JP2984406B2 - Method for producing steroid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention is expected to be useful as an intermediate in the production of 1α, 25-dihydroxy-22-oxa-vitamin D ₃ and its derivatives (R)-.
Or (S) -1α, 3β-diacetoxy-pregna
The present invention relates to a novel method for producing 5,7-dien-20-ol and a novel intermediate compound obtained in the production process of the above compound.

[0002]

2. Description of the Related Art It is known that 1α, 25-hydroxyvitamin D ₃ is an active vitamin D ₃ having high biological activity. Furthermore, recently, so-called vitamin D
It was elucidated that it also has a differentiation-inducing action in addition to the activity.
However, when conventional active vitamin D ₃ is used as an anticancer drug based on its differentiation-inducing action, its vitamin D activity is rather a side effect. Therefore, studies on active vitamin D derivatives having no vitamin D activity and methods for synthesizing the same have been conducted for the purpose of separating these functions, and typical examples thereof include 1α, 25-dihydroxy-20-oxa-21-norvitamin. D ₃ (N. Kubodera, Chem. Phar
m. Bull., 34 , 2286 (1986)) or 1
α, 25-dihydroxy-22-oxavitamin D ₃ (E.
Murayama, Chem. Pharm. Bull., 34 , 4410 (1
986)) are known.

[0003] The synthesis of these active vitamin D ₃ is generally carried out by irradiating the provitamin D ₃ with light and then thermally isomerizing the previtamin D ₃ produced. In the synthesis of provitamin D ₃ , the introduction of a 1α-hydroxyl group into the steroid skeleton and the construction of a 5,7-diene moiety are key steps.

The side chain after building the 5,7-diene portion of dehydroepiandrosterone as common intermediate - [0004] The active form synthesis of vitamin D ₃ is obtained the dehydroepiandrosterone by enzymatic treatment 1α- hydroxy This is accomplished by constructing the 5,7-diene moiety after introduction or synthesis of the side chain. However, the 1α-position hydroxylation of dehydroepiandrosterone as the starting material has a low yield,
Processing is also difficult. As is well known, the conventional method for constructing 5,7-diene (debromination-free HBr) produces a large amount of isomer 4,6-diene as a by-product, and its yield is low and purification is difficult. Is also difficult.

Further, 22-oxa-1α, 25-using 1α-hydroxy-dehydroepiandrosterone.
Intermediate dihydroxyvitamin D _3, pregna-5,7
In the synthesis of diene derivatives, only the 20S-form is obtained.

Japanese Patent Application Laid-Open No. 2-96591 discloses the synthesis of a pregna-5,7-diene derivative, but the reaction step is long, and the product is a mixture of diastereomers.

[0007]

Therefore, in order to efficiently obtain these active vitamin D derivatives, a simple synthesis method for obtaining the corresponding provitamin D compound in a stereoselective and higher yield is required. Development of an intermediate compound for that purpose is desired.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve these problems, and as a result, the following intermediates, which are important intermediates in the pro-form synthesis of active vitamin D having a hydroxyl group at 1α-position, are shown. Formula (XXV) or Formula (XXVI)

[0009]

Embedded image And a production method thereof.

That is, the present invention provides the following formula (I) or (II)

[0011]

Embedded image (R)-or (S) -20-hydroxytrienone compound represented by the following formula (XXV) in a relatively small number of steps and in a high yield through a reaction step unknown so far. ) And a process for preparing compounds of formula (XXVI), and novel compounds obtained in the intermediate course of this process.

The method of the present invention comprises (R)-or (S) -2.
0-Hydroxy-pregna-5-en-3-ol is converted to D
The following formula (I) or formula (II) obtained by DQ oxidation

[0013]

Embedded image Protecting the hydroxyl group at the 20-position of the 20-hydroxytrienone compound represented by the following formula (III) or (IV)

[0014]

Embedded image (Wherein, X represents a protecting group)
Then, the compound of the formula (III) or the formula (IV) is subjected to an enol acetylation reaction using isopropenyl acetate to give the following formula (V) or the formula (VI)

[0015]

Embedded image Wherein X is as defined above, and then the compound of formula (V) or formula (VI) is subjected to a reduction reaction to give a 1,3,5,7-tetraene compound Formula (VII) or Formula (VIII)

[0016]

Embedded image Wherein X is as defined above, and then the compound of formula (VII) or (VIII) is converted to 4-phenyl-1 , 2,4-triazoline-3,5-dione to react with the following formula (IX) or (X)

[0017]

Embedded image Wherein X is as defined above, which is a Diels-Alder-type addition reaction product, and then the compound of formula (IX) or (X) has a bulky 3-hydroxyl group. Formula (XI) or Formula (XII)

[0018]

Embedded image (Wherein X and Y each represent a protecting group). Subsequently, the protecting group of the hydroxyl group at the 20-position of the compound of the formula (XI) or (XII) is removed to obtain the following formula (XI
II) or formula (XIV)

[0019]

Embedded image (Wherein Y is as defined above), and subsequently, the compound of formula (XIII) or (XI
The hydroxyl group at position 20 of the compound of V) is used in the subsequent step.
Protected with a protecting group that is stable to a reagent such as iAlH _4, the following formula (XV) or (XVI)

[0020]

Embedded image (Wherein Y and Z each represent a protecting group), and then the compound of formula (XV) or (XVI) is treated with an epoxidizing agent to obtain the following formula (XVII) or (XVII) XVIII)

[0021]

Embedded image (Wherein Y and Z are as defined above), and then the protecting group for the hydroxyl group at the 3-position of the compound of formula (XVII) or (XVIII) is removed. And then formula (XIX) or formula (XX)

[0022]

Embedded image (Wherein Z is as defined above), and subsequently the compound of formula (XIX) or (X
The compound of the formula (X) is subjected to a reduction reaction using LiAlH ₄ to give the following formula (XXI) or (XXII)

[0023]

Embedded image Wherein Z is as defined above, and then the 1- and 3-position hydroxyl groups of the compound of formula (XXI) or (XXII) are subjected to an acetylation reaction. And the following formula (XXIII) or formula (XXIV)

[0024]

Embedded image And then removing the protecting group at the 20-position of the compound of the formula (XXIII) or (XXIV) to obtain the compound of the following formula (XXV) or (XXVI)

[0025]

Embedded image (R)-and (S) -1α, 3β-diacetoxy-pregna-5,7-dien-20-ol represented by the following formulas:

The intermediate compounds (V) to (XXIV) synthesized in the production process in the above method are novel compounds which have not been published in any literature.

In the specific reaction procedure of the method of the present invention described above, the starting compound of formula (I) or (II) is protected at the hydroxyl group at the 20-position first, and this protecting group is It is possible to use a group that is stable under acidic conditions in the reaction treatment, for example, an acetyl group, a benzoyl group, a benzyl group and the like. However, an acetyl group is preferred in consideration of the reactivity and ease of removal. This acetylation can be easily performed using conventional acetic anhydride-pyridine, acetyl chloride-pyridine and the like. The thus obtained formula (III) or formula (I
The compound (V) is subjected to an enol acetylation reaction using isopropenyl acetate under acidic conditions to give a tetraene compound of the formula (V) or (VI). Examples of the acid used to make the reaction acidic include paratoluenesulfonic acid, methanesulfonic acid, and the like, which are used in an amount of 0.1 to 2.2 with respect to the compound of formula (III) or (IV). It is used in an amount of 0 equivalents, and isopropenyl acetate is used in an amount of 1 to 50 equivalents.
This reaction can be generally carried out in an organic solvent under reflux, and the reactant isopropenyl acetate itself can be used as a solvent.

The compound of formula (V) or (VI) thus obtained is then reduced with a reducing agent such as NaBH ₄ , Ca (B
H ₄ ) ₂ , Zn (BH ₄ ) _{2 and the} like are subjected to reduction treatment to obtain a compound of the formula (VII)
Alternatively, a 3β-hydroxy-1,5,7-triene compound of the formula (VIII) is formed.

The resulting compound of the formula (VII) or (VIII) is reacted with PTAD to give a Diels-Alder type addition reaction product of the formula (IX) or (X), and then the 3-position of this product A bulky protecting group such as t-
The compound of formula (XI) or (XII) is protected by a butyldimethylsilyl group, and the protecting group at position 20 of the compound of formula (XI) or (XII) is removed (for example, in the case of an acetyl group, Hydrolysis with potassium) to give formula (XIII)
Alternatively, after forming a compound of the formula (XIV), the hydroxyl group is further protected with another protecting group to obtain a compound of the formula (XV) or the formula (XVI). As the protecting group in this case, a group which is stable to the alkali metal aluminum hydride or the alkali metal borohydride used in the next step, for example, a tetrahydropyranyl group, a benzyl group, a monomethoxymethyl group, or the like is used. Can be This step is preferably performed by treating with dihydropyran in the presence of pyridinium paratoluenesulfonate (hereinafter abbreviated as PPTS) to protect the hydroxyl group at the 20-position as tetrahydropyranyl ether.

The compound of formula (XV) or (XVI) is then treated with an epoxidation reagent such as m-chloroperbenzoic acid to selectively react with the α-formula of formula (XVII) or (XVIII).
Epoxy compounds.

The compound of the formula (XVII) or (XVIII) is then subjected to removal of the 3-position protecting group to give a compound of the formula (XIX) or (XX). This deprotection step is performed, for example, when the protecting group is a t-butyldimethylsilyl group.
It is performed by treating with ₄ NF tetrahydrofuran solution.

The compound of formula (XIX) or (XX) is then converted to an alkali metal aluminum hydride or alkali metal borohydride such as LiAlH ₄ , NaAlH ₄ ,
Reduction with KAlH ₄ , LiBH ₄ , NaBH ₄ , KBH ₄ or the like gives the compound of formula (XXI) or formula (XXII).

The compound of the formula (XXI) or the formula (XXII) is acetylated by a conventional method, for example, using acetic anhydride-pyridine or acetyl chloride-pyridine to give the compound of the formula (XXIII).
Or a compound of the formula (XXIV).

The thus-obtained compound of the formula (XXIII) or (XXIV) is freed from the protecting group at the 20-position. For example, when the protecting group is a tetrahydropyranyl group,
By treating in ethanol in the presence of PPTS or p-toluenesulfonic acid, this protecting group is eliminated and thus the desired compound of formula (XXV) or (XXVI), ie (R)-or (S) -1α, 3β-
Diacetoxy-pregna-5,7-dien-20-ol is obtained.

When the method of the present invention is exemplified by a reaction using specific reaction reagents, the following reaction scheme is shown.

[0036]

Embedded image

[0037]

Embedded image

[0038]

Embedded image

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are described for the purpose of describing the present invention by specific examples, and the present invention is not limited thereto. Not to be interpreted.

Example 1 (R) -20-acetoxy-pregna-1,4,6-trien-3-one (III) (R) -pregna-5-ene-
3β, 20-diol (25.0 g) was added to dioxane (50
0 ml), and DDQ (75.0 g) was added.
The mixture was heated under reflux for 16 hours. The hydroquinone formed was removed by filtration and the solvent was distilled off. The residue was extracted with ethyl acetate, washed with 10% KOH and brine, and the ethyl acetate was distilled off. The residue was subjected to silica gel chromatography (chloroform / ethyl acetate = 9/1) to obtain 15.6 g of compound (I). 15 ml of acetic anhydride,
Pyridine (50 ml) was added and heated at 90-95 ° C for 1 hour. After extraction with ethyl acetate and washing with 10% hydrochloric acid, aqueous NaHCO ₃ and brine, the solvent was distilled off. The residue was subjected to silica gel chromatography (eluted with chloroform) to give the title compound (III).
3 g were obtained (51%). Melting point: 162-163 ° C (MeOH); MS (m /
e): 355 (M ⁺ ); ¹ H-NMR (CDCl ₃ ): 5.
97 to 7.09 (5H, m, H-1, H-2, H-4,
H-6, H-7), 4.86 (1H, m, H-20),
_{2.00 (3H, s, COCH 3} ).

Example 2 (S) -20-Acetoxy-pregna-1,4,6-trien-3-one (IV) (S) -pregna-5-ene-3
The same treatment as in Example 1 was performed using β, 20-diol (10.0 g) to obtain 4.1 g of the title compound (IV) (3
7%). _{^{1 H-NMR (CDCl 3)}} ; 5.97~7.09 (5H,
m, H-1, H-2, H-4, H-6, H-7), 4.
91 (1H, m, H-20), 2.01 (3H, s, C
OCH _3).

Example 3 (R) -3,20-diacetoxy-pregna-1,3,5,
7-Tetraene (V) Compound (III) obtained in Example 1
14.3 g of isopropenyl acetate (150 ml),
Dissolved in butyl acetate (300 ml), added paratoluenesulfonic acid (7.0 g) and heated at reflux for 10 hours. The reaction mixture was washed with aqueous sodium bicarbonate, brine, then dried (MgSO ₄ ) and evaporated. The residue was crystallized from methanol to give 7.1 g (44%) of the title compound (V). Melting point: 159-160 ° C; MS (m / e): 397
(M ⁺ ); ¹ H-NMR (CDCl ₃ ): δ 5.63 to 5.
97 (5H, m, H-1, H-2, H-4, H-6, H
-7), 4.89 (1H, m, H-20), 2.06,
_{2.17 (6H, s, COCH 3} ).

Example 4 (S) -3,20-diacetoxy-pregna-1,3,5,
7-Tetraene (VI) Compound (IV) obtained in Example 2
The same treatment as in Example 3 was carried out using 4.1 g to give 1.6 g (35%) of the title compound (VI). Melting point: 148-149 ° C (MeOH); ¹ H-NMR
(CDCl ₃ ): δ 5.65 to 6.00 (5H, m, H−
1, H-2, H-4, H-6, H-7), 4.89 (1
H, m, H-20), 2.00, 2.17 (6H, s, C
OCH _3).

Example 5 (R) -20-acetoxy-3β-hydroxy-5α, 8
α- (3,5-dioxo-4-phenyl-1,2,4-triazolidino) -pregna-1,6-diene (IX) Calcium chloride (40 g) was dissolved in methanol (200 ml) and the solution was dissolved in 0 to -5. While cooling to ° C., a solution of sodium borohydride (20 g) in ethanol (300 ml) was added thereto.
Was added dropwise and kept at the same temperature for 1 hour.

Then, an ether solution (7.1 g) of 7.1 g of the compound (V) obtained in Example 3 was added to the mixture thus obtained.
00ml) was added dropwise at -10 ° to -15 ° C, and the mixture was stirred at the same temperature for 2 hours and kept at room temperature overnight. Then 50%
An aqueous acetic acid solution was added to decompose excess reagents, and the mixture was extracted with ethyl acetate.

To the solution thus obtained was added 4-phenyl-1,2,4-triazolidine-3,5-dione until the color of the solution turned red, and the ethyl acetate was distilled off. The residue was chromatographed on silica gel (eluent:
Purification by ethyl acetate / chloroform = 1/9) gave 6.7 g of the title compound (IX) (71%). MS (m / e): 357 (M ⁺ -175); ¹ H-NMR
(CDCl ₃ ): δ 7.37 (5H, m, C ₆ H ₆ ), 6.
29, 6.43 (2H, ABq, J = 8.0 Hz, H-
6, H-7), 5.86 (2H, s, H-1, H-
2) 5.03 (1H, t, H-3), 4.89 (1H,
t, H-20), 2.04 (3H, s, COCH 3).

Example 6 (S) -20-acetoxy-3β-hydroxy-5α,
8α- (3,5-dioxo-4-phenyl-1,2,4-
Triazolidino) -pregna-1,6-diene (X) Example 5 using 1.6 g of the compound (VI) obtained in Example 4
The same treatment as above was carried out to obtain 1.6 g of the title compound (X) (75%). ¹ H-NMR (CDCl ₃ ): δ 7.44 (5H, m, C
_{6 H 5), 6.26,6.43 (2H} , ABq, J = 8.0
Hz, H-6, H-7), 5.71 (2H, s, H-
1, H-2), 4.97 (2H, m, H-3, H-2)
0), 2.00 (3H, s , COCH 3).

Example 7 (R) -20-acetoxy-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-triazolidino) -pregna-1 , 6
-Diene (XI) 6.7 g of the compound (IX) obtained in Example 5 was dissolved in dimethylformamide (20 ml), and t-butyldimethylsilyl chloride (3.5 g) and imidazole (3.5) were dissolved.
g) was added and kept at 40 ° C. for 1 hour. The reaction mixture was extracted with ether, washed with brine and dried (M
gSO _4). The ether was distilled off, and methanol was added to the residue to precipitate crystals. The crystals were filtered to give 7.0 g (86%) of the title compound (XI). MS (m / e); 471 (M ⁺ -175); ¹ H-NMR
(CDCl ₃ ): δ 7.37 (5H, m, C ₆ H ₅ ), 6.
26, 6.41 (2H, ABq, J = 8.0 Hz, H-
6, H-7), 5.66 (2H, s, H-1, H-
2) 4.93 (1H, m, H-3), 4.84 (1H,
m, H-20), 2.03 (3H, s, COCH 3).

Example 8 (S) -20-Acetoxy-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-triazolidino) -pregna-1 , 6
-Diene (XII) 1.6 g of the compound (X) obtained in Example 6 was treated in the same manner as in Example 7 to give 1.0 g of the title compound (XII).
(52%). Melting point: 196-198 ° C; ¹ H-NMR (CDCl ₃ ):
δ 7.37 (m, 5H, C ₆ H ₅ ), 6.26, 6.43
(2H, ABq, J = 8.0 Hz, H-6, H-7),
5.66 (2H, s, H-1, H-2), 4.99 (2
H, m, H-3, H-20), 2.00 (3H, s, C
OCH _3).

Example 9 (R) -3β-t-butyldimethylsilyloxy-5α,
8α- (3,5-dioxo-4-phenyl-triazolidino) -pregna-1,6-dien-20-ol (XII
I) 7.0 g of the compound (XI) obtained in Example 7 was dissolved in ethanol (100 ml) containing potassium hydroxide (4.0 g) and stirred at room temperature for 30 minutes. After extraction with ethyl acetate and washing with brine, the solvent was distilled off. The title compound (XI
5.7 g of II) were obtained (87%). Melting point: 203-205 ° C; MS (m / e) 429 (M ⁺
-175); ¹ H-NMR (CDCl ₃ ): δ 7.37
_{(5H, m, C 6 H} 5), 6.26,6.43 (2H, AB
q, J = 8.0 Hz, H-6, H-7), 5.69 (2
H, s, H-1, H-2), 4.97 (1H, t, H-
3) 3.70 (1H, m, H-20).

Example 10 (S) -3β-t-butyldimethylsilyloxy-5α,
8α- (3,5-dioxo-4-phenyl-triazolidino) -pregna-1,6-dien-20-ol (X
IV) 1.0 g of compound (XII) obtained in Example 8
In the same manner as in Example 9 to give the title compound (X
IV) was obtained in an amount of 930 mg (99%). ¹ H-NMR (CDCl ₃ ): δ7.37 (5H,
_{m, C 6 H 5),} 6.26,6.43 (2H, AB
q, J = 8.0 Hz, H-6, H-7), 5.66 (2
H, s, H-1, H-2), 4.99 (1H, m, H-
3), 3.77 (1H, m, H-20).

Example 11 (R) -3β-t-butyldimethylsilyloxy-5α,
8α- (3,5-dioxo-4-phenyl-1,2,4-
Triazolidino) -20-tetrahydropyraniloxy-
Pregna-1,6-diene (XV) 5.7 g of the compound (XIII) obtained in Example 9 was dissolved in dichloromethane (100 ml), and dihydropyran (3.0) was dissolved.
g), pyridinium paratoluenesulfonate (300
mg) and stirred at room temperature for 4 hours. After washing with brine, it was dried (MgSO ₄ ) and dichloromethane was distilled off. 4.9 g of the title compound (XV) was obtained as a powder (75
%). MS (m / e): 513 (M ⁺ -175); ¹ H-NMR
(CDCl ₃ ): δ 7.37 (5H, m, C ₆ H ₅ ), 6.
26, 6.44 (2H, ABq, J = 8.0 Hz, H-
6, H-7), 5.66 (2H, s, H-1, H-
2) 4.97 (1H, t, H-3), 4.60 (1H,
s, THP), 3.90 (2H, m, THP, H-2)
0), 3.57 (1H, m, THP).

Example 12 (S) -3β-t-butyldimethylsilyloxy-5α,
8α- (3,5-dioxo-4-phenyl-1,2,4-
Triazolidino) -20-tetrahydropyraniloxy-
Pregna-1,6-diene (XVI) 930 mg of the compound (XIV) obtained in Example 10 was treated in the same manner as in Example 11 to give the title compound (XVI) in a quantity of 960 m.
g (91%). ¹ H-NMR (CDCl ₃ ): δ 7.38 (5H, m, C
_{6 H 5), 6.26,6.43 (2H} , ABq, J = 8.0
Hz, H-6, H-7), 5.66 (2H, s, H-
1, H-2), 4.94 (1H, m, H-3), 4.6
3, 4.70 (1H, s, CH (THP)), 3.91
(2H, m, H-20 , CH 2 (THP)), 3.51
_{(1H, m, CH 2 (} THP)).

Example 13 (R) -1α, 2α-epoxy-3β-hydroxy-5
α, 8α- (3,5-dioxo-4-phenyl-1,2,4
-Triazolidino) -20-tetrahydropyraniloxy-pregn-6-ene (XIX) 2.1 g of the compound (XV) obtained in Example 11 was dissolved in chloroform (100 ml), and m-chloroperbenzoic acid (4. 0 g) was added and the mixture was stirred overnight at room temperature. The reaction mixture was washed with a 10% aqueous potassium carbonate solution and then with brine, then dried (MgSO ₄ ) and chloroform was distilled off. 2.2 g of compound (XVII) was obtained (oil).

2.2 g of this compound (XVII) was dissolved in tetrahydrofuran (50 ml), and 1M tetrabutylammonium fluoride (tetrahydrofuran solution) was added thereto.
(9 ml) and stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate and washed with brine, after which the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate, chloroform = 1/9) to give 1.4 g of the title compound (XIX) as an oil (78).
%). MS (m / e): 414 (M ⁺ -175); ¹ H-NMR
(CDCl ₃ ): δ 7.41 (5H, m, C ₆ H ₅ ), 6.
20, 6.44 (2H, ABq, J = 8.0 Hz, H-
6, H-7), 5.03 (1H, t, H-3), 4.65
(1H, s, THP), 3.51-3.89 (3H, m,
H-20, CH ₂ (THP)), 3.21 (2H, m, H
-1).

Example 14 (S) -1α, 2α-Epoxy-3β-hydroxy-5
α, 8α- (3,5-dioxo-4-phenyl-1,2,4
-Triazolidino) -20-tetrahydropyraniloxy-pregn-6-ene (XX) 960 mg of the compound (XVI) obtained in Example 12 was treated in the same manner as in Example 13 to give 650 mg of the title compound (XX).
(79%). ¹ H-NMR (CDCl ₃ ): δ 7.38 (5H, m, C
_{6 H 5), 6.19,6.39 (2H} , ABq, J = 8.0
Hz, H-6, H-7), 4.99 (1H, m, H-
3), 4.60, 4.67 (1H, s, CH (TH
P)), 3.43~3.97 (3H, m, CH 2 (TH
P), H-20).

Example 15 (R) -1α, 3α-diacetoxy-20-tetrahydropyraniloxy-pregna-5,7-diene (XXIII) A solution of 1.4 g of the compound (XIX) obtained in Example 13 in tetrahydrofuran ( (40 ml) was added dropwise to a solution of LiAlH ₄ (3.0 g) in tetrahydrofuran (100 ml), and the mixture was further heated under reflux for 1 hour. After water was added to the reaction to decompose excess LiAlH ₄ , the solid was filtered off and extracted with chloroform. The extract was washed with brine, dried (MgSO _4). 600 mg of compound (XXI)
Obtained (oil).

600 mg of this compound (XXI) was dissolved in pyridine (10 ml), and acetic anhydride (2 ml) was added.
For 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with sodium bicarbonate water, brine, and dried.
Ethyl acetate was distilled off, and the residue was subjected to silica gel chromatography (eluted with CHCl ₃ ) to obtain 450 mg of the compound (XXIII) as an oil (36%). MS (m / e): 441 (M + -CH 3 COOH); 1 H
-NMR (CDCl ₃ ): δ 5.40, 5.70 (2H,
m, H-6, H-7), 5.03 (2H, m, H-1,
H-3), 4.70 (1H, s, THP), 3.89 (2
H, m, H-20, CH ₂ (THP)), 3.51 (1
H, m, CH ₂ (THP)), 2.03, 2.10 (6
H, s, COCH _3).

Example 16 (S) -1α, 3β-diacetoxy-20-tetrahydropyraniloxy-pregna-5,7-diene (XXIV) Example 15 using 650 mg of the compound (XX) obtained in Example 14. And then subjecting the title compound (XXIV) to 3
20 mg were obtained (58%). ¹ H-NMR (CDCl ₃ ): δ 5.37, 5.63 (2
H, m, H-6, H-7), 5.00 (2H, m, H-
1, H-3), 4.57, 4.67 (1H, s, CH (T
HP)), 3.46~4.09 (3H, m, CH 2 (TH
P), H-20), 2.03, 2.09 (2H, s, CO
CH _3).

Example 17 (R) -1α, 3β-diacetoxy-pregna-5,7-
Dien-20-ol (XXV) 450 mg of the compound (XXIII) obtained in Example 15 was dissolved in ethanol (10 ml), pyridinium paratoluenesulfonate (100 mg) was added, and the mixture was stirred at 40 to 45 ° C for 3 hours. Reacted. The reaction mixture was extracted with ethyl acetate, washed with brine, and then the ethyl acetate was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / chloroform = 1/9) to obtain 308 mg (82%) of the title compound (XXV). Melting point: 188-1
89 ° C; MS (m / e): 357 (M ⁺ -CH ₃ COO
H); UV (λ _max ): 282 nm (ε = 11,500, E
tOH); ¹ H-NMR (CDCl ₃ ): δ 5.37;
5.70 (2H, m, H-6, H-7), 4.99 (2
H, m, H-1, H-3), 3.73 (1H, m, H-
20), 2.03,2.08 (6H, s , COCH 3).

Example 18 (S) -1α, 3β-diacetoxy-pregna-5,7-
Dien-20-ol (XXVI) The same treatment as in Example 17 was performed using 320 mg of the compound (XXIV) obtained in Example 16 to obtain 200 mg (75%) of the title compound (XXVI) as an oil. ¹ H-NMR (CDCl ₃ ): δ 5.39, 5.64 (2
H, m, H-6, H-7), 4.94 (2H, m, H-
1, H-3), 3.69 (1H, s, H-20), 2.0
₃ , 2.06 (6H, s, COCH3). UV
(Λ _max ): 282 nm (ε = 11,000, EtOH).

[0062]

According to the present invention, (R)-or (S)
Starting from a -20-hydroxytrienone compound as a starting material, (R)-or (S) -1 is obtained in a relatively small number of steps and in a high yield through a reaction step which has not been known so far.
α, 3β-diacetoxy-pregna-5,7-diene-2
0-ol is produced.

Furthermore, by using these compounds obtained by the present method, both 20R- and 20S-compounds of a 20-oxa-type active vitamin D derivative can be synthesized.

The compounds (V) to (XXIV) obtained in the production process of the method of the present invention are novel compounds which have not been described in any literature.

Claims (5)

(57) [Claims] 1. A compound represented by the following formula (VII) or (VIII): (Wherein, X represents a protecting group) 3β-hydroxy-1,5,7-triene compound represented by the formula: 2. A compound represented by the following formula (I) or formula (II): Protecting the hydroxyl group at the 20-position of the 20-hydroxytrienone compound represented by the following formula (III) or (IV): Wherein X is as defined above, and then the compound of formula (III) or (IV)
Is subjected to an enol acetylation reaction using isopropenyl acetate to give the following formula (V) or (VI): Wherein X is as defined above, and then subjecting the compound of formula (V) or (VI) to a reduction reaction The following formula (VII) or formula (VIII) (Wherein X is as defined above), a method for producing a 3β-hydroxy-1,5,7-triene compound represented by the formula: 3. A compound represented by the following formula (XXI) or formula (XXII): (Wherein, Z represents a protecting group). 4. A compound represented by the following formula (VII) or (VIII): (In the formula, X is as defined above) represented by the formula: 4-β-hydroxy-1,5,7-triene compound
By reacting with phenyl-1,2,4-triazoline-3,5-dione, the following formula (IX) or formula (X) (Wherein X is as defined above), a compound of the Diels-Alder type addition reaction represented by the formula (IX) or (X)
Protecting the hydroxyl group at the 1-position with a bulky protecting group, the following formula (XI)
Or a compound of formula (XII) (Wherein, X and Y each represent a protecting group), and the compound represented by the formula (XI) or (XI)
The protecting group for the hydroxyl group at the 20-position of the compound of I) is removed to give the following formula (XIII) or (XIV) Wherein Y is as defined above, and subsequently the hydroxyl group at position 20 of the compound of formula (XIII) or (XIV) is used in a subsequent step such as LiAlH ₄ Protected by a protecting group which is stable to the reagent, and then protected by the following formula (XV) or (XVI): Wherein Y and Z are as defined above, and then treating the compound of formula (XV) or (XVI) with an epoxidizing agent to form a compound of the following formula (XVII) or Formula (XVIII) Wherein Y and Z are as defined above, and then removing the protecting group for the hydroxyl group at the 3-position of the compound of formula (XVII) or (XVIII) The following formula (XIX) or formula (XX) Wherein Z is as defined above, and subsequently subjecting the compound of formula (XIX) or (XX) to a reduction reaction comprises the following formula (XXI) or Formula (XXII) (Wherein Z is as defined above). 5. A compound of the following formula (XXI) or formula (XXII): (Wherein Z is as defined above), the 1- and 3-position hydroxyl groups of the 5,7-diene compound are subjected to an acetylation reaction to obtain the following formula (XXIII) or (X
XIV) And then removing the protecting group at position 20 of the compound of formula (XXIII) or (XXIV) by the following formula (XXV) or (XXVI): A method for producing a compound of (R)-or (S) -1α, 3β-diacetoxy-pregna-5,7-dien-20-ol represented by the formula: