JP3228488B2 - 20-Episteroid derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 20-episteroid derivative and a method for producing the same. The 20-episteroid derivative provided by the present invention has (1) an effect on cell differentiation and / or proliferation as compared with a 1α-hydroxyvitamin D derivative in which the configuration at position 20 is the same as a naturally occurring steroid. (2) greater selectivity that favors potent effects on cell differentiation and / or proliferation than effects on calcium metabolism, (3) stronger effects on interleukin production and activity And (4) greater selectivity to favor effects on interleukin production and activity than effects on calcium metabolism. (See Japanese Patent Publication No. 4-506351) 2
It is useful as a synthetic intermediate for a 0-epi-1α-hydroxyvitamin D derivative.

[0002]

2. Description of the Related Art Unlike steroids whose steric configuration at position 20 is widely present in nature, compounds that can be synthetic intermediates of 20-epi-1α-hydroxyvitamin D derivatives include, for example, tetrahedron (Tetrahedr).
on), 43, 4609-4619 (1987).
Year) or "The 8th Vitamin D Workshop Abstracts (Vitamin D; Proceedings o
f the EightthWorkshop on V
itamin D), A Double Norman, Earl Bouillon, M. Tomaset (AW Norma)
n, R. Bouillon, M .; Thomasset)
Hen, Walter de Gruita
Gruyter), pages 163-164 (1991)
1), 3 (R) -bis (t)
tert-butyldimethylsilyloxy) -20 (R)-
Formyl-9,10-Secopregna-5 (E), 7
(E), 10 (19) -triene [hereinafter, (20R)-
Aldehyde derivatives] are known.

[0003]

However, the above (20R) -aldehyde derivative is a compound having a transvitamin skeleton and is chemically more stable as an intermediate for synthesizing a 20-epi-1α-hydroxyvitamin D derivative. There is no known compound having a provitamin skeleton which is considered to be advantageous for the subsequent chemical conversion. Further, with regard to the method for producing the (20R) -aldehyde derivative, according to the method described in the above tetrahedron, the (20R) -aldehyde derivative has the same steric configuration at position 20 as steroids which are widely present in nature. 1
(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) -formyl-9,10-secopregna-5 (E), 7 (E), 10 (19) -triene [hereinafter , (20S) -aldehyde derivative] as a by-product of the (20S) -aldehyde derivative in a yield of only 5%. In the 8th Vitamin D Workshop Abstracts,
The (20S) -aldehyde derivative is treated with sodium hydroxide to give the (20S) -aldehyde derivative and (20R)-
A method of preparing a mixture of aldehyde derivatives (mixing ratio about 1: 1) is described. Therefore, in any of the production methods, it is necessary to separate a large amount of the (20S) -aldehyde derivative in order to isolate the (20R) -aldehyde derivative. It is hard to say that it is an advantageous method. Therefore, 20-epi-1α-
At present, it is desired to provide a compound having a provitamin skeleton, which is useful as a synthetic intermediate of a hydroxyvitamin D derivative, and an industrially advantageous method for producing the compound.

An object of the present invention, therefore, is to provide a compound useful as a synthetic intermediate for a 20-epi-1α-hydroxyvitamin D derivative. Another object of the present invention is to provide a method for producing the compound.

[0005]

According to the present invention, the above object is achieved by the following [1] General formula (I)

[0006]

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(Wherein R represents a formyl group or a hydroxymethyl group, and R ¹ and R ² are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group). This is 20-
It may be referred to as episteroid derivative (I). ),
[2] The following general formula (II)

[0008]

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(Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group) (hereinafter sometimes referred to as aldehyde derivative (II)). Is converted to an enolate by treating with a basic substance, and then selectively protonated by treating with a proton donor, and, if necessary, protecting or deprotecting a hydroxyl group. I-1)

[0010]

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Wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a protecting group for a hydroxyl group.
It may be referred to as 0-episteroid derivative (I-1). ), Wherein the 20-episteroid derivative (I-1) is reduced.
-2)

[0012]

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(Wherein R ⁵ and R ⁶ are as defined above) (hereinafter referred to as 20-episteroid derivative (I-2)
It may be called. And [4] the aldehyde derivative (II) is converted to an enolate by treating with a basic substance, and then selectively protonated by treating with a proton donor, and if necessary, protecting the hydroxyl group. Alternatively, 20-episteroid derivative (I-1) is obtained by deprotection, and then the 20-episteroid derivative (I-1) is reduced.
-It is achieved by providing a method for producing the episteroid derivative (I-2).

The 20-episteroid derivative (I-1) and the 20-episteroid derivative (I-2) are compounds included in the 20-episteroid derivative (I).

The general formulas (I), (I-1) and (I-
In 2) or (II), R ¹ , R ² , R ³ , R ⁴ ,
The hydroxyl-protecting group represented by each of R ⁵ and R ⁶ may be any known protecting group as long as it functions as a hydroxyl-protecting group. Specifically, (a) a formyl group,
Lower alkanoyl groups such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group; (b) halogen atoms such as chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group; An acetyl group substituted with: (c) a benzoyl group, a p-methoxybenzoyl group, p
An acyl group such as a benzoyl group which may have a substituent such as -nitrobenzoyl group; (a) a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group; A lower alkoxycarbonyl group such as a tert-butoxycarbonyl group; (b) an aryloxycarbonyl group such as a phenoxycarbonyl group or a p-nitrophenoxycarbonyl group; an alkenyloxycarbonyl group such as an alloxycarbonyl group; (A) trimethylsilyl, triethylsilyl, triisopropylsilyl, ter
trisubstituted silyl groups such as trialkylsilyl groups such as t-butyldimethylsilyl group; (b) alkyldiarylsilyl groups such as tert-butyldiphenylsilyl group;
Having a substituent such as a methoxymethyl group, a 2-ethoxyethyl group, a 2-methoxyethoxymethyl group, a 2-methoxy-2-isopropyl group, a benzyloxymethyl group, a 2-tetrahydropyranyl group, or a 2-tetrahydrofuranyl group; An oxymethyl group which may be substituted.

The conversion of the aldehyde derivative (II) to the 20-episteroid derivative (I-1) is carried out by treating the aldehyde derivative (II) with a basic substance to convert it to an enolate and then protonating it with a proton donor. It is done by doing.

The basic substance used in such a reaction includes metal hydrides such as sodium hydride and potassium hydride; lithium amide, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium Metal amides such as tetramethylpiperazide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide; and metal alkoxides such as potassium tert-butoxide and sodium tert-amyloxide.

The amount of the basic substance used is not particularly limited as long as the aldehyde derivative (II) can be converted into an enolate, but it is usually 0.8 to 20 mol per mol of the aldehyde derivative (II). Preferably 1 to 5
Within the molar range.

The basic substance to be used may be in any form as long as it does not adversely affect the reaction, for example, the basic substance itself, a solution in a suitable organic solvent, a dispersion in mineral oil, and the like. Can also be used.

The proton donor used in such a reaction includes carboxylic acids such as acetic acid, propionic acid and trifluoroacetic acid; inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid;
Sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid; ammonium chloride, p
Salts such as pyridinium toluenesulfonate;

The amount of the proton donor used depends on the amount of the basic substance 1
It is usually within a range of 0.8 to 50 mol, preferably 1 to 20 mol, per mol.

The form of the proton donor used may be any as long as it does not adversely affect the reaction. For example, the proton donor itself, a solution in water or a suitable organic solvent can be used.

The reaction is usually carried out in a solvent, and the solvent used is a solvent such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, toluene, benzene, dimethylformamide, dimethylsulfoxide or the like. A mixed solvent is used, and its amount is usually in the range of about 5 to 200 times by weight based on the aldehyde derivative (II).

Hexamethylphosphoric triamide, N, N'-dimethylimidazolidinone, tetramethylethylenediamine, 1,4-diazabicyclo [2.
2.2] It is also possible to add a compound capable of forming a complex with a metal ion such as octane, and the amount used is usually in the range of about 1 to 50 mol per 1 mol of the aldehyde derivative (II). .

The reaction temperature is appropriately selected depending on the type of the basic substance and the proton donor to be used.
It is carried out at a temperature in the range from 100 ° C to 30 ° C. It is also possible to carry out the reaction at which the basic substance acts on the aldehyde derivative (II) and the reaction at which the proton donor subsequently acts at different temperatures.

The reaction will be described in more detail. The reaction mixture prepared by adding the solution of the aldehyde derivative (II) to the basic substance or adding the solution of the basic substance to the solution of the aldehyde derivative (II) is subjected to an inert gas atmosphere such as nitrogen or argon. After stirring for 5 minutes to 10 hours, a proton donor or a solution thereof is added, and the mixture is further stirred for 5 minutes.
By stirring for 2 to 2 hours, the 20-episteroid derivative (I-1) is obtained.

The thus obtained 20-episteroid derivative (I-1) can be isolated and purified from the reaction mixture by a method generally used in the isolation and purification of organic compounds. For example, the reaction mixture is poured into ice water, extracted with an organic solvent such as diethyl ether or ethyl acetate, and, if necessary, the resulting extract is washed with diluted hydrochloric acid, aqueous sodium bicarbonate, water and saline to obtain an acidic substance or a base. And water-soluble substances. Then, after drying using anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., a crude product is obtained by distilling off the solvent,
The 20-episteroid derivative (I-1) can be obtained by recrystallization and purification by chromatography as needed. Further, the crude product of the 20-episteroid derivative (I-1) can be used for the next reaction without purification.

The aldehyde derivative (II) used as a raw material for synthesis in such a reaction can be produced, for example, according to the method described in International Patent Application Publication No. 88/07545.

20-Episteroid derivative (I-1)
Can be converted to a 20-epi-1α, 25-dihydroxyvitamin D derivative by the following method, for example.

[0030]

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(Wherein, R ⁵ and R ⁶ are as defined above, Ph represents a phenyl group, and TES represents a triethylsilyl group.)

That is, the 20-episteroid derivative (I
-1), in the presence of a basic substance,
Organic chemistry (Journal of
Organic Chemistry), 53 volumes, 34
The sulfone represented by the formula (III), which can be prepared by the method described on pages 75 to 3465 (1988), is condensed, the resulting product is acetylated, and then subjected to a reductive elimination reaction with sodium amalgam. And deprotection of a hydroxyl group to give a compound of the formula (IV)
0-epi-1α, 25-dihydroxyprovitamin D ₂
Convert to This can be converted into 20-epi-1α, 25-dihydroxyvitamin D _{2 represented} by the formula (V) by subjecting it to an isomerization step by ultraviolet irradiation and thermal energy according to a conventional method.

Conversion of the 20-episteroid derivative (I-1) to the 20-episteroid derivative (I-2)
It is carried out by subjecting the 20-episteroid derivative (I-1) to a reduction reaction. The purified 20-episteroid derivative (I-1) can be used for the reaction, or the crude product can be used for the reaction without purification.

The reaction may be carried out by adding a solution of the 20-episteroid derivative (I-1) to the solution or suspension of the reducing agent which is cooled as required, or cooling the solution of the 20-episteroid derivative as necessary. The reaction is carried out by adding a reducing agent or a solution or suspension thereof to the solution of (I-1), and stirring the resulting reaction mixture under an atmosphere of an inert gas such as nitrogen or argon.

Examples of the reducing agent include sodium borohydride, lithium borohydride, potassium borohydride, zinc borohydride, calcium borohydride, lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, And diisobutylaluminum hydride.

The amount of the reducing agent used depends on the type of the reducing agent used, but the amount of the 20-episteroid derivative (I-
1) It is usually used in the range of 0.25 mol to 20 mol per 1 mol.

The reaction temperature varies depending on the reducing agent used, but is usually at a temperature in the range of -100 ° C to 70 ° C.

The reaction is usually carried out in a solvent. The solvent used depends on the nature of the reducing agent, but includes ethanol, methanol, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dioxane, toluene, dichloromethane and the like. Or a mixed solvent thereof. The amount of the solvent used is usually in the range of 5 to 200 times by weight based on the 20-episteroid derivative (I-1).

The isolation and purification of the 20-episteroid derivative (I-2) from the reaction mixture can be carried out by a method generally used in the isolation and purification of organic compounds. For example, if necessary, water, diluted hydrochloric acid, aqueous sodium hydroxide solution, etc. are added to the cooled reaction mixture to decompose excess reducing agent, insolubles are filtered off if necessary, and the filtrate is diluted with water as needed. After that, extraction with an organic solvent such as diethyl ether, ethyl acetate, or dichloromethane, and the resulting extract, if necessary, is washed with diluted hydrochloric acid, aqueous sodium bicarbonate, water, and a saline solution to obtain an acidic substance, a basic substance, and an aqueous solution. Remove toxic substances. Next, after drying using anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., a crude product is obtained by distilling the solvent, and recrystallization as necessary.
The 20-episteroid derivative (I-2) can be obtained by purifying by chromatography. Further, the crude product of the 20-episteroid derivative (I-2) can be used for the next reaction without purification.

The thus obtained 20-episteroid derivative (I-2) can be converted into a 20-epi-1α, 25-dihydroxyvitamin D derivative by the following method, for example.

[0041]

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(Wherein, R ⁵ and R ⁶ are as defined above, THP represents a 2-tetrahydropyranyl group, Me represents a methyl group, and Ts represents a p-toluenesulfonyl group.)

That is, the 20-episteroid derivative (I
After tosylation of the side-chain hydroxyl group of -2), the hydroxyl group is protected, deprotected or re-protected as required, thereby converting into the compound represented by the formula (VI). This is reacted with a Grignard reagent represented by the formula (VII) in the presence of a copper salt catalyst, followed by deprotection and methylation of a ketone to give a 20-epi-1,25-dihydroxy provitamin D represented by the formula (VIII). Convert to ₃ . This can be converted to 20-epi-1,25-dihydroxyvitamin D ₃ represented by the formula (IX) by subjecting it to an isomerization step by irradiation with ultraviolet light and heat energy according to a conventional method.

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (20S) -1α, 3β-bis (methoxycarbonyloxy) -20-methylpregna-5,7-diene-21
Dissolve 1.05 g (2.28 mmol) of Earle in 14 ml of a mixed solvent of hexamethylphosphoric triamide and tetrahydrofuran (volume ratio 2: 5), and stir at 0 ° C. while stirring 91 mg of sodium hydride (60% dispersion in mineral oil). object,
2.28 mmol) was added. After the reaction solution was stirred at 0 ° C. for 4 hours, it was added dropwise over 25 minutes to 41.5 ml of a mixture of acetic acid and ethyl acetate (volume ratio: 1.5: 40) cooled to 0 ° C. The obtained mixture was sequentially washed with water, a 5% aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The residue obtained after distilling off the solvent was purified by column chromatography [silica gel (60 g), eluted with a solution of ethyl acetate in benzene (1%)].
0R) -1α, 3β-bis (methoxycarbonyloxy) -20-methylpregna-5,7-diene-21
720 mg (yield 69%) were obtained.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.62 (3H, s),
1.00 (3H, s), 1.05 (3H, d, J = 6.
9Hz), 3.77 (3H, s), 3.79 (3H,
s), 4.83 (1H, m), 4.90 (1H, m),
5.39 (1H, m), 5.68 (1H, m), 9.5
5 (1H, d, J = 4.9 Hz).

Example 2 (20S) -1α, 3β-bis (methoxycarbonyloxy) -20-methylpregna-5,7-diene-21
The reaction and separation procedure were carried out in the same manner as in Example 1 using 1.05 g of arel to give 705 mg of (20
R) -1α, 3β-bis (methoxycarbonyloxy)
-20-Methylpregna-5,7-dien-21-al was obtained. This was dissolved in 15 ml of ethanol, and 63 mg of sodium borohydride was added thereto under ice cooling.
Stirred for minutes. Excess reducing agent was decomposed by adding 1N hydrochloric acid to the reaction mixture, and the reaction mixture was poured into a mixture of ice and saline. The resulting mixture was extracted with ethyl acetate, and the extract was washed with brine. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography [silica gel (20 g), eluted with a solution of ethyl acetate in n-hexane (20 to 50%)] to give (20R)-
1α, 3β-bis (methoxycarbonyloxy) -20
-Methylpregna-5,7-dien-21-ol 68
3 mg (total yield 65%) was obtained.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.70 (3H, s),
1.05 (3H, s), 1.07 (3H, d, J = 6.
8 Hz), 3.40 (1H, dd, J = 10.3, 6.
7 Hz), 3.70-3.80 (1H), 3.79 (3
H, s), 3.79 (3H, s), 4.84 (1H, b
rs), 4.90 (1H, m), 5.38 (1H,
m), 5.68 (1H, m).

Example 3 (20S) -3β-tert-butyldimethylsilyloxy-1α-hydroxy-20-methylpregna-5,
1.02 g (2.22 mmol) of 7-diene-21-al is dissolved in 14 ml of a mixed solvent of N, N'-dimethylimidazolidinone and tetrahydrofuran (volume ratio 2: 5), and the mixture is stirred at -40 ° C. 4.5 ml of a 1 N solution of lithium diisopropylamide in tetrahydrofuran (4.5
0 mmol) was added. After the reaction solution was stirred at -40 ° C for 4 hours, it was added dropwise over 20 minutes to 40 ml (1: 8 by volume) of a mixture of a saturated ammonium chloride aqueous solution and tetrahydrofuran cooled to -10 ° C. The aqueous layer of the obtained mixture was separated, and the organic layer was sequentially washed with a 5% aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The residue obtained after distilling off the solvent was purified by column chromatography [silica gel (60 g), eluted with ethyl acetate in n-hexane (3-35%)],
(20R) -3β-tert-butyldimethylsilyloxy-1α-hydroxy-20-methylpregna-5,
632 mg (62% yield) of 7-diene-21-al was obtained.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.08 (6H, s),
0.63 (3H, s), 0.89 (9H, s), 0.9
2 (3H, s), 1.06 (3H, d, J = 6.7H
z), 3.73 (1H, brs), 4.03 (1H,
m), 5.39 (1H, m), 5.70 (1H, m),
9.57 (1H, d, J = 4.9 Hz).

Example 4 (20S) -3β-tert-butyldimethylsilyloxy-1α-hydroxy-20-methylpregna-5,
Example 3 Using 1.02 g of 7-diene-21-al
By performing the reaction and separation operations in the same manner as in
30 mg of (20R) -3β-tert-butyldimethylsilyloxy-1α-hydroxy-20-methylpregna-5,7-dien-21-al were obtained. This was dissolved in 15 ml of tetrahydrofuran, cooled to −30 ° C., and 102 mg of lithium aluminum hydride was added.
Stir for 15 minutes. A saturated aqueous sodium sulfate solution was added to the reaction mixture to decompose excess reducing agent, and insolubles were filtered off using celite. The insoluble material was washed with ethyl acetate, the washing solution was combined with the filtrate, and the solvent was distilled off. The residue was subjected to column chromatography [silica gel (20 g), ethyl acetate n
-Elution with a hexane solution (20 to 50%)] to give (20R) -3β-tert-butyldimethylsilyloxy-1α-hydroxy-20-methylpregna-
615 mg of 5,7-dien-21-ol (total yield 6
0%).

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): -0.02 (6H,
s), 0.55 (3H, s), 0.80 (9H, s),
0.85 (3H, s), 0.88 (3H, d, J = 6.
7 Hz), 3.41 (1H, dd, J = 10.4, 6.
7Hz), 3.64 (3H), 3.94 (1H, m),
5.29 (1H, m), 5.61 (1H, m).

Example 5 977 mg of (20S) -1α, 3β-diacetoxy-20-methylpregna-5,7-dien-21-al
(2.28 mmol) was dissolved in 10 ml of tetrahydrofuran, 4.0 ml (2.40 mmol) of a 0.6 N toluene solution of sodium bis (trimethylsilyl) amide was added dropwise over 10 minutes while cooling to −50 ° C. and stirring. . After the temperature of the reaction mixture was raised to -30 ° C over 2 hours, it was cooled again to -50 ° C. P-
5.5 ml of a diethyl ether solution of 548 mg (2.88 mmol) of toluenesulfonic acid monohydrate was added dropwise over 5 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. After the aqueous layer was extracted with ethyl acetate, all the organic layers were combined and washed with brine.
After drying over anhydrous sodium sulfate and evaporating the solvent,
The residue was subjected to column chromatography [silica gel (60
g), eluted with a solution of ethyl acetate in benzene (1-3%)]
To give 655 mg (yield 67%) of (20R) -1α, 3β-diacetoxy-20-methylpregna-5,7-dien-21-al.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.62 (3H, s),
1.00 (3H, s), 1.05 (3H, d, J = 6.
7 Hz), 2.03 (3H, s), 2.08 (3H,
s), 4.99 (2H, m), 5.40 (1H, m),
5.68 (1H, m), 9.55 (1H, d, J = 4.
9 Hz).

Example 6 Using 977 mg of (20S) -1α, 3β-diacetoxy-20-methylpregna-5,7-dien-21-al, the reaction and separation were carried out in the same manner as in Example 5 to obtain 650 mg. (20R) -1α, 3β-diacetoxy-20-methylpregna-5,7-diene-
21-R was obtained. This was dissolved in ethanol (15 ml), and sodium borohydride (60 mg) was added thereto under ice cooling.
Stirred for 20 minutes. 1N hydrochloric acid was added to the reaction mixture to decompose excess reducing agent, and the reaction mixture was poured into a mixture of ice and saline. The resulting mixture was extracted with ethyl acetate, and the extract was washed with brine. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography [silica gel (20 g), eluted with n-hexane solution of ethyl acetate (20 to 50%)] to give (20R)
-1α, 3β-diacetoxy-20-methylpregna
608 mg of 5,7-dien-21-ol (total yield 6
2%).

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.64 (3H, s),
0.97 (3H, d, J = 6.7 Hz), 1.01 (3
H, s), 2.04 (3H, s), 2.08 (3H,
s), 3.49 (1H, dd, J = 11.0, 6.7H
z), 3.73 (1H, dd, J = 11.0, 3.7H
z), 4.98 (2H), 5.41 (1H, m), 5.
68 (1H).

Example 7 1.20 g (2.28 mmol) of (20S) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-dien-21-al It was dissolved in 14 ml of a mixed solvent of holic triamide and tetrahydrofuran (volume ratio 2: 5), and 267 mg of potassium tert-butoxide was stirred at 0 ° C.
(2.38 mmol) was added. After the reaction solution was stirred at 0 ° C. for 3 hours, it was added dropwise over 30 minutes to 42 ml of a mixture of acetic acid and ethyl acetate (volume ratio: 1.5: 40) cooled to 0 ° C. The obtained mixture was sequentially washed with water, a 5% aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to column chromatography [silica gel (60 g), ethyl acetate n
-Elution with hexane solution (2-20%)]
815 mg (70% yield) of (20R) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-dien-21-al was obtained.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.62, 0.64 (3
H, d, s), 0.92 (3H), 1.05 (3H,
d, J = 6.7 Hz), 3.3-3.7 (2H), 3.
7-4.3 (5.5H), 4.5-4.9 (1.5
H), 5.1-5.5 (1H), 5.36 (1H),
5.63 (1H), 9.6 (1H).

Example 8 The procedure of Example 4 was repeated, using 1.17 g of (20S) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-dien-21-al. By performing the reaction and the separation operation, 810 mg of (20R) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-dien-21-al was obtained. This was dissolved in 15 ml of ethanol, 65 mg of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. Excess reducing agent was decomposed by adding 1N hydrochloric acid to the reaction mixture, and the reaction mixture was poured into a mixture of ice and saline. The resulting mixture was extracted with ethyl acetate, and the extract was washed with brine. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography [silica gel (20 g), eluted with a solution of ethyl acetate in n-hexane (20 to 50%)].
R) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-diene-21
790 mg (total yield 67%) of all were obtained.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.64 (3H, s),
0.93 (3H, s), 0.98 (3H, d, J = 6.
7 Hz), 3.3-4.2 (8H), 4.6-4.9
(1.3H), 5.1-5.4 (0.7H), 5.35
(1H, m), 5.63 (1H, m).

[0061]

The synthetic intermediate of a 20-epi-1α-hydroxyvitamin D derivative having excellent activity as compared with a 1α-hydroxyvitamin D derivative having the same steric configuration at position 20 as naturally occurring steroids. And a method for producing the same are provided.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07J 9/00 C07J 75/00 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound represented by the following general formula (I) (Wherein, R represents a formyl group or a hydroxymethyl group, and R ¹ and R ² are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group). 2. The following general formula (II): Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a protecting group for a hydroxyl group. The steroid aldehyde derivative is converted to an enolate by treating with a basic substance, and then with a proton donor. The compound is selectively protonated by treatment, and protection or deprotection of a hydroxyl group is performed, if necessary, in the following general formula (I-1): (Wherein, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group).
-A method for producing episteroid derivatives. 3. The following general formula (I-1): (Wherein, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group).
-Reducing an episteroid derivative, represented by the following general formula (I-2): (In the formula, R ⁵ and R ⁶ are as defined above.)
A method for producing a 20-episteroid derivative represented by the formula: 4. The following general formula (II): Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a protecting group for a hydroxyl group. The steroid aldehyde derivative is converted to an enolate by treating with a basic substance, and then with a proton donor. The resulting compound is selectively protonated by treatment and, if necessary, protected or deprotected by a hydroxyl group to obtain a compound represented by the following general formula (I-1). (Wherein, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group).
-Reducing the 20-episteroid derivative, and then reducing the 20-episteroid derivative, represented by the following general formula (I-2): (In the formula, R ⁵ and R ⁶ are as defined above.)
A method for producing a 20-episteroid derivative represented by the formula: