JP2750175B2 - Method for producing steroid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 1α, 3β-prospect which is expected to be useful as an intermediate in producing 1α, 25-dihydroxyvitamin D.
Diacetoxy-23,24-dinorkola-5,7-diene-22-
All or -22-al, and 1α, 3β-diacetoxy-cola-5,7-dien-24-ol or -24-al and a novel method for producing the same, and a novel intermediate obtained in the production process of the above compound Body compounds.

[Conventional technology]

1α, 25-dihydroxyvitamin D ₃ is an active vitamin D ₃ exhibiting high biological activity and promotes absorption of calcium and phosphorus in the small intestine, promotes re-absorption of phosphorus and calcium in renal tubules, and mobilizes calcium from bone. In addition to the natural physiological effects of vitamin D such as calcification of osteoid tissue,
It has been reported to exhibit various pharmacological activities including an anticancer effect. In addition, various active vitamin D derivatives have been synthesized in order to obtain compounds having higher activity than these active vitamin D ₃ (T. Kametani, Med. Res. R
ev. 7 , 147 (1987); N. Ikekawa, Med. Res. Rev. 7 , 333 (19)
87)). These active vitamin D derivatives are generally synthesized by irradiating the corresponding provitamin D form with light and then thermally isomerizing the obtained provitamin D.

The key steps in the synthesis of these pro-forms are the introduction of a hydroxyl group at the 1α-position and the construction of a 5,7-diene moiety and a steroid side chain. Conventionally, naturally occurring compounds such as stigmasterol and coleic acid exist. Derived from steroid compounds
22-Hydroxy-23,24-dinorcola-1,4,6-trien-3-one (1) (Frst, Helv. Chim. Acta. 64 , 1870)
(1981)), 24-hydroxy-colla-1,4,6-trien-3-one (2) (N. Ikekawa, Chem. Pharm. Bull., 36 , 23).
03 (1988)), a hydroxyl group was introduced into the 1α-position by Birch reduction, and then a 5,7-diene moiety and then a side chain moiety were constructed to induce a provitamin D form.

However, since these methods use metal lithium-liquid ammonia during Birch reduction, they have operational risks, and when constructing the 5,7-diene moiety, It has the disadvantage that, in addition to the 7-diene compound, the isomeric 4,6-diene compound is produced as a large amount as a by-product.

The present inventors previously synthesized 1α-acetoxyergostyryl acetate (1) as shown in the following reaction scheme I (Y. Tachibana. Bull. Chem. Soc. Jpn., 61 , 3915 (19)
88)) and a compound (3) which is an important intermediate of an active vitamin D derivative by ozonolysis of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct (II).
(4) was synthesized (Japanese Patent Application Nos. 63-329177 and 329178), but these synthetic routes required relatively long reaction steps.

[Technical Problems to be Solved] Therefore, in order to efficiently obtain an active vitamin D derivative, a method for synthesizing a provitamin D form which is simpler, safer and moreover yields a desired product in a higher yield, and an intermediate method therefor There is a need for the development of body compounds.

[Technical means for solving the problem]

The present inventors have conducted intensive studies to solve these problems, and as a result, active vitamin D having a hydroxyl group at 1α-position
Is a key intermediate in the pro-form synthesis of
V), (XXVI), (XXVII) and (XXVIII) The present invention has been completed by finding a compound represented by the formula (1) and a novel production method thereof.

That is, the present invention provides the following formula: Starting from the 22-hydroxy or 24-hydroxytrienone compound represented by the above, in a relatively small number of steps through a reaction step which has not been known until now and without a danger in the reaction operation, a high yield is obtained. Formula (XXV), (X
XVI), (XXVII) and (XXVIII) and to novel compounds obtained by this method and in the intermediate stages of this method.

The method of the present invention comprises the following formula (I) or formula (II) Of a 22- or 24-hydroxytriene compound represented by
Protecting the hydroxyl group at the 22- or 24-position by the following formula (III) or (IV) (Where X is a protecting group for a hydroxyl group), and then the compound of formula (III) or (IV) is subjected to an enol acetylation reaction using isopropenyl acetate to obtain the following formula (V) Or equation (VI) And then subjecting the compound of formula (V) or (VI) to a reduction reaction to give the following formula (VII) or (VIII) 3β-hydroxy-1,5,7-triene compound represented by the following formula:
-Phenyl-1,2,4-triazoline-3,5-dione to react with the following formula (IX) or (X) A compound which is a Diels-Alder type addition reaction product represented by the formula (IX) or (X), and the 3-position hydroxyl group of the compound is protected by a bulky protecting group to obtain the following formula (XI) or Formula (XII) (Where Y is a bulky hydroxyl-protecting group), and the compound of formula (XI) or (XII) is subsequently removed by removing the protecting group at the 22- or 24-position to give the following formula (XIII ) Or formula (XIV) And subsequently the hydroxyl group at the 22- or 24-position of the compound of formula (XIII) or (XIV) is protected by a protecting group which is stable to LiAlH ₄ and tetrabutylammonium fluoride used in the subsequent step. Protect the following formula (XV) or formula (XVI) (Where Z is a hydroxyl-protecting group stable to LiAlH ₄ and tetrabutylammonium fluoride), and then the compound of the formula (XV) or (XVI) is
After treatment with chloroperbenzoic acid, the following formula (XVII) or formula (XVIII) The compound having the formula (XVII) or (XVIII) is treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran to remove the bulky protecting group. The following formula (XIX) or formula (XX) And then subjecting this compound of formula (XIX) or (XX) to a reduction reaction using LiAlH ₄ to give the following formula (XXI) or (XXII) And a 5,7-diene compound represented by the formula (XXI) or (XXII):
The hydroxyl groups at the 3- and 3-positions are subjected to an acetylation reaction to give the following formula (XXIII) or (XXIV) (Where Ac represents an acetyl group) and then a compound of the formula (XXIII) or (XXIV)
After removing the protecting group at the 2- or 24-position, the following formula (XXV) or formula (XXVI) 1α, 3β-diacetoxy-23,24-dinorkola-5,7-dien-22-ol or 1α, 3β-diacetoxy-colla-5,7-dien-24-ol represented by the following formula: XXV) or the compound of formula (XXVI) is oxidized to give the following formula (XXVII) or formula (XXVIII) 1α, 3β-diacetoxy-23,24-dinorkola-5,7-diene-22-al or 1α, 3β-diacetoxy-colla-5,7-diene-24-al represented by It is.

Among the compounds obtained in the middle of the reaction steps in the above method and the target compound, the compounds represented by the formulas (V), (VI), (VII), (VIII), (IX), (X) and (X) (X
I), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV),
Compounds represented by Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXII), Formula (XXVI), Formula (XXVII), and Formula (XXVIII) This is a new compound not listed in the literature.

In the specific reaction procedure of the method of the present invention described above, the starting compound of formula (I) or formula (II) is protected at the 22- or 24-position hydroxyl group first, and this protecting group is It is possible to use groups that are stable under acidic conditions in the reaction treatment, for example, acetyl, benzoyl, benzyl and the like. However, an acetyl group is preferred in consideration of the reactivity and ease of removal. This acetylation is carried out using conventional acetic anhydride-pyridine,
It can be easily carried out with acetyl chloride-pyridine or the like. Formula (III) or formula (IV) thus obtained
Is subjected to an enol acetylation reaction using isopropyl alcohol 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 para-toluenesulfonic acid, methanesulfonic acid, and the like, which are used in an amount of from 0.2 to about the compound of the formula (III) or (IV).
It is used in an amount of 2.0 equivalents, and isopropenyl acetate is used in an amount of 1 to 50 equivalents. This reaction can be generally performed in an organic solvent under reflux, and the isopropenyl acetate form of the reactant can be used as a solvent.

The tetraene compound of the formula (V) or the formula (VI) thus obtained is then reduced with a reducing agent which does not decompose the hydroxyl-protecting group at the 22-position or the 24-position, for example, Ca (BH ₄ ) ₂ , N
aBH ₄ for reduction treatment of formula (VII) or (VIII)
Of the 3β-hydroxy-1,5,7-triene compound.

The resulting compound of formula (VII) or (VIII) is converted to 4-
Reaction with phenyl-1,2,4-triazoline-3,5-dione as a Diels-Alder-type addition reaction product of the formula (IX) or (X), followed by bulking of the 3-position hydroxyl group of the product The compound of formula (XI) or (XII) is protected with a high protecting group, for example, a t-butyldimethylsilyl group, and the protecting group at the 22- or 24-position of the compound of formula (XI) or (XII) is After removal (for example, in the case of an acetyl group, hydrolysis using potassium hydroxide) to give a compound of the formula (XIII) or (XIV), the hydroxyl group is further protected with another protecting group to obtain a compound of the formula (XV ) Or a compound of formula (XVI). In this case, the protecting group is used in the next step
Groups that are stable to LiAlH ₄ and tetrabutylammonium fluoride, such as a tetrahydropyranyl group,
A benzyl group and a monomethoxymethyl group are used. This step is preferably carried out by treating with dihydropyran in the presence of pyridinium paratoluenesulfonate to protect the hydroxyl group at position 22 or 24 as tetrahydropyranyl ether.

The compound of formula (XV) or (XVI)
Treatment with chloroperbenzoic acid selectively gives the α-epoxy compound of the formula (XVII) or (XVIII). When the hydroxyl group at the 3-position is not protected in this reaction, it is known that a β-epoxy compound is obtained as a main product (C. Kaneko, Tetrahedron, 30 , 2701 (1974)). Protection with a bulky protecting group is an important step for obtaining an α-epoxy compound.

The compound of the formula (XVII) or the formula (XVIII) is then removed to a compound of the formula (XIX) or the formula (XX) by removing the protecting group at the 3-position. In this deprotection step, for example, when the protecting group is t
In the case of a -butyldimethylsilyl group, it is performed by treating with a tetrabutylammonium fluoride solution in tetrahydrofuran.

Then, the compound of the formula (XIX) or the formula (XX) is LiAlH
Reduction with ₄ gives the compound of formula (XXI) or formula (XXII).

The compound of the formula (XXI) or the formula (XXII) is acetylated using a conventional method such as acetic anhydride-pyridine or acetyl chloride-pyridine to obtain the compound of the formula (XXIII) or the formula (XXI).
V).

Formula (XXIII) or formula (XXI) thus obtained
The protecting group at position 22 or 24 is then removed from the compound of V). For example, when the protecting group is a tetrahydropyranyl group, this protecting group is eliminated by treatment in ethanol in the presence of pyridinium paratoluenesulfonate or paratoluenesulfonic acid, and thus one of the target compounds of the formula (XXV) ) Or formula (XXVI), ie 1α,
3β-diacetoxy-23,24-dinorkola-5,7-dien-22-ol or 1α, 3β-diacetoxy-colla-5,
7-Dien-24-ol is obtained.

According to the method of the present invention, the compound of formula (XXV) or formula (XXV)
When the 22-ol or 24-ol compound of I) is to be oxidized to obtain the corresponding aldehyde compound, a compound of the formula (XX)
V) or the compound of the formula (XXVI) is subjected to an oxidation treatment using polydinium chlorochromate or pyridinium dichlorochromate, etc.
α, 3β-diacetoxy-23,24-dinorkola-5,7-dien-22-al or 1α, 3β-diacetoxy-colla
This gives 5,7-diene-24-al.

The method of the present invention is exemplified by a reaction using a specific reaction reagent, as shown in the following reaction scheme (II).

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

Example 1 22-acetoxy-23,24-dinorcola-1,4,6-trien-3-one (compound III) 22-hydroxy-23,24-dinorkola-1,4,6-trien-3-one (compound III) 8.0 g of compound I) was dissolved in 20 ml of pyridine, 8 ml of acetyl chloride was added dropwise, and the mixture was reacted at room temperature for 1 hour with stirring. The reaction mixture was extracted with ethyl acetate,
The extract was washed sequentially with 10% aqueous hydrochloric acid, water, aqueous sodium bicarbonate, and brine, and the ethyl acetate was distilled off. The residue was purified by silica gel chromatography (eluent: chloroform) to obtain 8.1 g of the title compound III. Yield 90
% Mp. 91-92 ° C (hexane); m / e 368; ¹ H NMR (CDCl ₃ )
δ = 7.01, 5.91 to 6.23 (5H, m, H-1, H-2, H-4, H-6, H-
7), 3.98 (2H, m , H-22), 1.99 (3H, 6s, COCH 3).

Example 2 24-Acetoxy-colla-1,4,6-trien-3-one (Compound IV) 24-Hydroxy-colla-1,4,6 instead of compound (I)
The reaction and purification procedures of Example 1 were repeated except that 8.0 g of -trien-3-one (compound II) was used to give the title compound
7.8 g of IV was obtained. Yield 87% mp. 119-120 ° C (hexane); m / e 396 (M ⁺ ); ¹ H NMR
(CDCl ₃ ) δ = 7.03,5.94 to 6.26 (5H, m, H-1, H-2, H-4,
H-6, H-7), 4.00 (2H, m, H-24), 2.03 (3H, s, COC
H _3).

Example 3 3,22-diacetoxy-23,24-dinorkola-1,3,5,7-tetraene (compound V) 22-acetoxy-23,24-dinorkola-1,4,6-trien-3-one ( 4.0 g of compound III) was dissolved in 40 ml of isopropenyl acetate and 80 ml of butyl acetate, 2.0 g of paratoluenesulfonic acid was added, and the mixture was heated under reflux for 4 hours. The reaction mixture was washed successively with an aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from acetone to give the title compound V
2.3 g was obtained. Yield 55% mp. 138-140 ° C; UV: λ _max 252 nm (ε = 13,000, ethanol); ¹ H NMR (CDCl ₃ ) δ = 5.67 to 6.00 (5H, m, H-1, H-
2, H-4, H-6, H-7), 3.80 ~ 4.09 (2H, m, H-22), 2.0
_{7,2.17 (6H, s, COCH 3} ).

Example 4 22-acetoxy-3β-hydroxy-5α, 8α- (3,5
-Dioxo-4-phenyl-1,2,4-triazolidino)
-23,24-dinorkola-1,6-diene (compound IX) Dissolve 20 g of calcium chloride in 150 ml of methanol,
While cooling to 10 to -15 ° C, 150 ml of an ethanol solution of 10 g of sodium borohydride was added dropwise thereto, and the mixture was kept at the same temperature for 2 hours.

Subsequently, 1.5 g of 3,22-diacetoxy-23,24-dinorcola-1,3,5,7-tetraene (compound V) was added to 50 ml of dichloromethane-ether (3: 7).
Was added dropwise at -10 to -15 ° C, and the mixture was stirred at the same temperature for 2 hours and kept at 0 ° C overnight. Next, an excess reagent was decomposed by adding a 50% aqueous acetic acid solution, and the mixture was extracted with ethyl acetate.

The resulting solution was added to 4-phenyl-1,2,4
-Triazoline-3,5-dione was added until the color of the solution turned red, then ethyl acetate was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / chloroform = 1/9) to obtain 1.5 g of the title compound IX. Yield 75% mp. 196-198 ° C (methanol); m / e 370 (M ⁺ -175); ¹
H NMR (CDCl ₃ ) δ = 7.43 (5H, m, C ₆ H ₅ ), 6.29, 6.43 (2
H, ABq, H-6, H-7), 5.69 (2H, s, H-1, H-2), 5.00
(1H, bs, H-3), 3.80 (2H, m, H-22), 2.03 (3H, s, CO
CH ₃ ).

Example 5 24-Acetoxy-3β-hydroxy-5α, 8α- (3,5
-Dioxo-4-phenyl-1,2,4-triazolidino)
-Cola-1,6-diene (Compound X) 24-Acetoxy-Cola-1,4,6- obtained in Example 2
8.0 g of trien-3-one (compound IV) was dissolved in 80 ml of isopropenyl acetate and 80 ml of toluene, 4.0 g of paratoluenesulfonic acid was added, and the mixture was heated under reflux for 5 hours.
The reaction mixture was washed successively with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and the solvent was distilled off to give crude 3,24-diacetoxy-cola-1,3,5,7-tetraene (compound VI). ) 8.1 g was obtained as an oil. This compound
The reaction operation of Example 4 was performed for VI. That is,
Dissolve 80 g of calcium chloride in methanol, -10 to -1
While cooling to 5 ° C., an ethanol solution of 40 g of sodium borohydride was added dropwise thereto, and the mixture was kept at the same temperature for 2 hours. Then, an ether solution (100 ml) of 8.1 g of compound VI was added dropwise to the mixture at −20 ° C. After stirring at the same temperature for 4 hours, the mixture was left overnight at room temperature. Then, 50% acetic acid aqueous solution was added to decompose the excess reagent, followed by extraction with ethyl acetate.
The extract was washed successively with aqueous sodium bicarbonate and brine. 4-phenyl-1,1,
2,4-Triazoline-3,5-dione was added until the color of the solution turned red, and then ethyl acetate was distilled off. The residue was purified by silica gel chromatography to give the title compound X as 3.
7 g was obtained. Yield 32% m / e 399 (M ⁺ -175); ¹ H NMR (CDCl ₃ ) δ = 7.42 (5H,
_{m, C 6 H 5),} 5.97,6.46 (2H, ABq, H-6, H-7), 5.74 (2
H, s, H-1, H-2), 5.04 (1H, m, H-3), 4.03 (2H, m, H
-24), 2.03 (3H, s , COCH 3).

Example 6 22-acetoxy-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-
Triazolidino) -23,24-dinorcola-1,6-diene (compound XI) 22-acetoxy-3β-hydroxy-5α, 8α- (3,5-dioxo-4-phenyl-1, obtained in Example 4 2,4
-Triazolidino) -23,24-dinorcola-1,6-diene (Compound IX) (2.0 g) was dissolved in dimethylformamide (10 ml), t-butyldimethylsilyl chloride (1.0 g) and imidazole (1.0 g) were added, and the mixture was kept at 45 ° C. for 1 hour. did. The reaction mixture was extracted with ether, washed with brine and dried. Ether was distilled off from the dried extract, and methanol was added to the residue to precipitate crystals. The crystals were filtered to give 2.0 g of the title compound XI. Yield 83% mp. 184-185 ° C; m / e 484 (M ⁺ -175); ¹ H NMR (CDCl ₃ )
δ = 7.43 (5H, m, C 6 H 5), 6.29,6.46 (2H, ABq, H-6, H-
7), 5.71 (2H, s, H-1, H-2), 4.99 (1H, m, H-
3), 3.81, 4.12 (2H, m, H-22), 2.04 (3H, s, COC
H _3).

Example 7 24-Acetoxy-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-
Triazolidino) -chola-1,6-diene (compound XII) Instead of compound IX, 24-acetoxy-3β-hydroxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-
Triazolidino) -chora-1,6-diene (compound X) 2.5
The reaction operation and the purification operation of Example 6 were repeated except for using g, to obtain 1.9 g of the title compound XII. Yield 63% mp. 188-189 ° C (ether / methanol); m / e 513 (M
⁺ −175); ¹ H NMR (CDCl ₃ ) δ = 7.41 (5H, m, C ₆ H ₅ ), 6.2
4, 6.43 (2H, ABq, H-6, H-7), 5.66 (2H, s, H-1, H-
2), 4.97 (1H, m, H-3), 3.59 (2H, m, H-24), 2.03
_{(3H, s, COCH 3)} .

Example 8 3β-t-butyldimethylsilyloxy-5α, 8α- (3,
5-dioxo-4-phenyl-1,2,4-triazolidino)
-23,24-dinorcola-1,6-dien-22-ol (compound XIII) 22-acetoxy-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo) obtained in Example 6 −
2.0 g of 4-phenyl-1,2,4-triazolidino) -23,24-dinorkola-1,6-diene (compound XI) was dissolved in 20 ml of an ethanol solution of 1.0 g of potassium hydroxide and stirred at room temperature for 1 hour. . The mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Ethyl acetate was distilled off from the extract to obtain 1.8 g of the title compound. Yield 96% mp. 190-191 ° C (ether / hexane); m / e 442 (M ⁺
−175); ¹ H NMR (CDCl ₃ ) δ = 7.44 (5H, m, C ₆ H ₅ ), 6.3
0, 6.46 (2H, ABq, H-6, H-7), 5.70 (2H, s, H-1, H-
2), 4.96 (1H, m, H-3), 3.37, 3.65 (2H, m, H-2)
2).

Example 9 3β-t-butyldimethylsilyloxy-5α, 8α- (3,
5-dioxo-4-phenyl-1,2,4-triazolidino)
-Cola-1,6-dien-24-ol (Compound XIV) 24-Acetoxy-3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-) obtained in Example 7.
4-phenyl-1,2,4-triazolidino) -chola-1,6-
The procedure of Example 8 was repeated except that 1.0 g of diene (compound XII) was used to obtain 0.9 g of the title compound XIV. Yield 95% m / e 470 (M ⁺ -175); ¹ H NMR (CDCl ₃ ) 7.41 (5H, m, C ₆ H
₅ ), 6.24, 6.43 (2H, ABq, H-1, H-2), 5.65 (2H, s, H
-1, H-2), 4.97 (1H, m, H-3), 3.59 (2H, m, H-2)
Four).

Example 10 3β-t-butyldimethylsilyloxy-5α, 8α- (3,
5-dioxo-4-phenyl-1,2,4-triazolidino)
-22-Tetrahydropyraniloxy-23,24-dinorkola-1,6-diene (compound XV) 3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4) obtained in Example 8. −phenyl-1,
1.8 g of 2,4-triazolidino) -23,24-dinorcola-1,6-dien-22-ol (compound XIII)
After dissolving in 20 ml, dihydropyran 740 mg and pyridinium paratoluenesulfonate 150 mg were added, and the mixture was stirred at room temperature for 5 hours. The dichloromethane was distilled off from the reaction mixture at room temperature and extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and ether was distilled off to obtain 2.0 g of the title compound. Yield 98% m / e 526 (M ⁺ -175); ¹ H NMR (CDCl ₃ ) δ = 7.40 (5H,
_{m, C 6 H 5),} 6.26,6.43 (2H, ABq, H-6, H-7), 5.67 (2
H, s, H-1, H-2), 4.96 (1H, m, H-3), 4.47,4.56
(1H, s, CH (THP )), 3.23~3.91 (4H, m, H-22, CH 2 (TH
P)).

Example 11 3β-t-butyldimethylsilyloxy-5α, 8α- (3,
5-dioxo-4-phenyl-1,2,4-triazolidino)
-24-Tetrahydropyranyloxy-chola-1,6-diene (compound XVI) 3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4-phenyl-1 obtained in Example 9 ,
The procedure of Example 10 was repeated except that 620 mg of 2,4-triazolidino) -chola-1,6-dien-24-ol (compound XIV) was used to obtain 630 mg of the title compound XVI. Yield 90% m / e 470 (M ⁺ -DHP-175); ¹ H NMR (CDCl ₃ ) δ = 7.43
_{(5H, m, C 6 H} 5), 6.26,6.46 (2H, ABq, H-6, H-7), 5.
69 (2H, s, H-1, H-2), 4.99 (1H, m, H-3), 4.57 (1
H, s, CH (THP)), 3.33-3.91 (4H, m, H-24, CH ₂ (TH
P)).

Example 12 3β-t-butyldimethylsilyloxy-1α, 2α-epoxy-5α, 8α- (3,5-dioxo-4-phenyl-1,
2,4-triazolidino) -22-tetrahydropyraniloxy-23,24-dinorcola-6-ene (compound XVII) 3β-t-butyldimethylsilyloxy-5α, 8α- (3,5) obtained in Example 10. -Dioxo-4-phenyl-1,
2,4-triazolidino) -22-tetrahydropyraniloxy-23,24-dinorkola-1,6-diene (compound XV) 2.0 g
Was dissolved in 50 ml of chloroform, 2.0 g of m-chloroperbenzoic acid (m-CPBA) 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, and then dried over magnesium sulfate. Chloroform was distilled off to obtain 2.0 g of the title compound XVII. Yield 98% m / e 542 (M ⁺ -175); ¹ H NMR (CDCl ₃ ) δ = 7.43 (5H,
_{m, C 6 H 5),} 6.20,6.41 (2H, ABq, H-6, H-7), 4.91 (1
H, t, H-3), 4.49,4.57 (1H, s, CH (THP)), 3.37-3.
77 (4H, m, H- 22, CH 2 (THP)), 3.14~3.21 (2H, m, H-
1, H-2).

Example 13 3β-t-butyldimethylsilyloxy-1α, 2α-epoxy-5α, 8α- (3,5-dioxo-4-phenyl-1,
2,4-Triazolidino) -24-tetrahydropyraniloxy-cola-6-ene (compound XVIII) 3β-t-butyldimethylsilyloxy-5α, 8α- (3,5-dioxo-4) obtained in Example 11 −phenyl-1,
The procedure of Example 12 was repeated except that 630 mg of 2,4-triazolidino) -24-tetrahydropyraniloxy-chola-1,6-diene (compound XVI) was used, to give 590 mg of the title compound XVIII.
Obtained. Yield 92% ¹ H NMR (CDCl ₃ ) δ = 7.43 (5H, m, C ₆ H ₅ ), 6.21, 6.46
(2H, ABq, H-6, H-7), 4.97 (1H, m, H-3), 4.57 (1
H, s, CH (THP) ), 3.14~3.91 (4H, m, H-24, CH 2 (TH
P)), 3.14, 3.24 (2H, m, H-1, H-2).

Example 14 1α, 2α-Epoxy-3β-hydroxy-5α, 8α-
(3,5-dioxo-4-phenyl-1,2,4-triazolidino) -22-tetrahydropyraniloxy-23,24-dinorcola-6-ene (compound XIX) 3β-t- obtained in Example 12 Butyldimethylsilyloxy-1α, 2α-epoxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-triazolidino) -22-tetrahydropyraniloxy-23,24-dinorcola-6-ene 2.0 g of (Compound XVII) was dissolved in 40 ml of tetrahydrofuran, and 10 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, the extract was washed with brine, and the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate / chloroform = 1 /
Purification in 9) afforded 1.1 g of the title compound (XIX). Yield 65% m / e 428 (M ⁺ -175); ¹ H NMR (CDCl ₃ ) δ = 7.43 (5H,
_{m, C 6 H 5),} 6.17,6.40 (2H, ABq, H-6, H-7), 4.96 (1
H, t, H-3), 4.49, 4.57 (1H, s, CH (THP)), 3.39 ~
4.20 (4H, m, H- 22, CH 2 (THP)), 3.19 (2H, m, H-1, H-
2).

Example 15 1α, 2α-Epoxy-3β-hydroxy-5α, 8α-
(3,5-dioxo-4-phenyl-1,2,4-triazolidino) -24-tetrahydropyraniloxy-cola-6-ene (compound XX) 3β-t-butyldimethylsilyloxy obtained in Example 13 1α, 2α-epoxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-triazolidino) -24-tetrahydropyraniloxy-cola-6-ene (compound XVII
I) The procedure of Example 14 was repeated except for using 590 mg, to give 410 mg of the title compound XX. Yield 82% m / e 456 (M ⁺ -175); ¹ H NMR (CDCl ₃ ) δ = 7.43 (5H,
_{m, C 6 H 5),} 6.20,6.43 (2H, ABq, H-6, H-7), 5.00 (1
H, m, H-3), 4.57 (1H, s, CH (THP)), 3.30 to 3.90 (4
H, m, H-24, CH 2 (THP)), 3.17 (2H, m, H-1, H-2).

Example 16 22-Tetrahydropyraniloxy-23,24-dinorcola
5,7-Diene-1α, 3β-diol (compound XXI) 1α, 2α-epoxy-3 obtained in Example 14 was added to a mixture obtained by adding 2.0 g of LiAlH ₄ to 20 ml of tetrahydrofuran.
β-hydroxy-5α, 8α- (3,5-dioxo-4-phenyl-1,2,4-triazolidino) -22-tetrahydropyraniloxy-23,24-dinorcola-6-ene (compound X
IX) A solution of 1.1 g of tetrahydrofuran in 20 ml was added dropwise, and the mixture was heated under reflux for 2 hours. After excess LiAlH ₄ was decomposed by adding water to the reaction mixture, solids were removed and extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. Chloroform was distilled off to obtain 480 mg of the title compound. Yield 61% m / e 430 (M ⁺ ); ¹ H NMR (CDCl ₃ ) δ = 5.37,5.71 (2H,
m, H-6, H-7), 4.48, 4.57 (1H, m, CH (THP)), 4.07
(1H, bs, H-3), 3.40 to 3.91 (5H, H-1, H-22, CH ₂ (TH
P)).

Example 17 24-tetrahydropyraniloxy-chola-5,7-diene-
1α, 3β-diol (compound XXII) 1α, 2α-epoxy-3β-hydroxy-5α, 8α- (3,5-dioxo-4-phenyl- obtained in Example 15
The procedure of Example 16 was repeated except that 410 mg of 1,2,4-triazolidino) -24-tetrahydropyranyloxy) chola-6-ene (compound XX) was used to obtain 210 mg of the title compound XXII. Yield 71% mp. 118-121 ° C (methanol); m / e 458 (M ⁺ ); UV: λ
_max 282 nm (ε = 11,900, ethanol); ¹ H NMR (CDCl ₃ )
δ = 5.41, 5.76 (2H, m, H-6, H-7), 4.57 (1H, s, CH
(THP)), 4.09 (1H, m, H-3), 3.33-3.91 (5H, m, H
_{-1, H-24, CH 2} (THP)).

Example 18 1α, 3β-diacetoxy-23,24-dinorcola-5,7-dien-22-ol (compound XXV) 22-tetrahydropyraniloxy- obtained in Example 16
480 mg of 23,24-dinorkola-5,7-diene-1α, 3β-diol (compound XXI) was dissolved in 5 ml of pyridine, and acetic anhydride was added.
ml and heated to 80-90 ° C. for 1 hour. The reaction mixture was extracted with ethyl acetate, the extract was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and the ethyl acetate was distilled off to remove 1α, 3β-diacetoxy-22.
-Tetrahydropyraniloxy-23,24-dinorkola-5,7
-510 mg of a diene (compound XXIII) was obtained. Yield: 89% 510 mg of the compound XXIII thus obtained was dissolved in 10 ml of ethanol, 200 mg of pyridinium paratoluenesulfonate was added, and the mixture was reacted at 40 to 45 ° C. for 3 hours with stirring. After the reaction mixture was extracted with ethyl acetate and washed with brine, ethyl acetate was distilled off. The residue thus obtained was purified by silica gel chromatography (eluent: ethyl acetate / chloroform = 1/9) to give the title compound XXV
340 mg was obtained. Yield 80% mp.172-173 (ether / hexane); UV: λ _max 282 nm
(Ε = 12,000, ethanol); m / e 430 (M ⁺ ); ¹ H NMR (CD
Cl ₃ ) δ = 5.40, 5.69 (2H, m, H-6, H-7), 5.00 (2H,
m, H-1, H-3), 3.37, 3.64 (2H, m, H-22), 2.04, 2.
_{09 (6H, s, COCH 3} ).

Example 19 1α, 3β-Diacetoxy-colla-5,7-dien-24-ol (compound XXVI) 24-tetrahydropyraniloxy- obtained in Example 17
Colla-5,7-diene-1α, 3β-diol (compound XXI
I) The procedure of Example 18 was repeated except that 210 mg was used. In the middle of the reaction procedure, 1α, 3β-diacetoxy-24-tetrahydropyraniloxy-cola-5,7-diene (compound XXI)
V) 220 mg (90% yield) were obtained and the latter half of the procedure of Example 18 was repeated for this compound XXIV to give the title compound XXVI 1
40 mg were obtained. Yield 75% mp. 178-179 ° C (ether / hexane); m / e 485
(M ⁺ ); UV: λ _max 282 nm (ε = 11,700, ethanol); ¹ HN
MR (CDCl ₃ ) δ = 5.40, 5.69 (2H, m, H-6, H-7), 5.01
(2H, m, H-1, H-3), 3.63 (2H, t, H-24), 2.03,2.0
_{9 (6H, s, COCH 3} ).

Example 20 1α, 3β-diacetoxy-23,24-dinorkola-5,7-diene-22-al (compound XXVII) 1α, 3β-diacetoxy-23,24 obtained in Example 18
-Dinorcola-5,7-dien-22-ol (compound XXV)
Dissolve 50 mg in 10 ml of dichloromethane and add sodium acetate 15
0 mg and 100 mg of pyridinium chlorochromate were added and reacted at room temperature for 1 hour with stirring. After the reaction, insoluble materials were removed by filtration, and the solution was concentrated. The obtained residue was subjected to silica gel chromatography (eluent: chloroform / hexane =
Purification by 4/1) gave 30 mg of the title compound. Yield 60% mp. 133-135 ° C .; m / e 428 (M ⁺ ); UV: λ _max 282 nm (ε = 1
1,800, ethanol); ¹ H NMR (CDCl ₃ ) δ = 9.54 (1 H, d, C
HO), 5.40, 5.69 (2H, m, H-6, H-7), 5.01 (2H, m, H
-1, H-3), 2.03,2.09 (6H, s, COCH 3).

Example 21 1α, 3β-diacetoxy-colla-5,7-diene-24-al (compound XXVIII) 1α, 3β-diacetoxy-colla obtained in Example 19
The procedure of Example 20 was repeated except that 40 mg of 5,7-dien-24-ol (compound XXVI) was used to give 25 mg of the title compound XXVIII.
mg was obtained. Yield 63% mp. 167-168 ° C (ether / hexane); m / e 396 (M ⁺
—CH ₃ COOH); UV: λ _max 282 nm (ε = 11,800, ethanol); ¹ H NMR (CDCl ₃ ) δ = 9.71 (1H, s, CHO), 5.40, 5.
69 (2H, m, H-6, H = 7), 5.01 (2H, m, H-1, H-3), 2.
43,2.66 (2H, m, H- 23), 2.03 2.09 (6H, s, COCH 3).

Claims (5)

(57) [Claims] 1. The following formula (V) or (VI) (Where X is a protecting group for a hydroxyl group) 1,3,5,7
-Tetraene compounds. 2. The following formula (I) or formula (II) Of a 22- or 24-hydroxytriene compound represented by
Protecting the hydroxyl group at the 22- or 24-position, the following formula (III) or formula (IV) (Where X is a protecting group for a hydroxyl group), and then the compound of formula (III) or (IV) is subjected to an enol acetylation reaction using isopropenyl acetate to obtain the following formula (V) Or equation (VI) A method for producing a 1,3,5,7-tetraene compound represented by the formula: 3. The following formula (IX) or formula (X) A Diels-Alder type addition reaction product represented by 4. The following formula (I) or formula (II) Of a 22- or 24-hydroxytriene compound represented by
Protecting the hydroxyl group at the 22- or 24-position, the following formula (III) or formula (IV) (Where X is a protecting group for a hydroxyl group), and then the compound of formula (III) or (IV) is subjected to an enol acetylation reaction using isopropenyl acetate to obtain the following formula (V) Or equation (VI) And then subjecting the compound of formula (V) or (VI) to a reduction reaction to give the following formula (VII) or (VIII) And then converting the compound of formula (VII) or (VIII) to 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) A method for producing a Diels-Alder type addition reaction product represented by the formula: 5. The following formula (I) or formula (II) Of a 22- or 24-hydroxytriene compound represented by
Protecting the hydroxyl group at the 22- or 24-position, the following formula (III) or formula (IV) (Where X is a protecting group for a hydroxyl group), and then the compound of formula (III) or (IV) is subjected to an enol acetylation reaction using isopropenyl acetate to obtain the following formula (V) Or equation (VI) And then subjecting the compound of formula (V) or (VI) to a reduction reaction to give the following formula (VII) or (VIII) And then converting the compound of formula (VII) or (VIII) to 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) A compound which is a Diels-Alder type addition reaction product represented by the formula (IX) or (X), and the 3-position hydroxyl group of the compound is protected by a bulky protecting group to obtain the following formula (XI) or Formula (XII) (Where Y is a bulky hydroxyl-protecting group), and the compound of formula (XI) or (XII) is subsequently removed by removing the protecting group at the 22- or 24-position to give the following formula (XII
I) or formula (XIV) And subsequently the hydroxyl group at the 22- or 24-position of the compound of formula (XIII) or (XIV) is protected by a protecting group which is stable to LiAlH ₄ and tetrabutylammonium fluoride used in the subsequent step. Protect the following formula (XV) or formula (XVI) Wherein Z is a hydroxyl-protecting group stable to LiAlH ₄ and tetrabutylammonium fluoride, and then treating the compound of formula (XV) or (XVI) with m-chloroperbenzoic acid And then formula (XVII) or formula (XV
III) And a 1α, 2α-epoxy compound represented by the formula (XVII) or (XVIII):
The bulky protecting group of the hydroxyl group is treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran and deprotected to obtain the following formula (XIX) or (XX) And then subjecting this compound of formula (XIX) or (XX) to a reduction reaction using LiAlH ₄ to give the following formula (XXI) or (XXII) And then subjecting the 1- and 3-position hydroxyl groups of the compound of formula (XXI) or (XXII) to an acetylation reaction to give the following formula (XXIII) or (XXIV) ) (Where Ac represents an acetyl group), and then the compound of formula (XXIII) or (XXIV)
The following formula (XXV) or formula (XXVI) 1α, 3β-diacetoxy-23,24-dinorkola-5,7-dien-22-ol or 1α, 3β-diacetoxy-colla-5,7-dien-24-ol represented by the following formula: XXV) or the compound of formula (XXVI) is oxidized to give the following formula (XXVII) or formula (XXVIII) A method for producing 1α, 3β-diacetoxy-23,24-dinorkola-5,7-diene-22-al or 1α, 3β-diacetoxy-colla-5,7-diene-24-al represented by the formula: