JPH08333385A - Steroid derivative and its production - Google Patents

Abstract

PURPOSE: To obtain a new steroid derivative useful for e.g. producing e.g. an intermediate for vitamin D derivatives each having oxygen functional groups at 23 and 25 sites and also various functional groups at 26 and 27 sites. CONSTITUTION: This new compound is expressed by formula I (R<1> is H, OH or protected OH; R<2> is H or a OH-protecting group), e.g. 20-acetonyl-lα, 3β-bis(methoxymethoxy)-pregna-5,7-diene(20). The compound of formula I is obtained by reaction of a compound of formula II, with a methylated metal reagent such as methyllithium in an inert solvent such as THF.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate in the production of a vitamin D derivative and a method for producing the same. Specifically, the present invention is one of vitamin D derivatives 23
Intermediates of compounds having an oxygen functional group at positions 25 and 25 (for example, described in JP-A-63-45249), and 25
The present invention relates to an intermediate of a compound having an oxygen functional group at the position and a method for producing the same. More specifically, it relates to an intermediate of a vitamin D derivative having oxygen functional groups at the 23- and 25-positions and further having various functional groups at the 26- and 27-positions, and a process for producing the same.

[0002]

BACKGROUND OF THE INVENTION Vitamin D is useful as a therapeutic or prophylactic drug for various diseases caused by abnormal calcium absorption, transport or metabolism, such as rickets, osteomalacia and osteoporosis. Is based on the physiological activity of the 1α, 25 dihydroxy compound, which is a metabolite of vitamin D ₃ . However, the 1α, 25 dihydroxy compound itself has very strong side effects, and in recent years, the development of vitamin D derivatives for the purpose of separating the action has been of great interest (THE BONE 19955.3 V
ol. 9 No. 1 p. 53). For this reason, the search and development of vitamin D compounds having various functional groups on the side chains are being conducted.

Vitamin D having various functional groups on its side chain
Many of the reported methods for synthesizing derivatives have limitations on the side chains that can be introduced depending on the reaction conditions. For example, as a method for synthesizing a steroid derivative having an oxygen functional group at the 23- and 25-positions, for example, the following formula

Embedded image (In the formula, R ⁷ represents a hydrogen atom or a hydroxyl-protecting group.
R ³ represents an alkyl group, an aryl group or an aralkyl group. R ⁴ represents an alkyl group or a hydroxyl group-protecting group. R
⁵ represents a hydrogen atom or a hydroxyl group having a protective group. The method represented by the scheme (1) has been reported (JP-A-2-250865). However, this method cannot be used for the synthesis of a vitamin D derivative having a halogen atom in the side chain as described in JP-A-63-45249, and cannot be said to be a general synthetic method. . Therefore, it is desired to develop a general method for synthesizing a vitamin D derivative having oxygen functional groups at the 23- and 25-positions and further having various functional groups at the 26- and 27-positions.

[0004]

The object of the present invention is, for example, to have oxygen functional groups at the 23- and 25-positions, and further to the 26-position,
An object of the present invention is to provide an intermediate that can be used for the synthesis of a vitamin D derivative having various functional groups at the 27-position, and a method for producing the intermediate.

[0005]

Means for Solving the Problems The inventors of the present invention have made various investigations in order to solve the above problems, and as a result, the general formula (1)

[Chemical 4] (In the formula, R ¹ represents a hydrogen atom, a hydroxyl group or a hydroxyl group having a protective group. R ² represents a hydrogen atom or a protective group of a hydroxyl group.) By reacting with the aldehyde or ketone of the above, it has oxygen functional groups at the 23- and 25-positions,
The present invention has been completed by finding that a vitamin D derivative including those having various functional groups at the 6-position and the 27-position can be efficiently produced, and further found an efficient production method thereof.

The compound of the present invention and the method for producing the same will be described in detail below. The hydroxyl group-protecting group that can be used in the compound of the present invention and in the production method is not particularly limited, and includes any group that can be used in the reaction conditions of the method of the present invention and can be introduced by a known method. (For example, Protective Groups Org
anic Synthesis, John-Wile
y & Sons, New York, pp10-
142 (1991). ). Specifically, for example, a protecting group removed by an acid can be mentioned, and more specifically, for example, a substituted silyl group, a substituted methyl group,
A tetrahydropyranyl group etc. are mentioned.

Examples of the substituent of the substituted silyl group include a lower alkyl group and an aryl group. Examples of the lower alkyl group include alkyl groups having 6 or less carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl. The aryl group has, for example, 1 carbon atom.
Examples thereof include 0 or less aryl groups, and specific examples thereof include phenyl and naphthyl. Specific examples of the substituted silyl group include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, diethylisopropylsilyl group, t-butyldimethylsilyl group, diphenylmethylsilyl group, t-butyldiphenylsilyl group. Etc.

Examples of the substituent of the substituted methyl group include an alkoxy group, an alkylthio group, an aralkyloxy group and an alkoxyalkoxy group. Examples of the alkyl portion of these substituents include an alkyl group having 4 or less carbon atoms, and specific examples include methyl, ethyl,
Examples include propyl, isopropyl, butyl and the like. The aryl part of these substituents has, for example, 1 carbon atom.
Examples thereof include 0 or less aryl groups, and specifically, for example,
Examples thereof include phenyl and naphthyl. Specific examples of the substituted methyl group include a methoxymethyl group, a methylthiomethyl group, a benzyloxymethyl group and a methoxyethoxymethyl group.

Preferred protecting groups include, for example, a lower alkyl group, a silyl group substituted with an aryl group, a methyl group substituted with an alkoxy group, a tetrahydropyranyl group and the like. More preferable protecting groups include, for example, a substituted silyl group such as a triisopropylsilyl group, a t-butyldimethylsilyl group or a diphenylmethylsilyl group,
Substituted methyl groups such as methoxymethyl group, benzyloxymethyl group and methoxyethoxymethyl group, and tetrahydropyranyl group can be mentioned.

Examples of the halogen atom include chlorine atom, bromine atom and iodine atom.

Using the synthetic intermediates found in the present invention, for example, the following formula

Embedded image (In the formula, R ¹ and R ² have the same meanings as described above.) The vitamin D derivative (d) described in JP-A-63-45249 can be easily synthesized.
That is, the compound (a) of the present invention is photo-reacted to form a ring-opening compound (b) by ring-opening the B ring portion, and this compound is subjected to a thermal reaction to isomerize the unsaturated bond to thereby obtain a compound (c) having a vitamin D skeleton. ) And then aldol-reacted with hexafluoroacetone in the presence of a base, it is possible to very efficiently lead to a vitamin D derivative (d) having oxygen functional groups at the 23- and 25-positions.

The photo ring-opening reaction is carried out by a method known per se, that is, by irradiating the compound (a) with ultraviolet rays. The step of this ultraviolet irradiation is carried out in an inert solvent such as an organic solvent such as benzene, toluene, n-hexane, methanol, ethanol, diethyl ether, acetonitrile or a mixed solvent thereof such as an inert gas such as nitrogen or argon. It is done in an atmosphere. As the ultraviolet ray source, a commonly used one can be used. For example, a mercury lamp is given as an easily available source, and a filter may be used if necessary. Irradiation temperature is -10 to 40
C. range, preferably -10 to 30.degree. C. gives good results. Irradiation time depends on the source of ultraviolet rays, raw material compound (a)
The concentration may vary depending on the concentration, the type of solvent, etc., but is usually in the range of several minutes to several hours. The compound (b) obtained here can be purified by a means such as chromatography, but it is preferable to continuously heat up the reaction liquid without isolating it until the compound (c) is obtained. .

The thermal isomerization reaction is also a method known per se,
Compound (b) is carried out in a suitable inert solvent, preferably the solvent used in the above-mentioned ultraviolet irradiation step, under an atmosphere of an inert gas such as nitrogen or argon. The reaction temperature is in the range of 20 to 120 ° C, preferably 50 to 100 ° C.
It is carried out by heating in the range of 2 to 5 hours. The compound (c) obtained here can be purified by means such as chromatography.

Examples of the base used in the aldol reaction include metal salts of amines such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide and sodium amide, metal salts of alcohols such as potassium t-butoxide, and hydrogenation. Alkali metal hydrides such as sodium and potassium hydride, n-butyllithium, se
Organolithium compounds such as c-butyllithium and tert-butyllithium may be mentioned. Especially preferred are lithium bis (trimethylsilyl) amide and n-butyllithium. It is necessary to use an amount that allows the reaction to proceed sufficiently, but it is preferable to use an amount in the range of 1 to 3 equivalents relative to the compound (c). Hexafluoroacetone is also used in an amount sufficient for the reaction to proceed, but it is preferably used in the range of 1 to 1.5 equivalents relative to compound (c).

The reaction is carried out, for example, with ethers such as diethyl ether, tetrahydrofuran, dioxane, benzene,
Aromatic hydrocarbons such as toluene, acetonitrile, dimethylformamide, or a mixed solvent thereof is used. The reaction temperature is not particularly limited, but it is usually performed under cooling or under heating, preferably in the range of −78 ° C. to room temperature. Particularly preferably, it is performed in the range of -78 ° C to -30 ° C. In order, it is preferable to react the compound (c) with a base and then with hexafluoroacetone.

The following equation

[Chemical 6] (Wherein R ¹ and R ² have the same meanings as described above), the compound (a) can be obtained in the presence of a base in the same manner as for obtaining the compound (d) from the compound (c). The aldol reaction with hexafluoroacetone can lead to a 23-keto-26,26,26,27,27,27-hexafluoro compound (e), which is known in the art (for example, JP-A-63-63). (Described in JP-A-45249), the vitamin D derivative can be efficiently introduced.

Next, the method for producing the compound (1) of the present invention will be described in detail below.

[Chemical 7] (In the formula, R ¹ and R ² have the same meanings as described above.) The reaction with the methylated metal reagent is usually performed in an inert gas atmosphere. As the solvent, ethers, hydrocarbon solvents or mixtures thereof are used. Specific examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, t-butyl methyl ether, dioxane and the like. Further, examples of the hydrocarbon solvent include toluene, benzene, xylene, hexane, heptane and the like. Among these, diethyl ether and tetrahydrofuran are preferably used.

The amount of the solvent used is usually in the range of 5 to 100 times by weight the amount of the compound (2). Further, it is preferable to use these solvents that are dried before use. Examples of the methylated metal reagent include methyllithium, dimethylzinc, methylmagnesium halide and the like. Examples of methylmagnesium halides include methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide. The amount of the methylating metal reagent used is
The compound (2) is used in a molar ratio of 1.05 to 10 times, preferably 1.05 to 3 times.

The reaction is usually carried out in the range of -50 ° C to the boiling point of the solvent used. After completion of the reaction, for example, 0.1 to 3
The compound (1) is obtained by acid treatment with normal hydrochloric acid or sulfuric acid. Water is added to the reaction solution for extraction, neutralization, drying,
A usual post-treatment such as solvent removal may be performed.

The compound (1) thus produced can be purified by a method such as silica gel column chromatography and recrystallization. The compound (2) as a starting material can be obtained by the following method. When R ¹ is a protected hydroxyl group, it can be synthesized by a known method (for example, described in JP-A-5-59094), and when R ¹ is a hydrogen atom, it can be synthesized according to the method described in JP-A-5-59094. The following formula

Embedded image (In the formula, R ³ represents an alkyl group, an aryl group or an aralkyl group. R ⁶ represents a protective group for a hydroxyl group.)

The compound of the present invention has the following formula

[Chemical 9] (In the formula, R ¹⁰ represents a hydrogen atom or a hydroxyl group having a protective group. R ²⁰ represents a hydroxyl group-protecting group. X represents a halogen atom.). That is, a halide (f) having a protected hydroxyl group (for example, JP-A-5-
59094) and magnesium (g)
And then reacted with acetaldehyde to give (h),
It can be synthesized by subsequently oxidizing the hydroxyl group. The reaction of step A is usually carried out in an inert gas atmosphere using ethers, a hydrocarbon solvent or a mixture thereof as a solvent, and among them, diethyl ether and tetrahydrofuran are preferably used. The amount of the solvent used is usually in the range of 5 to 100 times the weight of the compound (f). Further, it is preferable to use these solvents that are dried before use.

It is preferable to use shavings of magnesium, and if necessary, iodine, dibromoethane, bromoethane, mercury chloride or the like may be used as an activator, and if necessary, ultrasonic waves are applied. While reacting, you may react. Further, it may be produced in the reaction system by the reaction of magnesium halide and alkali metal. The amount used is in the range of 1.05 to 10 times the molar ratio of the compound (f), and preferably in the range of 1.05 to 3 times. The reaction is usually 0
It is carried out within the range of from 0 ° C to the boiling point of the solvent used. The compound (g) produced by this reaction is very unstable, and therefore it is preferably used as it is in the next step without isolation.

Next, the step B will be described. The amount of acetaldehyde used is in the range of 1.05 to 10 times the molar ratio with respect to the compound (f), but preferably in the range of 1.05 to 3 times. , Acetaldehyde may be added as it is, or the compound (g) previously produced by dissolving it in the above reaction solvent may be added.
It may be added to the solution or may be blown in a gas state. Normally, the charging may be carried out at a temperature in the range of 0 ° C. to room temperature or lower, and then, if necessary, raised to a temperature not higher than the boiling point of the solvent.

The produced compound (h) may be purified by a method such as silica gel column chromatography or recrystallization, or may be subjected to the next oxidation step without purification.
As the oxidation reaction method (step C), any oxidation method that is usually used can be used as long as the protected hydroxyl group is not deprotected. For example, oxidation with chromic acid,
Oxidation with pyridinium chlorochromate, oxidation with dimethylsulfoxide (DMSO), Dess-Mar
tin reagent (1,1,1-triacetoxy-1-dihydro-1,2-benziodoxol-3 (1H) -one)
Ruthenium tetraoxide tetrapropylammonium salt-N-methylmorpholine-N-oxide (TPA
Oxidation by P) and the like.

The compound (1) whose hydroxyl group is not protected is, for example, Protective Grou.
ps in Organic Synthesis, J
own-Wiley & Sons, New Yor
k, pp10-142 (1991) and obtained by deprotection.

[0026]

EFFECT OF THE INVENTION Using the compound and the synthetic method of the present invention,
It enables efficient synthesis of vitamin D derivatives, including compounds having oxygen functional groups at the 23- and 25-positions and various functional groups at the 26- and 27-positions.

[0027]

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

Reference Example 1

[Chemical 10] (In the formula, Ts represents a p-toluenesulfonyl group.) 20-methyl-3β-methoxymethoxy-pregna-
1.93 g of 5,7-dien-21-ol and 4.2 ml of pyridine were dissolved in 50 ml of methylene chloride to give p-chloride.
Toluenesulfonyl (1.20 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel chromatography, and the fractions eluted with ethyl acetate: hexane (1: 7) were collected,
Target 20-methyl-21- (p-toluenesulfonyloxy) -3β-methoxymethoxy-pregna-5,7
-1.66 g of diene (10) was obtained (61% yield). ¹ H NMR (CDCl ₃ ) δ: 0.58 (3H,
s), 0.93 (3H, s), 1.02 (3H, d, J
= 6.0 Hz), 1.2-2.0 (16H, m), 2.
2-2.6 (2H, m), 2.46 (3H, s), 3.
38 (3H, s), 3.4-3.6 (1H, m), 3.
81 (1H, dd, J = 9.24, 6.27Hz),
3.98 (1H, dd, J = 9.24, 2.97H
z), 4.71 (2H, s), 5.36 (1H, m),
5.55 (1H, m), 7.35 (2H, d, J = 8.
25 Hz), 7.79 (2H, d, J = 8.25H
z).

Reference Example 2

[Chemical 11] 20-Methyl-21- (p-toluenesulfonyloxy) -3β-methoxymethoxy-pregna-5,7-diene (10) 0.74 g of dimethylformamide 10 m
225 mg of potassium cyanide was added to the suspension 1 and the mixture was mixed at 90 ° C for 1 hour.
Stirred for hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 21-cyano-20-methyl-3β-methoxymethoxy-pregna-5,7-diene (11) 0.80 g (crude). The product, as such, was used as the starting material in Example 2). ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H,
s), 0.94 (3H, s), 1.20 (3H, d, J
= 6.93 Hz), 1.2-2.6 (20H, m),
3.39 (3H, s), 3.5-3.6 (1H, m),
4.71 (2H, s), 5.39 (1H, m), 5.5
7 (1H, m).

Reference Example 3

[Chemical 12] 1.20 g of 20-methyl-21- (p-toluenesulfonyloxy) -3β-methoxymethoxy-pregna-5,7-diene (10) was dissolved in 30 ml of acetone,
Lithium bromide (3.0 g) was added, and the mixture was heated under reflux for 4 hours. After cooling, the mixture was partitioned with water and ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue is subjected to silica gel chromatography, and the fractions eluted with ethyl acetate: hexane (1:20) are collected to give the desired 21-bromo-20-methyl-3.
β-methoxymethoxy-pregna-5,7-diene (1
2) 904 mg was obtained (yield 91%). ¹ H NMR (CDCl ₃ ) δ: 0.64 (3H,
s), 0.94 (3H, s), 1.12 (3H, d, J
= 6.27 Hz), 1.2-2.0 (16 H, m),
2.3-2.6 (2H, m), 3.38 (3H, s),
3.3-3.4 (1H, m), 3.5-3.6 (2H,
m), 4.71 (2H, s), 5.40 (1H, m),
5.57 (1H, m).

Reference Example 4

[Chemical 13] Magnesium 3 mg and dibromoethane (3 μl) were added to tetrahydrofuran 1 ml and heated to reflux to activate magnesium. 50 mg of 21-bromo-20- there
Methyl-3β-methoxymethoxy-pregna-5,7-
A solution of diene (12) in 1 ml of tetrahydrofuran was added, and the mixture was heated and refluxed again to prepare a Grignard reagent. Acetaldehyde gas was introduced therein at room temperature and stirred for 10 minutes. After the reaction was completed, water and 1N-hydrochloric acid were added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was subjected to thin layer chromatography (developing solvent was ethyl acetate: chloroform (1: 1).
0)) to give the desired 20- (2-hydroxypropan-1-yl) -3β-methoxymethoxy-pregna.
12 mg of 5,7-diene (13) was obtained (yield 28%,
Low polar isomer: high polar isomer = 1: 4). Low polar isomer: ¹ H NMR (CDCl ₃ ) δ: 0.
65 (3H, s), 0.94 (3H, s), 0.99
(3H, d, J = 6.3 Hz), 1.19 (3H, d,
J = 5.9 Hz), 1.2-2.6 (20H, m),
3.38 (3H, s), 3.4-3.6 (1H, m),
3.91 (1H, m), 4.71 (2H, s), 5.3
8 (1H, m), 5.56 (1H, m). Highly polar isomer: ¹ H NMR (CDCl ₃ ) δ: 0.
63 (3H, s), 0.94 (3H, s), 0.98
(3H, d, J = 5.9 Hz), 1.18 (3H, d,
J = 5.9 Hz), 1.2-2.6 (20H, m),
3.38 (3H, s), 3.4-3.6 (1H, m),
3.91 (1H, m), 4.71 (2H, s), 5.3
8 (1H, m), 5.56 (1H, m).

Reference Example 5

Embedded image 9 mg of 20- (2-hydroxypropan-1-yl)
To a solution of -3β-methoxymethoxy-pregna-5,7-diene (13) and 0.5 ml of dichloromethane, 10 mg of N-methylmorpholine-N-oxide, 25 mg of powdered molecular sieves 4A, 3 mg of tetra-n-propylammonium parthenate. Were sequentially added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was directly subjected to silica gel column chromatography, and ethyl acetate: dichloromethane (1:
The fractions eluted in 2) were collected to obtain 2.0 mg of the desired 20-acetonyl-3β-methoxymethoxy-pregna-5,7-diene (14) (yield 23%).

Reference Example 6

[Chemical 15] (1S, 3R, 20R) -20-methyl-1,3-bis (methoxycarbonyloxy) -pregna-5,7-dien-21-ol (15) 300 mg was added to pyridine 10.
It was dissolved in ml, 0.5 g of p-toluenesulfonyl chloride was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with 1N-hydrochloric acid water, saturated aqueous sodium hydrogen carbonate,
The extract was washed successively with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel with ethyl acetate: chloroform (1:
Fractions eluted in 3) were collected and collected (1S, 3R, 20R)
-1,3-bis (methoxycarbonyloxy) -20-
0.42 g of methyl-21- (p-toluenesulfonyloxy) -pregna-5,7-diene (16) was obtained (yield 100%). ¹ H NMR (CDCl ₃ ) δ: 0.58 (3H,
s), 0.99 (3H, s), 1.00 (3H, d, J
= 5.0 Hz), 1.2-2.7 (16H, m), 2.
45 (3H, s), 3.77 (3H, s), 3.79.
(3H, s), 3.8-4.0 (2H, m), 4.8-
5.0 (2H, m), 5.35 (1H, m), 5.68
(1H, m), 7.35 (2H, d, J = 8.58H
z), 7.78 (2H, d, J = 8.25Hz).

Reference Example 7

Embedded image (1S, 3R, 20R) -1,3-Bis (methoxycarbonyloxy) -20-methyl-21- (p-toluenesulfonyloxy) -pregna-5,7-diene (1
6) 400 mg of sodium cyanide was added to a suspension of 540 mg of dimethyl sulfoxide, and the mixture was stirred at 90 ° C. for 2 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated saline,
After dried over magnesium sulfate, concentrated under reduced pressure (1S, 3R,
20R) -21-cyano-20-methyl-pregna
200 mg of 5,7-diene-1,3-diol (17)
(Crude product was used as it was as the starting material in Reference Example 8). ¹ H NMR (CDCl ₃ ) δ: 0.63 (3H,
s), 0.91 (3H, s), 1.17 (3H, d, J
= 6.6 Hz), 1.2-2.7 (20 H, m), 3.
74 (3H, s), 4.04 (1H, m), 5.35.
(1H, m), 5.68 (1H, d, J = 3.6H
z).

Reference Example 8

[Chemical 17] (1S, 3R, 20R) -21-Cyano-20-methyl-pregna-5,7-diene-1,3-diol (1
7) To a solution of 190 mg and lutidine 0.3 ml in dichloromethane 20 ml was added t-butyldimethylsilyl triflate 0.35 ml, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure (1S, 3R, 20R) -1,3-bis (t-).
Butyldimethylsilyloxy) -21-cyano-20-
Methyl-pregna-5,7-diene (18) 200 mg
(Crude product, used as is in the starting material of Example 3). ¹ H NMR (CDCl ₃ ) δ: 0.0-0.06 (1
2H, s × 2), 0.88 (18H, s × 2), 0.6
4 (3H, s), 0.90 (3H, s), 1.19 (3
H, d, J = 6.59 Hz), 1.2-2.6 (18
H, m), 3.69 (1H, m), 4.07 (1H,
m), 5.31 (1H, m), 5.58 (1H, d, J
= 5.3 Hz).

Reference Example 9

Embedded image (1S, 3R, 20R) -1,3-bis (t-butyldimethylsilyloxy) -21-acetonyl-pregna
2,7-Diene (21) (29.4 mg) was dissolved in diethyl ether (300 ml) and the atmosphere was replaced with argon gas for 1 hour, followed by irradiation with a low pressure mercury lamp (10 W) for 90 minutes (0 to 10 ° C.). High pressure mercury lamp (100W)
And use Pyrex glass and 0.1 MSnCl2 / 5N HCl as a filter for an additional 100
Irradiated for 5 minutes (5 to 30 ° C.). The reaction mixture was concentrated under reduced pressure at 15 ° C or lower, the residue was dissolved in 100 ml of ethyl acetate,
The mixture was heated under reflux for 3 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography,
(1S, 3R, 20R) -1,3-Bis (t-butyldimethylsilyloxy) -20-acetonyl-9,10-
Secopregna-5Z, 7E, 10 (19) -triene (19) (8.0 mg, yield 26%) was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.05-0.06
(12H, m), 0.57 (3H, s), 0.88 (1
8H, s × 2), 0.93 (3H, d, J = 6.5H
z), 1.1-2.7 (19H, m), 2.12 (3
H, s), 4.18 (1H, m), 4.36 (1H,
m), 4.86 (1H, d, J = 2.5Hz), 5.1
7 (1H, s), 6.01 (1H, J = 11.0H
z), 6.23 (1H, J = 11.0 Hz).

Example 1

[Chemical 19] To a solution of 21-cyano-20-methyl-1α, 3β-bis (methoxymethoxy) -pregna-5,7-diene 25 mg and tetrahydrofuran 0.50 ml, methyllithium 0.99M tetrahydrofuran solution 0.56 ml
Was added dropwise, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution and 1N-hydrochloric acid were added, the mixture was stirred at room temperature for 30 minutes, and then extracted twice with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, the fractions eluted with ethyl acetate: chloroform (1:10) were collected, and the desired 20-acetonyl-1α, 3β-bis (methoxymethoxy) -pregna-5,7- was collected. 3.0 mg of diene (20) was obtained (yield 12%). ¹ H NMR (CDCl ₃ ) δ: 0.67 (3H,
s), 0.93 (3H, d, J = 6.0 Hz), 0.9
6 (3H, s), 1.2-2.6 (18H, m), 2.
13 (3H, s), 3.37 (3H, s), 3.41
(3H, s), 3.65 (1H, m), 3.92 (1
H, m), 4.63, (1H, d, J = 6.9 Hz),
4.69 (2H, s), 4.81 (1H, d, J = 7.
2Hz), 5.37 (1H, m), 5.68 (1H,
m).

Example 2

Embedded image To a solution of 21-cyano-20-methyl-3β-methoxymethoxy-pregna-5,7-diene (11) 0.80 g (crude product, obtained in Reference Example 2) in tetrahydrofuran 5 ml was added methyllithium. 3 ml of a 0.99 M tetrahydrofuran solution was added dropwise. After stirring at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, the fractions eluted with ethyl acetate: n-hexane (1:10) were collected, and the desired 20-acetonyl-3β-methoxymethoxy-pregna-5,7-diene (14 ) 58 mg was obtained (25% yield from (10)). ¹ H NMR (CDCl ₃ ) δ: 0.66 (3H,
s), 0.94 (3H, s), 0.96 (3H, d, J
= 7.59 Hz), 1.2-2.6 (20H, m),
2.13 (3H, s), 3.38 (3H, s), 3.4
-3.6 (1H, m), 4.71 (2H, s), 5.3
8 (1H, m), 5.57 (1H, m).

Example 3

[Chemical 21] (1S, 3R, 20R) -1,3-Bis (t-butyldimethylsilyloxy) -21-cyano-20-methyl-
To a solution of 51 mg of pregna-5,7-diene (18) and 3 ml of tetrahydrofuran, 0.37 ml of a 1.0 M solution of methyllithium in tetrahydrofuran at -40 ° C.
Was added dropwise, and the reaction mixture was slowly heated to -20 ° C.
It was stirred at that temperature for a further 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate.
The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate: hexane (1: 7) were collected,
S, 3R, 20R) -1,3-Bis (t-butyldimethylsilyloxy) -21-acetonyl-pregna-5
44 mg of 7-diene (21) was obtained (yield 85%). ¹ H NMR (CDCl ₃ ) δ: 0.05-0.10
(12H, m), 0.66 (3H, s), 0.88 (1
8H, s × 2), 0.96 (3H, d, J = 6.5H
z), 1.1-2.7 (18H, m), 2.13 (3
H, s), 3.69 (1H, m), 4.03 (1H,
m), 5.31 (1H, m), 5.58 (1H, d, J
= 5.6 Hz).

Claims (2)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ represents a hydrogen atom, a hydroxyl group or a hydroxyl group having a protective group, and R ² represents a hydrogen atom or a protective group of a hydroxyl group.). 2. A compound of the general formula (2) (Wherein R ¹ and R ² have the same meanings as in claim 1), and a method of producing a compound of claim 1 by reacting a compound represented by the formula (1) with a methylated metal reagent.