JPH07188281A - 20-episteroid derivative and production thereof - Google Patents

Abstract

PURPOSE:To obtain a novel 20-episteroid derivative which is useful as a synthetic intermediate for 20-epi-1alpha-hydroxyvitamin D derivatives which has an excellent action on cellular differentiation. CONSTITUTION:A compound is expressed by formula I (R is formyl, hydroxymethyl; R<1>, R<2> are H, a protected hydroxyl group), for example, (20 R)-1alpha,3beta-bis(methoxycarbonyloxy)-20-methylpregna-5,7-diene-21-al. The compound of formula I is obtained by, for example, treating a sterol aldehyde derivative of formula II (R<3>, R<4> are H, a protected hydroxyl group) with a basic substance to effect conversion into the enolate, then treating the enolate with a proton donor to effect selective protonation, when needed, followed by protection or deprotection of hydroxyl groups.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION 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 the 1α-hydroxyvitamin D derivative, which has the same configuration as the steroids in which the configuration at the 20-position is widespread in nature. Is stronger, (2) has a higher selectivity than a strong effect on cell differentiation and / or proliferation than an effect on calcium metabolism, and (3) has a stronger effect on interleukin production and activity. It is reported that one or more advantages of (4) higher selectivity for predominant effects on interleukin production and activity over effects on calcium metabolism are observed. Yes (see Japanese Patent Publication No. 4-506351)
It is useful as a synthetic intermediate for 0-epi-1α-hydroxyvitamin D derivatives.

[0002]

BACKGROUND OF THE INVENTION Unlike steroids in which the configuration at the 20-position is widespread in nature, examples of compounds that can be synthetic intermediates for 20-epi-1α-hydroxyvitamin D derivatives include tetrahedron (Tetrahedr).
on), 43, 4609-4619 (1987).
Year), or "8th Vitamin D Workshop Abstracts (Vitamin D; Proceedings o
f the EightWorkshop on V
itamin D) ", A Double Norman, Earl Bouillon, M Tomasett (AW Norma)
n, R.N. Bouillon, M .; Thomasasset)
Edited by Walter de Gruite
Gruyter, pp. 163-164 (1991).
Year)), 1 (S), 3 (R) -bis (t
ert-butyldimethylsilyloxy) -20 (R)-
Formyl-9,10-secopregna-5 (E), 7
(E), 10 (19) -triene [hereinafter, (20R)-
Aldehyde derivative] and the like are known.

[0003]

However, the above (20R) -aldehyde derivative is a compound having a transvitamin skeleton and is chemically more stable as a synthetic intermediate of a 20-epi-1α-hydroxyvitamin D derivative. However, no compound having a provitamin skeleton, which is considered to be advantageous for the subsequent chemical conversion, is known. Further, regarding the method for producing the (20R) -aldehyde derivative, according to the method described in the above tetrahedron, the (20R) -aldehyde derivative has the same configuration as the steroids in which the configuration at the 20-position is 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 referred to as , (20S) -aldehyde derivative] is produced as a by-product of the (20S) -aldehyde derivative in a yield of only 5%. In addition, in the 8th Vitamin D Workshop Abstracts,
The (20S) -aldehyde derivative and (20R)-
A method for preparing a mixture of aldehyde derivatives (mixing ratio of about 1: 1) is described. Therefore, in any of the production methods, in order to isolate the (20R) -aldehyde derivative, it is necessary to separate a large amount of the (20S) -aldehyde derivative. It is hard to say that this 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 for a hydroxyvitamin D derivative, and an industrially advantageous method for producing the compound.

Accordingly, one object of the present invention is to provide a compound useful as a synthetic intermediate for 20-epi-1α-hydroxyvitamin D derivatives. 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 [1] the following general formula (I):

[0006]

[Chemical 9]

(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 group-protecting group). 20-
It may be referred to as an episteroid derivative (I). ),
[2] The following general formula (II)

[0008]

[Chemical 10]

(In the formula, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) (Hereinafter, this may be 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 a hydroxyl group is protected or deprotected as necessary. I-1)

[0010]

[Chemical 11]

(In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) A 20-episteroid derivative (hereinafter, referred to as 2
Sometimes referred to as 0-episteroid derivative (I-1). [3] 20-episteroid derivative (I-1) is reduced, the following general formula (I)
-2)

[0012]

[Chemical 12]

(In the formula, R ⁵ and R ⁶ are as defined above.) (20-episteroid derivative (I-2)
Sometimes called. ), And the [4] aldehyde derivative (II) is converted to an enolate by treating with a basic substance, and then treated with a proton donor to selectively protonate, and if necessary, protection of a hydroxyl group. Alternatively, deprotection is performed to obtain a 20-episteroid derivative (I-1), and then the 20-episteroid derivative (I-1) is reduced.
-Achieved by providing a method for producing an 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 above general formulas (I), (I-1) and (I-
2) or (II), R ¹ , R ² , R ³ , R ⁴ ,
The hydroxyl-protecting group represented by R ⁵ and R ⁶ may be any conventionally known protecting group as long as it functions as a hydroxyl-protecting group. Specifically, (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) benzoyl group, p-methoxybenzoyl group, p
-Acyl group such as benzoyl group which may have a substituent such as nitrobenzoyl group; (a) methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group Group, lower alkoxycarbonyl group such as tert-butoxycarbonyl group; (b) aryloxycarbonyl group such as phenoxycarbonyl group and p-nitrophenoxycarbonyl group; oxycarbonyl group such as alkenyloxycarbonyl group such as allyloxycarbonyl group ; (A) Trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, ter
a trialkylsilyl group such as t-butyldimethylsilyl group; (b) a trisubstituted silyl group such as an alkyldiarylsilyl group such as tert-butyldiphenylsilyl group;
It has a substituent such as methoxymethyl group, 2-ethoxyethyl group, 2-methoxyethoxymethyl group, 2-methoxy-2-isopropyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group. Oxymethyl group which may be present, and the like.

The conversion of the aldehyde derivative (II) into the 20-episteroid derivative (I-1) is performed by treating the aldehyde derivative (II) with a basic substance to convert it into 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 and lithium. Examples thereof include 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 it can convert the aldehyde derivative (II) into an enolate, but is usually 0.8 to 20 mol per 1 mol of the aldehyde derivative (II), Preferably from 1 to 5
Within the molar range.

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

As the proton donor used in such a reaction, 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, camphorsulfonic acid; ammonium chloride, p
-Salts such as pyridinium toluenesulfonate, and the like.

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

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

The reaction is usually carried out in a solvent, and as the solvent to be used, a solvent such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, toluene, benzene, dimethylformamide, dimethylsulfoxide, or the like. A mixed solvent can be mentioned, and the amount thereof is usually in the range of about 5 to 200 times by weight with respect to 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 within 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 basic substance and proton donor used, but it is usually −
It is carried out at a temperature in the range of 100 ° C to 30 ° C. It is also possible to carry out the reaction of reacting the basic substance on the aldehyde derivative (II) and the reaction of subsequently reacting the proton donor 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 the solution of the basic substance to the solution of the aldehyde derivative (II) is placed under an atmosphere of an inert gas such as nitrogen or argon. After stirring for 5 minutes to 10 hours, the proton donor or a solution thereof is added, and the mixture is further added to
The 20-episteroid derivative (I-1) is obtained by stirring for 2 hours from the minute.

Isolation / purification of the 20-episteroid derivative (I-1) thus obtained from the reaction mixture can be carried out by a method used in the usual isolation / 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 the resulting extract is washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate, water, or saline as necessary to prepare an acidic substance or a base. Removes soluble substances and water-soluble substances. Then dried over anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., the solvent is distilled off to obtain a crude product,
The 20-episteroid derivative (I-1) can be obtained by recrystallizing and purifying by chromatography, if necessary. Further, the 20-episteroid derivative (I-1) can be used as a crude product in the next reaction without purification.

The aldehyde derivative (II) used as a synthetic raw material 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 into a 20-epi-1α, 25-dihydroxyvitamin D derivative by the following method, for example.

[0030]

[Chemical 13]

(In the formula, 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 basic substances, Journal of
Organic chemistry (Journal of
Organic Chemistry), 53, 34
75-3465 (1988), the sulfone of formula (III) can be condensed and the resulting product is acetylated, followed by reductive elimination reaction with sodium amalgam. By further deprotecting the hydroxyl group, 2 represented by 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 this to UV irradiation and an isomerization step by heat energy according to a conventional method.

The conversion of the 20-episteroid derivative (I-1) into the 20-episteroid derivative (I-2) is as follows:
It is carried out by subjecting the 20-episteroid derivative (I-1) to a reduction reaction. A purified 20-episteroid derivative (I-1) can be used in the reaction, or a crude product can be directly used in the reaction without purification.

Such a reaction is carried out by adding a solution of the 20-episteroid derivative (I-1) to a solution or suspension of a reducing agent which is cooled as necessary, or by cooling the solution of the 20-episteroid derivative if necessary. The reducing agent or its solution or suspension is added to the solution of (I-1), and the resulting reaction mixture is stirred 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, Examples thereof include diisobutylaluminum hydride.

The amount of the reducing agent used varies depending on the kind of the reducing agent used, but it is 20-episteroid derivative (I-
1) It is usually used within the range of 0.25 to 20 mol per 1 mol.

The reaction temperature will differ depending on the reducing agent used, but it is usually carried out at a temperature within the range of -100 ° C to 70 ° C.

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

Isolation / purification of the 20-episteroid derivative (I-2) from the reaction mixture can be carried out by a method used in the usual isolation / purification of organic compounds. For example, if necessary, water, diluted hydrochloric acid, sodium hydroxide aqueous solution, etc. are added to the cooled reaction mixture to decompose excess reducing agent, insoluble matter is filtered off if necessary, and the filtrate is diluted with water as necessary. After that, extract with an organic solvent such as diethyl ether, ethyl acetate, or dichloromethane, and wash the resulting extract with diluted hydrochloric acid, aqueous sodium hydrogen carbonate, water, or saline, if necessary. Remove volatile substances. Then dried over anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., to obtain a crude product by distilling off the solvent, recrystallization as necessary,
The 20-episteroid derivative (I-2) can be obtained by purification by chromatography. Further, the 20-episteroid derivative (I-2) can be used as a crude product in the next reaction without purification.

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

[0041]

[Chemical 14]

(In the formula, 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
The side chain hydroxyl group of -2) is tosylated, and then the hydroxyl group is optionally protected, deprotected or reprotected to be converted to 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 to carry out deprotection and methylation of the ketone to obtain the 20-epi-1,25-dihydroxyprovitamin D represented by the formula (VIII). Convert to ₃ . Which can be converted according to conventional methods ultraviolet irradiation, by going through the isomerization step by thermal energy to the 20-epi -1,25- dihydroxyvitamin D ₃ represented by the formula (IX).

Hereinafter, the present invention will be specifically described 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
-Ar 1.05 g (2.28 mmol) was dissolved in 14 ml of a mixed solvent of hexamethylphosphoric triamide and tetrahydrofuran (volume ratio 2: 5), and sodium hydride 91 mg (60% mineral oil dispersion while stirring at 0 ° C). object,
2.28 mmol) was added. The reaction solution was stirred at 0 ° C. for 4 hours and then added dropwise to 41.5 ml of a mixture of acetic acid and ethyl acetate (volume ratio 1.5: 40) cooled to 0 ° C. over 25 minutes. The obtained mixture was washed successively with water, 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 benzene solution of ethyl acetate (1%)], and (2
0R) -1α, 3β-Bis (methoxycarbonyloxy) -20-methylpregna-5,7-diene-21-
Earl 720 mg (yield 69%) was obtained.

Proton nuclear magnetic resonance spectrum (deuteriochloroform) 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
-By carrying out the reaction and separation operation in the same manner as in Example 1 using 1.05 g of Earl, 705 mg of (20
R) -1α, 3β-bis (methoxycarbonyloxy)
-20-Methylpregna-5,7-diene-21-al was obtained. Dissolve this in 15 ml of ethanol, add 63 mg of sodium borohydride under ice cooling, and add 30
Stir for 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 brine. The resulting mixture was extracted with ethyl acetate and the extract was washed with brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, the residue was purified by column chromatography [silica gel (20 g), eluted with ethyl acetate in n-hexane solution (20 to 50%)], and (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 was dissolved in 14 ml of a mixed solvent of N, N′-dimethylimidazolidinone and tetrahydrofuran (volume ratio 2: 5) and stirred at −40 ° C. 4.5 ml of 1N tetrahydrofuran solution of lithium diisopropylamide (4.5 ml
0 mmol) was added. The reaction solution was stirred at -40 ° C for 4 hours and then added dropwise to 40 ml of a mixture of a saturated aqueous ammonium chloride solution and tetrahydrofuran cooled to -10 ° C (volume ratio 1: 8) over 20 minutes. The aqueous layer of the obtained mixture was separated, and the organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was purified by column chromatography [silica gel (60 g), eluted with ethyl acetate in n-hexane solution (3-35%)],
(20R) -3β-tert-butyldimethylsilyloxy-1α-hydroxy-20-methylpregna-5
632 mg of 7-diene-21-al was obtained (yield 62%).

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, br s), 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 7-diene-21-are
By performing the reaction and the separation operation in the same manner as
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 and cooled to -30 ° C, and then 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 the insoluble matter was 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
-Eluted with hexane solution (20 to 50%)] and purified with (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 (20S) -1α, 3β-diacetoxy-20-methylpregna-5,7-diene-21-are 977 mg
(2.28 mmol) was dissolved in 10 ml of tetrahydrofuran, 4.0 ml (2.40 mmol) of a 0.6N toluene solution of sodium bis (trimethylsilyl) amide was added dropwise over 10 minutes while cooling to -50 ° C and stirring. . The reaction mixture was heated to -30 ° C over 2 hours and then cooled again to -50 ° C. P- in the reaction mixture
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 saturated aqueous sodium hydrogen carbonate solution, 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 benzene solution of ethyl acetate (1-3%)]
Purification by (20R) -1α, 3β-diacetoxy-20-methylpregna-5,7-diene-21-al to give 655 mg (yield 67%).

Proton nuclear magnetic resonance spectrum (deuteriochloroform) Chemical shift (ppm): 0.62 (3H, s),
1.00 (3H, s), 1.05 (3H, d, J = 6.
7Hz), 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 (20S) -1α, 3β-diacetoxy-20-methylpregna-5,7-diene-21-al 977 mg was used to carry out a reaction and a separation operation in the same manner as in Example 5 to obtain 650 mg. (20R) -1α, 3β-diacetoxy-20-methylpregna-5,7-diene-
21-are obtained. Dissolve this in 15 ml of ethanol, add 60 mg of sodium borohydride under ice cooling,
Stir 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 evaporated and the residue was purified by column chromatography [silica gel (20 g), eluted with ethyl acetate in n-hexane solution (20 to 50%)] (20R).
-1α, 3β-diacetoxy-20-methylpregna
5,7-Dien-21-ol 608 mg (total yield 6
2%) was obtained.

Proton nuclear magnetic resonance spectrum (deuterated chloroform) Chemical shift (ppm): 0.64 (3H, s),
0.97 (3H, d, J = 6.7Hz), 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 (20S) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-dien-21-al 1.17 g (2.28 mmol) of hexamethylphosphine It is dissolved in 14 ml of a mixed solvent of folic triamide and tetrahydrofuran (volume ratio 2: 5), and 267 mg of potassium tert-butoxide while stirring at 0 ° C.
(2.38 mmol) was added. The reaction solution was stirred at 0 ° C. for 3 hours and then added dropwise to 42 ml of a mixture of acetic acid and ethyl acetate (volume ratio 1.5: 40) cooled at 0 ° C. over 30 minutes. The obtained mixture was washed successively with water, 5% aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was subjected to column chromatography [silica gel (60 g), ethyl acetate n
-Eluted with hexane solution (2-20%)],
815 mg (yield 70%) of (20R) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-diene-21-al was obtained.

Proton nuclear magnetic resonance spectrum (deuteriochloroform) 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 (20S) -1α, 3β-Bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-diene-21-al 1.17 g was used in the same manner as in Example 4. The reaction and separation operation were carried out to obtain 810 mg of (20R) -1α, 3β-bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-dien-21-al. 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. 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 brine. The resulting mixture was extracted with ethyl acetate and the extract was washed with brine. After drying over anhydrous sodium sulfate, the solvent was evaporated and the residue was purified by column chromatography [silica gel (20 g), eluted with ethyl acetate in n-hexane solution (20 to 50%)], (20
R) -1α, 3β-Bis (2-tetrahydropyranyloxy) -20-methylpregna-5,7-diene-21
-All 790 mg (total yield 67%) was obtained.

Proton nuclear magnetic resonance spectrum (deuteriochloroform) 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]

EFFECTS OF THE INVENTION A synthetic intermediate of 20-epi-1α-hydroxyvitamin D derivative having excellent activity as compared with 1α-hydroxyvitamin D derivative, which has the same steric configuration at the 20-position and is widely used in nature. And a method for producing the same are provided.

Claims (4)

[Claims] 1. The following general formula (I): (In the formula, 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 protective group for a hydroxyl group.) 20-episteroid derivative. 2. The following general formula (II): (In the formula, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) The steroid aldehyde derivative is converted to an enolate by treating with a basic substance, and then a proton donor is used. The compound is selectively protonated by treatment, and the hydroxyl group is protected or deprotected as necessary, and the following general formula (I-1): (In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) 20
-A method for producing an episteroid derivative. 3. The following general formula (I-1): (In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) 20
-The following general formula (I-2) characterized by reducing an episteroid derivative (In the formula, R ⁵ and R ⁶ are as defined above.)
A method for producing a 20-episteroid derivative represented by: 4. The following general formula (II): (In the formula, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) The steroid aldehyde derivative is converted to an enolate by treating with a basic substance, and then a proton donor is used. The compound is selectively protonated by treatment and, if necessary, is protected or deprotected with a hydroxyl group to give the following general formula (I-1): (In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group.) 20
-The following general formula (I-2), characterized in that an episteroid derivative is obtained and then the 20-episteroid derivative is reduced. (In the formula, R ⁵ and R ⁶ are as defined above.)
A method for producing a 20-episteroid derivative represented by: