JPH07126284A - Hydroxyketone derivative and its production - Google Patents

Abstract

PURPOSE:To obtain the derivative industrially and advantageously useful as a synthetic intermediate for hydroxyvitamin D derivatives by reacting a specific carbaldehyde with a methyl ketone in the presence of a basic substance. CONSTITUTION:The derivative of formula I (R<1> and R<2> are lower alkyl or form a ring with a carbon atom bonded to R<1> and R<2>; R<3> and R<5> are H or an OH-protecting group; R<4> to R<5> are H or OH-protecting group) is obtained by reacting a carbaldehyde of formula II (R<10> and R<11> are H or OH-protecting group) with a methly ketone of formula III in the presence of a base and optionally protecting or deprotecting the OH group.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an intermediate compound useful in a method for producing a 1α, 3β-dihydroxycholesta-5,7,22-trien-24-one derivative, and 1α, 3β from the intermediate compound. -Dihydroxycholesta-
The present invention relates to a method for producing a 5,7,22-trien-24-one derivative and a method for producing the intermediate compound. 1α, 3β-dihydroxycholesta obtained by the present invention
The 5,7,22-trien-24-one derivative has psoriasis,
1α, 24S-dihydroxy-22-ene-26, which is expected as a therapeutic agent for calcium metabolism deficiency
27-dehydrocholesterol vitamin D _3, 1,24R- dihydroxyvitamin D _3, vitamin D derivatives having a hydroxyl group at the 24-position such as 22-dehydro -1,24S- dihydroxyvitamin D ₃ (hereinafter 24-hydroxyvitamin D derivatives May be abbreviated).

[0002]

2. Description of the Related Art Conventionally, as a method for producing 24-hydroxyvitamin D derivatives, for example, chemical and
Pharmaceutical Bulletin (Chemica
l & Pharmaceutical Bulleti
n), 32, 3866-3872 (1984). According to this method, dinorcholenic acid acetate is used as a starting material, and the 22-position is converted to an aldehyde by a multi-step reaction. Then, the 22
Introducing a side chain by reacting an aldehyde derivative with isobutyrylmethylene triphenylphosphorane,
Via the -bromo form, 1α, 3β-diacetoxycholesta-4,6,22-trien-24-one (4,6-
Diene) and 1α, 3β-diacetoxycholester
A mixture of 5,7,22-trien-24-one (5,7-diene form) is obtained. The 5,7-diene body obtained was 1
Treated with -phenyl-1,2,4-triazoline-3,5-dione and isolated as an adduct. The adduct is 24
It is possible to obtain a 1,24-dihydroxyvitamin D derivative by ring-opening after forming a hydroxy form.

[0003]

However, in the above method, an expensive Wittig reagent is used in the step of introducing a side chain into the 22-aldehyde derivative, and triphenylphosphine oxide which is complicated to remove due to such a reaction. Has a problem such as by-product,
It is hard to say that it is an industrially suitable method. In addition, in the conventional method for producing 24-hydroxyvitamin D derivatives, including the above method, the desired 24-hydroxyvitamin D
It was necessary to select the reaction conditions at the time of introducing the side chain in each case according to the type of the side chain of the derivatives. Therefore, at present, it is desired to provide a method for industrially advantageously producing 24-hydroxyvitamin D derivatives having various side chains from a certain intermediate compound under the same reaction conditions. .

Accordingly, the object of the present invention is to provide various 24-
Intermediate compounds useful in a method for producing a 1α, 3β-dihydroxycholesta-5,7,22-trien-24-one derivative, which can be a synthetic intermediate of hydroxyvitamin D derivatives, and 1α, 3β from the intermediate compound −
Dihydroxycholesta-5,7,22-triene-24
It is to provide a method for producing an -one derivative. Another object of the present invention is to provide a method for producing the intermediate compound.

[0005]

According to the present invention, the above objects are (1) the following general formula (I):

[0006]

[Chemical 8]

(Wherein R ¹ and R ² each represent a lower alkyl group or form a ring together with the carbon atom to which they are bonded, and R ³ , R ⁴ and R ⁵ are respectively A hydroxyketone derivative represented by a hydrogen atom or a protective group for a hydroxyl group (hereinafter, abbreviated as hydroxyketone derivative (I)), (2) a hydroxyketone derivative (I) having a hydroxyl group After deprotection, the following general formula (I-1)

[0008]

[Chemical 9]

(Wherein R ¹ and R ² are as defined above, and R ⁶ and R ⁷ represent a hydrogen atom or a hydroxyl-protecting group, respectively). Ketone derivative (I-1)
Is abbreviated. ) And the resulting hydroxyketone derivative (I-1) is dehydrated in the presence of an acidic substance, a basic substance or a dehydrating agent to protect or deprotect the hydroxyl group as necessary. General formula (II)

[0010]

[Chemical 10]

(In the formula, R ¹ and R ² are as defined above, and R ⁸ and R ⁹ are each a hydrogen atom or a hydroxyl-protecting group.) (II)), and (3) the following general formula (III).

[0012]

[Chemical 11]

(In the formula, R ¹⁰ and R ¹¹ each represent a hydrogen atom or a hydroxyl-protecting group.) A carbaldehyde derivative (hereinafter abbreviated as carbaldehyde derivative (III)) is used as a base. In the presence of a volatile substance, the following general formula (IV)

[0014]

[Chemical 12]

(Wherein R ¹ and R ² are as defined above) and reacted with a methyl ketone (hereinafter abbreviated as methyl ketone (IV)), and if necessary, protection of a hydroxyl group. Alternatively, it is achieved by providing a method for producing a hydroxyketone derivative (I), which comprises deprotection.

The hydroxyketone derivative (I-1)
Are a group of compounds included in the hydroxyketone derivative (I).

The above general formulas (I), (I-1) and (II)
Examples of the lower alkyl group represented by R ¹ and R ² in (IV) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like. R ¹
When R ² and R ² form a ring together with the carbon atom to which they are bonded, examples of the ring include cyclopropane ring, cyclobutane ring, cyclopentane ring, cycloalkane ring such as cyclohexane ring and the like.

The above general formulas (I), (I-1) and (II)
Or in (III), R ³ , R ⁴ , R ⁵ , R ⁶ , R
^As the protective group for the hydroxyl group represented by ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , a commonly used protective group can be used, and specifically, an acetyl group, a propionyl group,
Butyryl group, isobutyryl group, valeryl group, isovaleryl group, 4-methylvaleryl group, pivaloyl group, benzoyl group, monochloroacetyl group, trifluoroacetyl group and other acyl groups; methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, allyl Alkoxycarbonyl groups such as oxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group and phenoxycarbonyl group; trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethyl Trisubstituted silyl groups such as silyl group and tert-butyldiphenylsilyl group; methoxymethyl group, methoxyethoxymethyl group, 1-ethoxyethyl group, methoxyisopropyl group, tet Hidorofuraniru group, tetrahydropyranyl good alkoxymethyl group which may have a substituent group such as and the like.

The conversion of the carbaldehyde derivative (III) into the hydroxyketone derivative (I) is carried out by subjecting the carbaldehyde derivative (III) to an addition reaction with methylketone (IV) in the presence of a basic substance to give the following general formula (I '). )

[0020]

[Chemical 13]

[0021] (wherein, R ¹ and R ² are as defined above, R ^{3 ',} R ^4' and R ^{5 'represents.} Each hydrogen atom or a hydroxyl-protecting group) hydroxyketone derivative represented by the (Hereinafter, this is abbreviated as hydroxyketone derivative (I ′)), and the hydroxyl group is protected or deprotected as necessary.

[0022] Here, R ³ ', R ^4' Examples of the hydroxyl protecting groups represented respectively and ^{R 5 'R 3, R 4} ,
The same groups as the hydroxyl-protecting group for R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ can be mentioned.

Methyl ketone (IV) in such a reaction
The amount used is usually about 1 to 20 mol, preferably about 1 to 3 mol, per 1 mol of carbaldehyde derivative (III).

The basic substance used in such a reaction includes metal hydrides such as sodium hydride and potassium hydride; organometallic compounds such as methyllithium, butyllithium and phenyllithium; lithium amide, sodium amide, lithium diisopropyl. Amide, lithium tetramethylpiperazide, lithium hexamethyldisilazide,
Examples thereof include metal amides such as sodium hexamethyldisilazide and potassium hexamethyldisilazide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The amount of the basic substance used varies depending on the type of the basic substance used, but the carbaldehyde derivative (III)
It is usually in the range of about 0.8 to 20 mol, preferably about 1 to 2 mol per mol.

The reaction can be carried out in the presence or absence of a solvent, but it is preferably carried out in a solvent. Specific examples of the solvent that can be used include, for example, tetrahydrofuran, dimethoxyethane, diethyl ether,
Solvents such as dioxane, benzene, toluene and the like, or a mixed solvent thereof may be mentioned. The amount of solvent used is usually in the range of about 5 to 200 times by weight, preferably about 5 to 10 times by weight, of the carbaldehyde derivative (III). The reaction is usually performed at a temperature within the range of about -100 ° C to 0 ° C. Moreover, it is preferable to carry out under an inert gas atmosphere.

Isolation / purification of the hydroxyketone derivative (I ') from the reaction mixture is carried out in the same manner as that used in usual isolation / purification of organic compounds. For example, the reaction mixture is poured into water or an aqueous solution of ammonium chloride, or vice versa for small scale reactions. Then
Extraction was performed with an organic solvent such as diethyl ether, methylene chloride, ethyl acetate, the extract was washed successively with water and brine, dried and concentrated to obtain a crude product. It is carried out by purification by recrystallization, chromatography or the like.

The hydroxyketone derivative (I ') thus obtained corresponds to the hydroxyketone derivative (I) as it is, but if necessary, the hydroxyketone derivative (I') is protected by a conventional method for protecting the hydroxyl groups. Alternatively, it may be subjected to deprotection, and the product thereof also corresponds to the hydroxyketone derivative (I).

The carbaldehyde derivative (III) used as a synthetic raw material in the method for producing the hydroxyketone derivative (I) is, for example, International Patent Application Publication No. 88/0.
It can be manufactured according to the method described in Japanese Patent No. 7545.

Conversion of the hydroxyketone derivative (I-1) to the steroid derivative (II) is carried out by dehydrating the hydroxyketone derivative (I-1) in the presence of an acidic substance, a basic substance or a dehydrating agent, Formula (II ′)

[0030]

[Chemical 14]

(Wherein R ¹ and R ² are as defined above, and R ^{8 ′} and R ^{9 ′} each represent a hydrogen atom or a hydroxyl-protecting group.) (Abbreviated as steroid derivative (II ′)) is obtained, and the hydroxyl group is protected or deprotected as necessary.

Here, the protecting groups for the hydroxyl groups represented by R ^{8 '} and R ^9' are R ³ , R ⁴ , R ⁵ , R ⁶ and
The same groups as the hydroxyl-protecting groups for R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ can be mentioned.

As the acidic substance used in such a reaction, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; p-
Examples thereof include organic acids such as toluenesulfonic acid, acetic acid, and oxalic acid; and organic acid salts such as pyridinium p-toluenesulfonate. Examples of the basic substance include metal hydrides such as sodium hydride and potassium hydride; organometallic compounds such as methyllithium, butyllithium and phenyllithium; lithium amide, sodium amide, lithium diisopropylamide, lithium tetramethylpiperazide, Metal amides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; sodium methoxide, sodium ethoxide,
Examples include metal alkoxides such as potassium t-butoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The term "dehydrating agent" as used herein means that a hydroxyl group is once substituted with a substituent having a high elimination ability such as halogen or ester, and then a hydrogen atom substituted on an adjacent carbon atom and the substituent are 1,2- It means a reagent used when the two-step reaction of elimination is performed all at once without isolation of the intermediate. Specifically, halogenating agents such as thionyl chloride and thionyl bromide; and esterifying agents such as phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc., preferably basic such as pyridine, etc. Use in combination with a substance.

The amount of the acidic substance, basic substance or dehydrating agent used in such a reaction varies depending on the type of the acidic substance, basic substance or dehydrating agent used, but is based on 1 mol of the hydroxyketone derivative (I-1). Usually about 0.05
It is in the range of -10 mol, preferably about 0.1-2 mol.

The above dehydration reaction can be carried out in the presence or absence of a solvent, but it is preferably carried out in a solvent. Specific examples of the solvent that can be used include solvents such as benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, chloroform, and mixed solvents thereof. The amount of solvent used is usually in the range of about 5 to 200 times by weight, preferably about 5 to 20 times by weight, of the hydroxyketone derivative (I-1). The reaction is usually performed at a temperature within the range of about 0 ° C to 100 ° C.

Isolation / purification of the steroid derivative (II ') from the reaction mixture is carried out in the same manner as that used in usual isolation / purification of organic compounds. For example,
The reaction mixture was poured into water, an aqueous solution of ammonium chloride or an aqueous solution of sodium bicarbonate, extracted with an organic solvent such as diethyl ether, methylene chloride, ethyl acetate, the extract was washed with water and brine, dried and concentrated to give a crude product. The product is obtained, and the crude product is purified by recrystallization, chromatography or the like, if necessary.

The steroid derivative (II ') thus obtained is the steroid derivative (II) as it is.
Corresponding to the steroid derivative (I
I ') may be subjected to hydroxyl group protection or deprotection by a conventional method, and the product thereof also corresponds to the steroid derivative (II).

The steroid derivative (II) obtained by the present invention can be converted into, for example, 2 by the method shown in the following reaction step.
It can lead to vitamin D derivatives having a hydroxyl group at the 4-position.

[0040]

[Chemical 15]

(In the above reaction step, R ¹ , R ² , R ⁸ and R ⁹ are as defined above,

[0042]

[Chemical 16]

The line indicated by represents a single bond or a double bond. )

That is, the steroid derivative (II) is optionally subjected to a reduction reaction of the side chain double bond, and then the carbonyl group at the 24-position is reduced and, if necessary, separated by the general formula (V). To obtain the alcohol represented by. The alcohol represented by the general formula (V) is subjected to a photoreaction or a thermal isomerization reaction, and the protective group for the hydroxyl group is removed, if necessary, to have a hydroxyl group at the 24-position represented by the general formula (VI). A vitamin D derivative can be obtained.

[0045]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Under a nitrogen atmosphere, 12.8 ml of diisopropylamine was dissolved in 60 ml of tetrahydrofuran, and the mixture was stirred at -60 ° C. to prepare a 1.6M hexane solution of n-butyllithium 54.
3 ml was added dropwise, and the mixture was stirred for 30 minutes while being cooled. A solution of 9.8 ml of methyl isopropyl ketone dissolved in 30 ml of tetrahydrofuran was added dropwise to the obtained solution, and the mixture was stirred for 1 hour while being cooled, and then 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene- Two
20 g of 0-carbaldehyde was added to tetrahydrofuran 16
The solution dissolved in 0 ml was added dropwise, and the mixture was stirred for 2 hours while being cooled. Aqueous ammonium chloride solution was added to the obtained reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 23.4-hydroxy-2-alpha-1α, 3β-bis (methoxycarbonyloxy) cholesta-5,7-dien-24-one having the following physical properties.
g was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.60 to 0.66 (s, 3H), 0.94 (d, J = 7.6Hz, 3H),
1.01 (s, 3H), 1.11 (d, J = 7.2Hz, 6H), 3.78 (s, 3H), 3.79
(s, 3H), 4.05 to 4.21 (m, 1H), 4.78 to 4.99 (m, 2H), 5.32 to
5.43 (m, 1H), 5.64-5.73 (m, 1H)

Example 2 4.1 g of 22-hydroxy-1α, 3β-bis (methoxycarbonyloxy) cholesta-5,7-dien-24-one was dissolved in a mixed solvent of 50 ml of benzene and 20 ml of chloroform under a nitrogen atmosphere. , P-toluenesulfonic acid (0.634 g) was added at room temperature for 1 hour, and then 4
Stirred at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution, water, and then saturated brine, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1α, 3 having the following physical properties.
β-bis (methoxycarbonyloxy) cholesta-5
3.7g of 7,22-trien-24-one was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.66 (s, 3H), 1.01 (s, 3H), 1.08 to 1.11 (m, 9
H), 3.78 (s, 3H), 3.79 (s, 3H), 4.78-4.99 (m, 2H), 5.30
~ 5.43 (m, 1H), 5.61 ~ 5.72 (m, 1H), 6.09 (d, J = 16.0Hz, 1
H), 6.73 (dd, J = 16.0,8.5Hz, 1H)

Example 3 Under a nitrogen atmosphere, 2.99 ml of hexamethyldisilazane was dissolved in 15 ml of tetrahydrofuran, and the mixture was stirred at -65 ° C., and a 1.6 M hexane solution of n-butyllithium was used in 8.8.
6 ml was added dropwise, and the mixture was stirred for 35 minutes while being cooled. To the resulting solution, 1.61 g of 3-ethylpentan-2-one
Was added dropwise to a solution of tetrahydrofuran in 8 ml,
After stirring for 1 hour while cooling, 1α, 3β-bis (t
A solution of 6.25 g of -butyldimethylsilyloxy) pregna-5,7-diene-20-carbaldehyde dissolved in 40 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 2 hours while being cooled. Aqueous ammonium chloride solution was added to the obtained reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 22-hydroxy-1α, 3β-bis (t-butyldimethylsilyloxy) -26,27-dimethylcholesta-5,7-diene-24- having the following physical properties was obtained. 5.5 g of on was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.06 (s, 6H), 0.08 (s, 3H), 0.11 (s, 3H), 0.
60 to 0.67 (s, 3H), 0.73 to 1.05 (m, 12H), 0.89 (s, 18H),
3.66 to 3.76 (brs, 1H), 3.98 to 4.16 (m, 1H), 4.07 to 4.22
(m, 1H), 5.30-5.40 (m, 1H), 5.57-5.68 (m, 1H)

Example 4 In a nitrogen atmosphere, 5 g of 22-hydroxy-1α, 3β-bis (t-butyldimethylsilyloxy) -26,27-dimethylcholesta-5,7-dien-24-one was added to 60 ml of benzene and 60 ml of benzene. It is dissolved in a mixed solvent of 25 ml of chloroform, 1 g of p-toluenesulfonic acid is added and the temperature is 50 ° C
It was stirred for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1α, 3β having the following physical properties.
-Dihydroxy-26,27-dimethylcholesta-5
1.8 g of 7,22-trien-24-one was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.66 (s, 3H), 0.73 to 1.07 (m, 12H), 3.73 to
3.81 (brs, 1H), 3.97-4.16 (m, 1H), 5.30-5.42 (m, 1H),
5.65 ~ 5.77 (m, 1H), 6.13 (d, J = 15.9Hz, 1H), 6.74 (dd, J =
(15.9Hz, 8.5Hz, 1H)

Example 5 Under a nitrogen atmosphere, 0.273 ml of diisopropylamine was dissolved in 2 ml of tetrahydrofuran, and the mixture was stirred at -65 ° C., and a 1.6M hexane solution of n-butyllithium 1.2 was added.
2 ml was added dropwise, and the mixture was stirred for 30 minutes while being cooled. The resulting solution was charged with 1-cyclopentylethane-1-one 0.
A solution prepared by dissolving 219 g in 2 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 1 hour while being cooled, and then 1α, 3β-
Bis (tetrahydropyranyloxy) pregna-5,7
A solution of 0.5 g of -diene-20-carbaldehyde dissolved in 5 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 1.5 hours while cooling. Aqueous ammonium chloride solution was added to the obtained reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 22-hydroxy-1α, 3β-bis (tetrahydropyranyloxy) -26,27-dimethylenecholesta-5,7-dien-24-one having the following physical properties was obtained. 0.254g was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.60 to 0.67 (s, 3H), 0.96 (d, 3H), 1.01 (s, 3
H), 3.44 to 4.21 (m, 6H), 4.69 to 5.00 (m, 3H), 5.32 to 5.44
(m, 1H), 5.62 to 5.70 (m, 1H)

Example 6 22-hydroxy-1α, 3β-bis (tetrahydropyranyloxy) -26,27-dimethylenecholesta-5,7-dien-24-one 0.254 under nitrogen atmosphere
g was dissolved in a mixed solvent of 3 ml of benzene and 2 ml of chloroform, 0.1 g of p-toluenesulfonic acid was added, and the mixture was stirred at 50 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and had the following physical properties.
α, 3β-dihydroxy-26,27-dimethylenecholesta-5,7,22-trien-24-one was added to 0.10
7 g was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.65 (s, 3H), 0.95 (s, 3H), 1.09 (d, J = 8.0H
z, 3H), 3.72 to 3.82 (brs, 1H), 3.97 to 4.15 (m, 1H), 5.30
~ 5.44 (m, 1H), 5.66 ~ 5.78 (m, 1H), 6.13 (d, J = 16.0Hz, 1
H), 6.75 (dd, J = 16.0Hz, 8.5Hz, 1H)

Example 7 Under a nitrogen atmosphere, 0.46 ml of diisopropylamine was dissolved in 3 ml of tetrahydrofuran and stirred at -65 ° C.
n-Butyllithium 1.6M hexane solution 2.04 ml
Was added dropwise, and the mixture was stirred for 30 minutes while being cooled. To the resulting solution, 0.27 g of 1-cyclopropylethan-1-one
Was added dropwise to 2 ml of tetrahydrofuran,
After stirring for 1.5 hours with cooling, a solution of 1 g of 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde in 8 ml of tetrahydrofuran was added dropwise, and while cooling, 2 Stir for hours. Aqueous ammonium chloride solution was added to the obtained reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and had the following physical properties 26, 27.
-Dehydro-22-hydroxy-1α, 3β-bis (methoxycarbonyloxy) cholesta-5,7-diene-
1.02 g of 24-one was obtained. ¹ H-NMR spectrum (90 MHz) CDCl ₃ ,
TMS, δ: 0.59 to 0.68 (s, 3H), 0.86 to 1.11 (m, 4H), 0.
97 (d, J = 6.8Hz, 3H), 1.01 (s, 3H), 3.78 (s, 3H), 3.79 (s, 3
H), 4.10 ~ 4.22 (m, 1H), 4.80 ~ 4.98 (m, 2H), 5.32 ~ 5.42
(m, 1H), 5.63 to 5.72 (m, 1H)

Reference Example 1 Under a nitrogen atmosphere, 2.5 g of 1α, 3β-bis (methoxycarbonyloxy) cholesta-5,7,22-trien-24-one was dissolved in 6 ml of tetrahydrofuran and stirred under cooling with ice water. A solution prepared by dissolving 1.88 g of cerium chloride heptahydrate in 20 ml of methanol was added to the obtained solution, 400 mg of sodium borohydride was then added, and the mixture was stirred for 5 hours while cooling. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified using high performance liquid chromatography to obtain 0.7 g of 24S-hydroxy-1α, 3β-bis (methoxycarbonyloxy) cholesta-5,7,22-triene.

Reference Example 2 24S-hydroxy-1α, 3β-bis (methoxycarbonyloxy) cholesta-5,7,22-triene 0.
7 g was dissolved in 700 ml of diethyl ether, stirred under cooling with ice water under nitrogen flow, and the obtained mixed solution was irradiated with ultraviolet rays for 10 minutes by a high pressure mercury lamp using a Vycor filter. The reaction mixture was concentrated under reduced pressure and hexane 500 ml
Was added and the mixture was heated to reflux for 2 hours. The resulting reaction solution was concentrated under reduced pressure to obtain a 2N potassium hydroxide methanol solution 10m.
1 was added and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was purified using silica gel column chromatography and high performance liquid chromatography to give the 22-dehydro -1,24S- dihydroxyvitamin D ₃ in 75.4 mg.

[0055]

INDUSTRIAL APPLICABILITY According to the present invention, a novel hydroxyketone derivative useful as a synthetic intermediate for 24-hydroxyvitamin D derivatives is provided. The hydroxyketone derivative is a relatively inexpensive ketone (I
By using V), it is industrially advantageously produced.
Further, various 24-hydroxyvitamin D derivatives can be easily produced from the hydroxyketone derivative.

Claims (3)

[Claims] 1. The following general formula (I): (In the formula, R ¹ and R ² each represent a lower alkyl group or form a ring together with the carbon atom to which they are bonded, and R ³ , R ⁴ and R ⁵ are each a hydrogen atom or Represents a hydroxyl-protecting group). 2. The following general formula (I): (In the formula, R ¹ and R ² each represent a lower alkyl group or form a ring together with the carbon atom to which they are bonded, and R ³ , R ⁴ and R ⁵ are each a hydrogen atom or A hydroxyketone derivative represented by the following formula (I) represents a hydroxyl group-protecting group. (In the formula, R ¹ and R ² are as defined above, and R ^1
6 and R ⁷ each represent a hydrogen atom or a hydroxyl-protecting group. ), The obtained hydroxyketone derivative is dehydrated in the presence of an acidic substance, a basic substance or a dehydrating agent, and the hydroxyl group is protected or deprotected as necessary. The following general formula (II): (In the formula, R ¹ and R ² are as defined above, and R ^1
8 and R ⁹ each represent a hydrogen atom or a hydroxyl-protecting group. The manufacturing method of the steroid derivative shown by these. 3. The following general formula (III): (In the formula, R ¹⁰ and R ¹¹ each represent a hydrogen atom or a hydroxyl-protecting group.), And a carbaldehyde derivative represented by the following general formula (IV): (Wherein R ¹ and R ² each represent a lower alkyl group or, together with the carbon atom to which they are bonded, form a ring), and optionally react with a methyl ketone. The following general formula (I) is characterized in that the hydroxyl group is protected or deprotected. (In the formula, R ¹ and R ² are as defined above, and R ^1
3 , R ⁴ and R ⁵ each represent a hydrogen atom or a hydroxyl-protecting group. The manufacturing method of the hydroxyketone derivative shown by these.