JPH09328498A - Production of 24,25-dihydroxycholesterol and its synthetic intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To stereoselectively obtain the subject compound useful as a raw material for vitamin D3 , etc., by reacting cyclochol-22-ene-24-aldehyde with nitromethane in the presence of a Ln binuclear catalyst, converting the nitro group into an ester group, and further subjecting the product to a reduction reaction, a methylation reaction, etc. SOLUTION: 6α-Methoxy-3α,5α-cyclochol-22-ene-24-aldehyde is reacted with nitromethane in the presence of a binuclear catalyst containing (R) or (S)- binaphthol derivative of formula II (R<1> is H, trimethylsilylethynyl, triethylsilylethynyl; Ln is lanthanum, samarium) as an asymmetric source. The hydroxyl group of the obtained new nitroaldol compound of formula III (* is asymmetric carbon) is protected. The nitro group of the protected compound is converted into a carboxyl group and subsequently esterified. The esterified product is subjected to the hydrogenation of the double bond, a methylating agent treatment and the removal of the protecting agent to obtain the objective of 24,25-dihydroxycholesterol of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 24 (R), 25-dihydroxyvitamin D ₃ or 2 which is useful as a medicine.
4 (S), it relates to the synthesis of 25-dihydroxyvitamin D _3. More particularly, it relates to a method for producing 24,25-dihydroxycholesterol useful as a synthetic intermediate thereof. More specifically, it relates to a method for producing 24,25-dihydroxycholesterol, which comprises stereoselectively constructing a hydroxyl group at the 24-position by an asymmetric nitroaldol reaction with 24-aldehydes.

[0002]

BACKGROUND OF THE INVENTION 24 (R), 25-dihydroxyvitamin D ₃ or 24 (S), 24 (R), 25-dihydroxycholesterol or 24 (S), which are important synthetic intermediates of 25-dihydroxyvitamin D ₃ , 25-Dihydroxycholesterol, a stereoselective synthetic method is described in J.
Am. Chem. Soc. , 98, 3739 (197)
6), J. Chem. Soc. Parkin I. , 1
401 (1983), and JP-A-6-256270. However, in all of these methods, the hydroxyl group at the 24-position is constructed by an oxidative method such as epoxidation or dihydroxylation, and construction by carbon-carbon bond formation has not been known.

On the other hand, Journal of Organic Synthesis Chemistry, Vol. 51, 972-
984, it is known that the asymmetric nitroaldol reaction proceeds in a highly stereoselective manner by using a dinuclear catalyst composed of rare earth-binaphthol-alkali metal.

[0004]

The problem to be solved by the present invention is to provide a method for synthesizing 24,25-dihydroxycholesterol using 24-aldehydes, which are easily available steroids, as a starting material. .

That is, in the prior art, it was necessary to construct a hydroxyl group at the 24-position after extending the carbon chain from the 24-aldehyde of steroids, but stereoselection of the hydroxyl group at the 24-position at the same time when the carbon-carbon bond was formed. If it can be constructed in a constructive manner, it may be a more direct method for synthesizing 24,25-dihydroxycholesterol. This 24,25-dihydroxycholesterol is useful as a synthetic intermediate for not only 24,25-dihydroxyvitamin D ₃ but also other vitamin D ₃ .

[0006]

Means for Solving the Problems As a result of earnest research on the above problems, the present inventor has found that when a corresponding aldehyde precursor and nitromethane are reacted in the presence of a dinuclear catalyst composed of a rare earth-lithium-binaphthol, a high stereochemistry is obtained. We found that the asymmetric nitroaldol reaction proceeded selectively.
Then, utilizing this reaction, they succeeded in synthesizing 24,25-dihydroxycholesterol and reached the present invention.

That is, the first invention is the following formula (I):

[0008]

[Chemical 6]

A compound represented by the following formula (II)

[0010]

[Chemical 7]

[In the formula, R ¹ represents a hydrogen atom, a trimethylsilylethynyl group or a triethylsilylethynyl group, and Ln represents lanthanum or samarium. ] (R) or (S) -binaphthol derivative represented by the following formula (III), which is characterized by reacting in the presence of a binuclear catalyst constituted as an asymmetric source.

[0012]

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[In the formula, R and * indicate that the isomer derived from the asymmetric carbon is biased to one isomer. ] It is a manufacturing method of the nitro aldol compound represented by these.

In this reaction, if the binaphthol derivative having the R configuration is used, a compound having the S configuration with the asymmetric carbon configuration marked with * in the above formula (III) is preferentially obtained, and the S configuration as the binaphthol derivative is obtained. If the compound having the asymmetric carbon configuration is used, the compound having the R configuration is preferentially obtained.

In the second invention, after the hydroxyl group of the nitroaldol compound represented by the above formula (III) is optionally protected, it is treated with a reaction agent capable of converting the nitro group into a carboxyl group for esterification, By further reducing the double bond, the following formula (IV)

[0016]

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[Wherein R ² is a hydrogen atom, an acyl group having 2 to 8 carbon atoms, a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group, 1- (alkoxy group having 1 to 4 carbon atoms)] Substituted C1-6 alkyl group, 2- (C1-4 alkoxy group) substituted C1-6 alkyl group, 2-methoxyethoxymethyl group, or 2-tetrahydropyranyl group , R ³ represents an alkyl group having 1 to 9 carbon atoms or an aryl group having 6 to 9 carbon atoms, and the asterisk indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ]
The following formula (V) is characterized in that it is converted into an ester compound represented by and then reacted with a methylating agent to remove the protecting group.

[0018]

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[In the formula, the asterisk indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] It is a manufacturing method of the 24,25- dihydroxy cholesterol represented by this.

The present invention also includes a nitroaldol compound represented by the above formula (III).

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The binaphthol derivative used in a reaction between a compound represented by the above formula (I) and nitromethane, which is used as a chiral source for the binaphthol derivative represented by the above formula (II), is a binaphthol derivative. Is binaphthol,
6,6'-di (trimethylsilylethynyl) binaphthol, or 6,6'-di (triethylsilylethynyl)
Although it is binaphthol, 6,6′-di (triethylsilylethynyl) binaphthol is particularly preferable. As such a binuclear catalyst, a combination of lanthanum and 6,6′-di (triethylsilylethynyl) binaphthol is particularly preferable.

The amount of the multinuclear catalyst used is usually 1 to 100.
It is in the range of mol%, preferably 5 to 30 mol%.

Among the binaphthol derivatives which are the constituent components of the binuclear catalyst represented by the above formula (II), binaphthol is commercially available, and 6,6 '-(triethylsilylethynyl) binaphthol is reported by Shibasaki et al. (J. Org). Chem.,
60,7388 (1995)), it can be synthesized from commercially available 6,6′-dibromobinaphthol in a one-step reaction. 6,6′-Di (trimethylsilylethynyl) binaphthol can be obtained in the same manner.

Further, the binuclear catalyst represented by the above formula (II) is reported by Shibasaki et al. (J. Am. Chem. Soc., 1).
17, 6194 (1995)), and can be prepared from the corresponding rare earth trialkoxide, binaphthol derivative, and butyllithium. The reaction formula is shown below.

[0025]

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[Wherein R ¹ and Ln are the same as defined in the above formula (II), R ⁴ is an isopropyl group, t-
It represents an alkyl group such as a butyl group. ]

The reaction solvent used in the reaction of the compound represented by the above formula (I) with nitromethane is, for example, tetrahydrofuran, diethyl ether, dichloromethane,
Toluene may be mentioned, but it is preferable to use tetrahydrofuran. The reaction temperature is -70 ° C to 30 ° C, preferably -50 ° C to -30 ° C. The reaction time varies depending on the amount of the catalyst used, the reaction temperature, etc., but is usually several hours to several tens hours.

In the compound represented by the above formula (IV),
R ² is a hydrogen atom, an acyl group having 2 to 8 carbon atoms, a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group, 1- (having 1 carbon atom)
-4 alkoxy group) substituted C 1-6 alkyl group, 2- (C 1-4 alkoxy group) substituted C 1-6 alkyl group, 2-methoxyethoxymethyl group,
Alternatively, it represents a 2-tetrahydropyranyl group. Examples of the acyl group having 2 to 8 carbon atoms (including carbonyl carbon) include an acetyl group, a pivaloyl group, a hexanoyl group, a benzoyl group and an ethoxycarbonyl group. Particularly, an acetyl group is preferable.

Examples of the tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group of R ² include trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group and the like. And preferably a t-butyldimethylsilyl group.

Further, the 1- or 2- (alkoxy group having 1 to 4 carbon atoms) -substituted C 1-6 alkyl group for R ² includes, for example, a methoxymethyl group and a 2-ethoxyethyl group. And preferably a 2-ethoxyethyl group.

As R ² , a 2-tetrahydropyranyl group and a 2-ethoxyethyl group are particularly preferable.

The protection of the hydroxyl group of the nitroaldol compound represented by the above formula (III) is not necessary when the hydroxyl group is not damaged by the reagent used in the subsequent steps, for example, when concentrated hydrochloric acid is used for conversion of the nitro group. .

Examples of the reactant capable of converting the nitro group of the nitroaldol compound represented by the above formula (III) into a carboxyl group include concentrated hydrochloric acid, potassium permanganate in the presence of potassium hydroxide, sodium nitrite and nitrous acid. Examples include a combination of propyl nitrate and molybdenum pentoxide in the presence of triethylamine. Of these, a combination of sodium nitrite and propyl nitrite is preferable.

Appropriate conditions are selected for the solvent and temperature of this reaction depending on the kind of the reactant. When a combination of sodium nitrite and propyl nitrite is used, it is used in dimethyl sulfoxide, HMPA or a mixed solvent thereof in a temperature range of -20 ° C to 50 ° C, preferably 0 ° C.
From room temperature.

The esterification after converting the nitro group of the nitroaldol compound represented by formula (III) into a carboxyl group is carried out as a pretreatment for introducing a methyl group by reaction with a methylating agent. Thus, in the formula ester compound represented by (IV), R ³ represents an alkyl group or an aryl group having a carbon number of 6-9 of 1-9 carbon atoms, and such R ^3, with a methylating agent Anything that does not interfere with the reaction may be used. Examples thereof include a methyl group, an ethyl group, a phenyl group, and a benzyl group. Of these, a methyl group is preferred.

This esterification reaction can be carried out by a usual method. For example, in the case of methyl esterification, for example, methanol in the presence of an acid catalyst, methyl iodide in the presence of a base, or diazomethane can be used.

For the reduction of the double bond of the nitroaldol compound represented by the above formula (III), a general catalytic reduction method using a homogeneous catalyst or a heterogeneous catalyst can be adopted. As the catalyst, for example, Wilkinson complex,
Pt / C and Pd / C are mentioned.

In the conversion of the nitroaldol compound represented by the above formula (III) into the ester compound represented by the above formula (IV), even if the double bond is reduced after conversion of the nitro group, The conversion of the nitro group may be performed after the reduction of the heavy bond.

The 24,25-hydroxycholesterol represented by the formula (V) is obtained by reacting the ester compound represented by the formula (IV) with a methylating agent such as methyllithium or methylmagnesium halide such as bromide. After that, it is obtained by removing the protective group for the hydroxyl group.

The reaction with the methylating agent is carried out in an ether solvent such as tetrahydrofuran or diethyl ether at a temperature range of -70 ° C to 80 ° C, preferably 0 ° C to room temperature.

Among the hydroxyl protecting groups, i-methyl ether, which is a hydroxyl protecting group in the nitroaldol reaction, is deprotected by acid hydrolysis. R ² is i
When a protecting group that is not removed during deprotection of methyl ether is used, it can be removed by a general method depending on the type of the protecting group. Further, deprotection of i-methyl ether may be performed prior to the reaction with the methylating agent.

The compound represented by the above formula (I) is
Obtained from stigmasterol by the following route (Tetrahedron Asymmetry, 6,
767 (1995)).

[0043]

[Chemical 12]

[0044]

【Example】

 [Example 1]

[0045]

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6β-methoxy-3α, 5α-cyclocol-22-ene-24-aldehyde (1) (55 mg,
Nitromethane (0.4 ml, 7.5 mmol) was added to a THF solution (1 ml) of 0.15 mmol) at -30 ° C.
Cooled to room temperature, and a THF solution of a dinuclear catalyst consisting of lanthanum- (S) -binaphthol-lithium (0.6 ml, 0.03
(mmol) was added dropwise and stirred for 90 hours. After the reaction,
1N HCl water (25 ml) was added, and ethyl acetate (25 ml) was added.
ml). The organic layer was washed with a saturated saline solution (25 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After silica gel (20 g) was used for column purification with hexane: ethyl acetate (5: 1 → 2: 1), further HPLC fractionation (column: YMC-SIL,
Eluent: hexane / THF = 5/1)
The desired product, 3α, 5α-cyclo-24-hydroxy-
6β-methoxy-25-nitro-26,27-norcholest-22-ene (2) (55 mg, 0.13 mmo
1, 86%). The stereoisomeric ratio for the hydroxyl group at the 24-position was determined by HPLC analysis (Chiralcel OD-
H, hexane / i-PrOH = 91, 1.0 ml / mi
n, 210 nm, 35 ° C.), R: S = 86: 14
I decided.

¹ H-NMR (CDCl ₃ , ppm) δ; 0.74 (3H, s) 1.03 (3H, s) 0.35-2.40 (22H, m) 2.78 (1H, b) ) 3.33 (3H, s) 4.40-4.55 (2H, m) 4.70-4.90 (1H, m) 5.30-5.45 (1H, m) 5.55-5 .85 (1H, m)

[Example 2]

[0049]

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6β-methoxy-3α, 5α-cyclocol-22-ene-24-aldehyde (1) (55 mg,
Nitromethane (0.4 ml, 7.5 mmol) was added to a THF solution (1 ml) of 0.15 mmol), and -50
Cooled to 0 ° C. and a THF solution of a dinuclear catalyst consisting of lanthanum- (S) -binaphthol-lithium (0.6 ml, 0.0
(3 mmol) was added dropwise and the mixture was stirred for 42 hours. After completion of the reaction, 1N HCl water (25 ml) was added, and the mixture was extracted with ethyl acetate (25 ml). The organic layer is saturated saline (25m
It was washed with l), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After silica gel (20 g) was used for column purification with hexane: ethyl acetate (5: 1 → 2: 1), further HPLC fractionation (column: YMC-).
SIL, eluent: hexane / THF = 5/1) to give the desired product 3α, 5α-cyclo-24-hydroxy-6β-methoxy-25-nitro-26,27-.
Norcholest-22-ene (2) (38 mg, 0.09)
mmol, 59%) was obtained. The stereoisomeric ratio for the hydroxyl group at the 24-position was determined by HPLC analysis (Chiralcel).
OD-H, hexane / i-PrOH = 91, 1.0 ml
/ Min, 210 nm, 35 ° C.), R: S = 9
It was decided to be 1: 9.

[Embodiment 3]

[0052]

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6β-methoxy-3α, 5α-cyclocol-22-ene-24-aldehyde (1) (55 mg,
Nitromethane (0.4 ml, 7.5 mmol) was added to a THF solution (1 ml) of 0.15 mmol) at -50 ° C.
And cooled to a THF solution of a dinuclear catalyst consisting of samarium- (S) -binaphthol-lithium (0.6 ml, 0.0
(3 mmol) was added dropwise and the mixture was stirred for 111 hours. After completion of the reaction, 1N HCl water (25 ml) was added, and the mixture was extracted with ethyl acetate (25 ml). The organic layer is saturated saline (25m
It was washed with l), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After silica gel (20 g) was used for column purification with hexane: ethyl acetate (5: 1 → 2: 1), further HPLC fractionation (column: YMC-).
SIL, eluent: hexane / THF = 5/1) to give the desired product 3α, 5α-cyclo-24-hydroxy-6β-methoxy-25-nitro-26,27-.
Norcholest-22-ene (2) (30 mg, 0.07
mmol, 47%) was obtained. The stereoisomeric ratio for the hydroxyl group at the 24-position was determined by HPLC analysis (Chiralcel).
OD-H, hexane / i-PrOH = 9/1, 1.0 m
1 / min, 210 nm, 35 ° C.), R: S = 9
It was decided to be 2: 8.

[Embodiment 4]

[0055]

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6β-methoxy-3α, 5α-cyclocol-22-ene-24-aldehyde (1) (55 mg,
Nitromethane (0.4 ml, 7.5 mmol) was added to a THF solution (1 ml) of 0.15 mmol) at -30 ° C.
And cooled to a THF solution of a dinuclear catalyst composed of lanthanum- (S) -6,6'-di (triethylsilylethynyl) -binaphthol-lithium (0.6 ml, 0.03 mmo).
1) was added dropwise and the mixture was stirred for 114 hours. After completion of reaction, 1N
HCl water (25 ml) was added, and ethyl acetate (25 m
Extracted in l). The organic layer was washed with a saturated saline solution (25 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After silica gel (20 g) was used for column purification with hexane: ethyl acetate (5: 1 → 2: 1), further HPLC fractionation (column: YMC-SIL,
Eluent: hexane / THF = 5/1)
The desired product, 3α, 5α-cyclo-24-hydroxy-
6β-methoxy-25-nitro-26,27-norcholest-22-ene (2) (59 mg, 0.14 mmo
1, 47%). The stereoisomeric ratio for the hydroxyl group at the 24-position was determined by HPLC analysis (Chiralcel OD-
H, hexane / i-PrOH = 9/1, 1.0 ml / m
in, 210 nm, 35 ° C.), R: S = 92: 8
I decided.

[Embodiment 5]

[0058]

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3α, 5α-cyclo-24-hydroxy-
6β-methoxy-25-nitro-26,27-norcholest-22-ene (2) (183 mg, 0.43 mmo
l) in dichloromethane (2 ml), dihydropyran (1.0 ml, 11.1 mmol), p-TsOH.
H ₂ O (20 mg, 0.10 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution (40 ml) was added, and ethyl acetate (40 m
Extracted in l). The organic layer was washed with saturated brine (40 ml), dried over anhydrous magnesium sulfate, filtered and concentrated,
A crude product was obtained. After purification using silica gel (20 g) with hexane: ethyl acetate (20: 1 → 10: 1), further HPLC fractionation (column: YMC-SIL, eluent: hexane / THF = 15/1) was performed. ,
The target product, 3α, 5α-cyclo-6β-methoxy-2
5-Nitro-24- (2'-tetrahydropyranyloxy) -26,27-norcholest-22-ene (3)
(197 mg, 0.38 mmol, 90%) was obtained.

¹ H-NMR (CDCl ₃ , ppm) δ; 0.73 (3H, s) 1.02 (3H, s) 0.35-2.20 (28H, m) 2.78 (1H, b) ) 3.32 (3H, s) 3.40-4.00 (3H, m) 4.30-4.90 (3H, m) 5.05-5.80 (2H, m)

[Embodiment 6]

[0062]

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Sodium nitrite (519 mg, 7.52
mmol) in DMSO (1 ml) at room temperature for 3α,
5α-cyclo-6β-methoxy-25-nitro-24-
(2'-Tetrahydropyranyloxy) -26,27-
Norcholest-22-ene (3) (122 mg, 0.2
4 mmol) of HMPA solution (3 ml) and propyl nitrite (0.3 ml, 3.13 mmol) were sequentially added, and 16
Stirred for hours. After the reaction was completed, 50% saturated saline solution (25 m
1) was added, and the mixture was extracted with ethyl acetate (25 ml). The organic layer was washed with 50% saturated saline (25 ml × 2), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude carboxylic acid. This is acetonitrile (1 ml)
Dissolved in diisopropylethylamine (0.23m
1, 1.32 mmol), MeI (0.08 ml, 1.
(28 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 1N HCl water (25 ml) was added, and the mixture was extracted with ethyl acetate (25 ml). The organic layer is saturated saline (4
0 ml), and dried over anhydrous magnesium sulfate.
Filtration and concentration gave a crude product. This crude product was subjected to silica gel (20 g) using hexane: ethyl acetate (20:
Column purification with 1 → 5: 1) and further HPLC fractionation (column: YMC-SIL, eluent: hexane / THF = 1)
5/1) to give the desired product, 3α, 5α-cyclo-6β-methoxy-24- (2′-tetrahydropyranyloxy) -25-homocor-22-enoic acid methyl ester (4) (76 mg, 0.15 mmol, 62
%) Was obtained.

¹ H-NMR (CDCl ₃ , ppm) δ; 0.74 (3H, s) 1.03 (3H, s) 0.35-2.25 (27H, m) 2.78 (1H, b) ) 3.33 (3H, s) 3.75 (3H, s) 3.40-4.00 (2H, m) 4.55-4.80 (2H, m) 5.30-5.85 (2H) , M)

[Embodiment 7]

[0066]

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3α, 5α-cyclo-6β-methoxy-2
4- (2′-Tetrahydropyranyloxy) -25-homocor-22-enoic acid methyl ester (4) (20 m
g, 0.039 mmol) in ethanol solution 1.5 m
5% Pt / C (10 mg) was added to l), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. After filtration through Celite, the filtrate was concentrated to obtain a crude product. This crude product was treated with silica gel (20
g) and hexane: ethyl acetate (20: 1 → 5:
By column purification in 1), 3α,
5α-Cyclo-6β-methoxy-24-2′-tetrahydropyranyloxy) -25-homocholanic acid methyl ester (5) (17 mg, 0.033 mmol, 85%)
I got

¹ H-NMR (CDCl ₃ , ppm) δ; 0.71 (3H, s) 1.02 (3H, s) 0.35-2.05 (31H, m) 2.80 (1H, b) ) 3.34 (3H, s) 3.73 (3H, s) 3.30-4.00 (3H, m) 4.20-4.70 (2H, m)

[Embodiment 8]

[0070]

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3α, 5α-cyclo-6β-methoxy-2
4- (2'-Tetrahydropyranyloxy) -25-homocholanic acid methyl ester (5) (14 mg, 0.02
7 mmol) in THF (1 ml), and a 0.93 M THF solution of methylmagnesium bromide (0.
5 ml, 0.47 mmol) was added dropwise. After stirring at room temperature for 30 minutes, saturated aqueous ammonium chloride solution (25 ml) was added, and the mixture was extracted with ethyl acetate (25 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. This crude product was treated with silica gel (20 g),
By performing column purification with hexane: ethyl acetate (20: 1 → 4: 1), the desired product, 24-dihydroxy-
6β-methoxy-3α, 5α-cyclocholesterol-
24- (2′-tetrahydropyranyl) ether (6)
(14 mg, 0.027 mmol, 100%) was obtained.

¹ H-NMR (CDCl ₃ , ppm) δ; 0.72 (3H, s) 1.02 (3H, s) 0.35-2.05 (37H, m) 2.80 (1H, b) ) 3.34 (3H, s) 3.30-4.00 (3H, m) 4.20-4.70 (2H, m)

[Embodiment 9]

[0074]

[Chemical 21]

24-dihydroxy-6β-methoxy-3
α, 5α-Cyclocholesterol 24- (2′-tetrahydropyranyl) ether (6) (14 mg, 0.02
Water (0.75 ml) and p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol) were added to a solution of 7 mmol,) in dioxane (1.5 ml), and the mixture was heated at 80 ° C. for 2 hours.
The mixture was heated and stirred for an hour. After completion of the reaction, water (40 ml) was added and the mixture was extracted with ethyl acetate (40 ml × 2). The organic layer was washed with saturated brine (40 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. After purification with ethyl acetate using silica gel (20 g), further HPLC fractionation (column: YMC-SIL, eluent: hexane / ethyl acetate = 1/1) was carried out to obtain 24,25-dihydroxy as the target product. Cholesterol (7)
(9 mg, 0.021 mmol, 79%) was obtained. The ¹ H-NMR data of this product was in agreement with that of the standard product.

¹ H-NMR (CD ₃ OD, ppm) δ; 0.74 (3H, s) 0.98 (3H, d, J = 6 Hz) 1.03 (3H, s) 0.85-2. 35 (23H, m) 1.14 (3H, s) 1.17 (3H, s) 5.30-5.40 (1H, m)

[0077]

INDUSTRIAL APPLICABILITY According to the present invention, 24 (R), 25-dihydroxycholesterol or 24 (S), 25-dihydroxycholesterol can be efficiently produced using a readily available precursor as a starting material.

The nitroaldol compound represented by the above formula (III) of the present invention is an optically active compound which is also useful as a synthetic intermediate for other vitamin D ₃ derivatives.

Claims (5)

[Claims] 1. A compound represented by the following formula (I): A compound represented by the following formula and nitromethane are represented by the following formula (II): [In the formula, R ¹ represents a hydrogen atom, a trimethylsilylethynyl group, or a triethylsilylethynyl group, and Ln represents lanthanum or samarium. ] (R)
Alternatively, the reaction is carried out in the presence of a dinuclear catalyst composed of an (S) -binaphthol derivative as an asymmetric source, represented by the following formula (III): [In the formula, * indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] The manufacturing method of the nitro aldol compound represented by these. 2. The method for producing a nitroaldol compound according to claim 1, wherein in the (R) or (S) -binaphthol derivative of the above formula (II), Ln is lanthanum. 3. The method for producing a nitroaldol compound according to claim 1, wherein in the binaphthol derivative of the formula (II), the configuration of the binaphthol derivative is S configuration. 4. A nitroaldol compound represented by the above formula (III). 5. The hydroxy group of the nitroaldol compound represented by the above formula (III) is optionally protected and then treated with a reaction agent capable of converting the nitro group to a carboxyl group for esterification, and further a double bond is formed. By reducing the
The following formula (IV): [In the formula, R ² represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group, 1-
(Alkoxy group having 1-4 carbon atoms) Substituted alkyl group having 1-6 carbon atoms, 2- (Alkoxy group having 1-4 carbon atoms) substituted alkyl group having 1-6 carbon atoms, 2-methoxyethoxymethyl group Or a 2-tetrahydropyranyl group, R
³ represents an alkyl group having 1 to 9 carbon atoms or an aryl group having 6 to 9 carbon atoms, and * indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] It is converted to an ester compound represented by the following, and then it is reacted with a methylating agent to remove the protecting group, and the following formula (V): [In the formula, * indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ], 2 represented by
Method for producing 5-dihydroxycholesterol.