain (II) (210 mg).

Melting point 172-174 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s), 1.00 (3H, d, J = 6.6H
z), 1.04 (3H, d, J = 6.5Hz), 1.13, 1.17 (3H, s each), 4.2
2 (1H, m), 4.42 (1H, m), 5.01 (1H, s), 5.28 (2H, m), 5.
34 (1H, s), 6.03, 6.36 (2H, ABq, J = 11.2Hz).

Example 13 420 mg of (24S) -1α-hydroxyvitamin D ₂ (III) compound (XXIX) was treated in the same manner as in Example 11 to obtain 140 mg of (III).

Melting point 151-153 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 0.83 (3H, d, J = 6.8H
z), 0.86 (3H, d, J = 6.8Hz), 0.91 (3H, d, J = 6.9Hz), 4.
22 (1H, m), 4.43 (1H, m), 5.00 (1H, s), 5.25 (2H, m),
5.32 (1H, s), 6.01, 6.36 (2H, ABq, J = 11.2Hz).

Example 14 (24R) -1α, 25-dihydroxy-vitamin D
₂ (I) 3.1 g of the compound (XXIV) obtained in Example 8 was dissolved in 25 ml of dimethylformamide, 3.1 g of imidazole and 3.1 g of triethylchlorosilane were added, and the mixture was reacted at 60 ° C. for 1 hour. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated to obtain 3.2 g of compound (XXIII).

¹ H NMR (CDCl ₃ ) δ: 0.54-0.61 (9 H, m), 0.
93 to 1.02 (15H, m), 1.10 (3H, s), 1.16 (3H, s), 3.26 (3
H, s), 4.17 (1H, d), 4.88 (1H, s), 4.99 (1H, d), 5.04
(1H, s), 5.16-5.29 (2H, m).

0.6 ml of selenium dioxide is added to 70 ml of methylene chloride.
g of 2,3M t-butyl hydroperoxide 2,2,4-
After adding 6 ml of trimethylpentane solution and stirring at room temperature for 1 hour, 3.2 g of methylene chloride solution (XXIII) was added dropwise at 10 ° C., and the mixture was reacted at the same temperature for 1 hour. The reaction was stopped by adding 150 ml of 10% NaOH aqueous solution, the methylene chloride layer was separated, dried (MgSO ₄ ) and the solvent was distilled off. The residue was purified by silica gel chromatography to give the compound (XXX
1.2 g of V) was obtained (this contains a small amount of 1β form).

¹ H NMR (CDCl ₃ ) δ: 0.54-0.62 (9 H, m), 0.
92 ~ 1.01 (15H, m), 1.10 (3H, s), 1.16 (3H, s), 3.25 (3
H, s), 4.20 (2H, m), 4.93 (1H, s), 5.18 ~ 5.31 (4H,
m).

1.2 g of the compound (XXXV) was dissolved in 10 ml of acetic acid and reacted at 55 ° C. for 15 minutes. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. Saturated NaHCO ₃ aqueous solution,
After washing with brine and drying (MgSO ₄ ), ethyl acetate was distilled off. The residue is 1 by silica gel chromatography
The β-form and trans-form were separated and purified to obtain 590 mg of compound (XXXVII).

¹ H NMR (CDCl ₃ ) δ: 0.54-0.61 (9 H, m), 0.
93 ~ 1.02 (15H, m), 1.11 (3H, s), 1.17 (3H, s), 2.04 (3
H, s), 4.40 (1H, m), 5.01 (1H, s), 5.15 ~ 5.32 (3H,
m), 5.34 (1H, s), 6.02 (1H, m), 6.34 (1H, m).

To 590 mg of compound (XXXVII) was added 10 ml of 1M tetrabutylammonium fluoride tetrahydrofuran solution, and the mixture was stirred at 50 ° C. for 1 hour. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO ₄ ), and the solvent was distilled off. 410 mg of the residue (XXX) was added with 4 ml of 10% ethanol KOH, and the mixture was stirred for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with brine, dried (MgSO ₄ ),
The solvent was concentrated. The residue was purified by silica gel chromatography and then crystallized to obtain 325 mg of (24R) -1α, 25-dihydroxyvitamin D ₂ (I).

Melting point 156-158 ° C. [α] _D ²⁵ + 80.5 ° (C 0.2, EtOH) ¹ H NMR (CDCl ₃ ) δ: 0.56 (3H, s), 0.97 (3H, d, J = 6.6 H
z), 1.01 (3H, d, J = 6.5Hz), 1.15, 1.18 (each 3H, s), 4.2
3 (1H, m), 4.43 (1H, m), 4.99 (1H, s), 5.28 (2H, m), 5.
33 (1H, s), 6.02, 6.34 (2H, ABq, J = 11.2Hz). E _1cm ¹ % 405 (λ _max 265nm, EtOH)

Example 15 (24S) -1α, 25-dihydroxyvitamin D ₂ (I
I) The compound (3.3 g) obtained in the previous step of Example 9 was treated in the same manner as in Example 14 to obtain 290 mg of (II).

Melting point 172 to 174 ° C. [α] _D ²⁵ +48.0 (C 0.2, EtOH) ¹ H NMR (CDCl ₃ ) δ: 0.55 (3H, s), 1.00 (3H, d, J = 6.6H)
z), 1.04 (3H, d, J = 6.5Hz), 1.13, 1.17 (each 3H, s), 4.2
2 (1H, m), 4.42 (1H, m), 5.01 (1H, s), 5.28 (2H, m), 5.
34 (1H, s), 6.03, 6.36 (2H, ABq, J = 11.2Hz). E _1cm ¹ % 408 (λ _max 265nm, EtOH)

Claims (2)

[Claims] 1. A compound of formula (I), (II) or (III): In producing the active vitamin D ₂ and its derivative represented by the formula (IV): (In the formula, X represents a protecting group for the hydroxyl group at the 3-position, Ph represents a phenyl group), and 4-phenyl-1,2,4-triazoline-3,5-dione of ergosterol (PTA
D) Ozone-oxidizing the adduct to give formula (V) And an aldehyde compound represented by the formula (V
I), (VII) or (VIII) (Wherein THP represents a tetrahydropyranyl group) and is condensed with a sulfone derivative represented by the formula (IX), (X) or (X
I) [Chemical 5] A compound represented by the formula (XII), (XIII) or (XIV) A compound of formula (XV), (XVI) or (XVII) The compound of formula (XVIII), (XIX) or (XX) is prepared by removing the 5,7-diene protecting group of this compound. 5,7-diene compound of formula (XXI), (XXII) or (XXII)
(XXIII) embedded image Vitamin D ₂ and its derivative represented by formula (X) are tosylated and treated with methanol in the presence of a base to give formula (X
XIV), (XXV) or (XXVI) In the cyclovitamin D ₂ compound represented, the 1α-position of the cyclo vitamin D ₂ compounds selectively hydroxylated formula (XXVII), (XXVIII) or (XXIX) embedded image And a compound represented by the formula
(XXX), (XXXI) or (XXXII) (Wherein Ac represents an acetyl group), and then the compound is hydrolyzed to remove the 3β-position acetyl group, or the above formulas (I), (II) or
(III) A method for producing active vitamin D ₂ and its derivative. 2. A compound of formula (I) or (II): In producing the active vitamin D ₂ and its derivative represented by the formula (IV): (In the formula, X represents a protecting group for the hydroxyl group at the 3-position, Ph represents a phenyl group), and 4-phenyl-1,2,4-triazoline-3,5-dione of ergosterol (PTA
D) Ozone oxidation of the adduct to give formula (V) And an aldehyde compound represented by the formula (VI)
Or (VII) (Wherein THP represents a tetrahydropyranyl group) and is condensed with a sulfone derivative of formula (IX) or (X) A compound of formula (XII) or (XIII) The compound of formula (XV) or (XVI) embedded image is prepared by removing the protective groups for the hydroxyl groups at the 3- and 25-positions of this compound. The compound of formula (XVIII) or (XIX) is prepared by removing the 5,7-diene protecting group of this compound. 5,7-diene compound represented by formula (XXI) or (XXII) Vitamin D ₂ and its derivative represented by formula (X) are tosylated and treated with methanol in the presence of a base to give formula (X
XIV) or (XXV) In the cyclovitamin D ₂ compound represented the formula to protect the 25-position hydroxyl group of the cyclo vitamin D ₂ compound (XXXII
I) or (XXXIV) (Wherein, R ₄ represents a protecting group of hydroxyl group) and cycloalkyl vitamin D ₂ compound represented by the 1α-position of the cyclo vitamin D ₂ compounds selectively hydroxylated formula (XXXV) or
(XXXVI) [Chemical formula 24] And a compound represented by the formula
(XXXVII) or (XXXVIII) (Wherein Ac represents an acetyl group), and a protecting group for the hydroxyl group at the 25-position of the compound is eliminated to remove the compound of formula (XXX) or (XXXI) (Wherein Ac represents an acetyl group) to obtain a 3-acetate compound, which is then hydrolyzed to remove the acetyl group at the 3β-position, which is represented by the above formula (I) or (II). A method for producing active vitamin D ₂ and its derivative.