JPS6314720B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 24(R) or 24(S)-hydroxycholesterols. For more details see 24
-Oxo-△ ²⁵ -Cholesterol is reduced with lithium aluminum hydride in the presence of optically active 2,2'-dihydroxy-1,1'-binaphthyl,
24(R) or 24(S)-hydroxy-△ ²⁵ -cholesterols, and then catalytic reduction to convert the double bond at position 25 into a single bond, resulting in 24(R) or
The present invention relates to a method for producing 24(S)-hydroxycholesterols. Conventionally, 24-hydroxycholesterols, such as 24-hydroxycholesterol and 1α,24-dihydroxycholesterol, have been converted into 3β,24-dihydroxycholesta-5,7-diene or 1α,
It is known that 24-hydroxycholecalciferol or 1α,24-dihydroxycholecalciferol, which is useful as a pharmaceutical, is derived through 3β,24-trihydroxycholester-5,7-diene, and The 24-position epimer of 1α,24-dihydroxycholecalciferol, 1α,24(R)-dihydroxycholecalciferol and 1α,24(S)-dihydroxycholecalciferol, have subtle pharmacological effects. It is known that there are significant differences (FEBS Letters, 76 ,
177 (1977), Biochem.Biophys.Res.Commun.
91, 827 (1979)). Furthermore, in the case of 24-hydroxycholecalciferol, it is known that the pharmacological properties of 24(R)-hydroxycholecalciferol and 24(S)-hydroxycholecalciferol are different. (Biochem.Biophys.Res.
Commun., 62 , 485 (1975)). However, conventionally, such 24(R) or 24(S)-
Hydroxycholecalciferol, or 1α,
24(R) or 24(S)-hydroxycholesterol, which can lead to 24(R) or 1α,24(S)-dihydroxycholecalciferol, or 1α,24(R)
Or, as a method for obtaining an epimer of either 1α,24(S)-dihydroxycholesterol,
For example, a racemic mixture of 1α,3β,24-trihydroxycholest-5-ene derived from 1α,24-dihydroxycholesterol or 1α,3β,24-trihydroxycholest-5,7-diene is prepared using a special carrier. A method of separating each epimer by subjecting it to chromatography and obtaining one of the epimers (J.Chem.Soc.,
Parkin Trans 1975 , 1421, Tetrahedron Lett.,
1975, 2203), and it is only known that 24(R) or 24(S)-hydroxycholesterol or 1α,24(R) or 1α,24(S) can be directly produced by reaction.
- There is no known method for producing either epimer of dihydroxycholesterol. However, the present inventors discovered that 24-hydroxycholesterol, 1α,24, is a useful intermediate that can lead to 24-hydroxycholecalciferol or 1α,24-dihydroxycholecalciferol.
- As a result of intensive research to find a method for producing either one of the 24-position epimers of hydroxycholesterols such as dihydroxycholesterol, we found that 24-
By treating oxo- ^Δ25 -cholesterol with lithium aluminum hydride in the presence of optically active 2,2'-dihydroxy-1,1'-binaphthyl and lower aliphatic alcohols, the 24-cholesterol The oxo group of the compound is reduced to obtain either a 24(R) or 24(S)-hydroxy epimer, and the double bond at position 25 of such compound is further catalytically reduced to form a single bond. The present invention was achieved by discovering that 24(R)- or 24(S)-hydroxycholesterols can be obtained by converting 24(R)- or 24(S)-hydroxycholesterols. That is, the present invention is based on the following formula [] [In the formula, R ₁ represents a hydrogen atom or a protecting group, and R ₂ represents a hydrogen atom. ] 24-oxo-△ ²⁵ -cholesterol represented by optically active 2,2'-dihydroxy-1,
The following formula is characterized by reduction with lithium aluminum hydride in the presence of 1'-binaphthyl and lower aliphatic alcohols in an inert organic solvent. [In the formula, R ₁ represents a hydrogen atom or a protecting group, and R ₂ represents a hydrogen atom. ] This is a method for producing 24(R) or 24(S)-hydroxycholesterol represented by the following. The 24-oxo-Δ ²⁵ -cholesterols represented by the above formula [] used as a starting material in the present invention are new compounds that have not been described in the literature, such as 3β-tetrahydropyranyloxy-col-cholesterols obtained from cholenic acid. By reacting 5-en-24-al with propenylmagnesium bromide, 24-hydroxy-△ ²⁵ -cholesterol-3β
-tetrahydropyranyl ether, which is
For example, it can be obtained by oxidation with pyridinium dichromate. In the above formula [], R ₁ is a hydrogen atom or a protective group, and R ₂ is a hydrogen atom. Protecting groups include acetyl, propanoyl, butanoyl, pentanoyl, capronyl, cyclohexanoyl, chloroacetyl, bromoacetyl,
Bonded with an acetyl group such as benzoyl, p-bromobenzoyl, p-nitrobenzoyl, ethylbenzoyl, a hydroxyl group such as a tetrahydropyranyl, methoxymethyl group, or a trialkylsilyl group such as a trimethylsilyl group or t-butyldimethylsilyl group. Examples include groups that form ether bonds. Specific examples of the compounds represented by the above formula [] are as follows. (1) 24-oxo-cholester-5,25-diene-
3β-ol, (2) 24-oxo-cholesta-5,25-diene-
3β-ol-3-tetrahydropyranyl ether, (3) 24-oxo-cholesta-5,25-diene-
3β-ol-3-acetate, (4) 24-oxo-cholesta-5,25-diene-
3β-ol-3-propionate, (5) 24-oxo-cholesta-5,25-diene-
3β-ol-3-butyrate, (6) 24-oxo-cholester-5,25-diene-
3β-ol-3-methoxymethyl ether, (7) 24-oxo-cholesta-5,25-diene-
3β-ol-3-trimethylsilyl ether. In the present invention, first, 24 represented by the above formula []
-Oxo-△ ²⁵ -Cholesterol is reduced with lithium aluminum hydride in the presence of optically active 2,2'-dihydroxy-1,1'-binaphthyl and lower aliphatic alcohol in an inert organic solvent. . By performing such an operation, the oxo group at position 24 of the compound of the above formula [] is reduced to 24(R)-hydroxy or 24(S)-hydroxy, and the compound of the above formula having a double bond at the 25th position is reduced to 24(R)-hydroxy or 24(S)-hydroxy. 24 represented by []
(R) or 24(S)-hydroxycholesterols are produced. The optically active 2,2'-dihydroxy-1,1'-binaphthyl used here is produced by Bull.Soc.Chim.
Fr. 43 , 1388 (1928), the obtained (±)-binaphthyl phosphoric acid was optically resolved with cinchonine, and this was treated with lithium aluminum hydride to obtain (S)-(- )−2,2′−
It can be obtained as dihydroxy-1,1'-binaphthyl or (R)-(+)-2,2'-dihydroxy-1,1'-binaphthyl. Examples of lower aliphatic alcohols include methanol, ethanol, isopropyl alcohol,
Examples include propyl alcohol, butyl alcohol, t-butyl alcohol, pentyl alcohol, hexyl alcohol, among others, methanol, ethanol, isopropyl alcohol,
Lower aliphatic alcohols having 1 to 4 carbon atoms such as t-butyl alcohol are preferred. Examples of inert organic solvents include aliphatic or aromatic ethers such as tetrahydrofuran, dioxane, diglyme, and anisole, n-hexane, heptane, cyclohexane, decalin,
aliphatic hydrocarbons such as methylcyclohexane,
Examples include aromatic hydrocarbons such as benzene, toluene, quinolene, and ethylbenzene. Moreover, a mixed solvent of these can also be used in the same manner. The optically active 2,2'-dihydroxy-
The amount of 1,1'-binaphthyl used is the raw material compound.
The amount is 0.8 to 1.5 mol, preferably equimolar, per 1 mol of 24-oxo-Δ ²⁵ -cholesterol.
In addition, the amount of lower aliphatic alcohols used is 0.8 to 2
mol, preferably 1 to 1.2 mol. In addition, the amount of lithium aluminum hydride used as a reducing reagent is 24-oxo-△ ²⁵ −
0.8 to 1.5 mol per 1 mol of cholesterol,
Preferably, the amounts are equimolar. 24-Oxo-△ ²⁵ -cholesterol is actually hydrogenated in the presence of optically active 2,2'-dihydroxy-1,1'-binaphthyl and lower aliphatic alcohols in the above-mentioned inert organic solvent. The following method is preferably employed for reduction with aluminum lithium. That is, the inert organic solvent (usually 1.5 to 2.0M solution) of lithium aluminum hydride is prepared, and an inert organic solution of lower aliphatic alcohol (0.7M relative to lithium aluminum hydride) is prepared.
~1.3M equivalent) was added and stirred, and to this was added an inert organic solution of optically active 2,2'-dihydroxy-1,1'-binaphthyl (0.3 to 1.5M equivalent relative to lithium aluminum hydride). Stir further. 24-oxo-
△ ²⁵ - Inert organic solution of cholesterol (0.2 to 1.0 equivalent to lithium aluminum hydride)
The reduction reaction is suitably carried out by adding dropwise. The temperature when reducing by dropping an inert organic solution of 24-oxo-△ ²⁵ -cholesterol is usually in the range of -200 to 50°C, preferably in the range of -100 to 0.
℃ range. The reaction time varies depending on the amount of reaction, the type of solvent used, the temperature, etc., but is usually about several minutes to one hour. As in the present invention, when reduction is carried out with lithium aluminum hydride in the presence of optically active 2,2'-dihydroxy-1,1'-binaphthyl and lower aliphatic alcohols, optically active 2,2'- Dihydroxy-1,1'-binaphthyl, lower aliphatic alcohols and lithium aluminum hydride have the formula [R' is a lower alkyl group of a lower aliphatic alcohol. ] Form a complex represented by 24-oxo-△ ²⁵
- It is thought to reduce cholesterol (see Journal of American Chemical Society, 101 , 5843 (1979)). In addition, in the reduction method as in the present invention, (S)
By using -(-)-2,2'-dihydroxy-1,1'-binaphthyl, 24(S)-hydroxy-
△ ²⁵ -Cholesterol is (R)-(+)-2,
By using 2'-dihydroxy-1,1'-binaphthyl, 24(R)-hydroxy-Δ ²⁵ -cholesterols are obtained. 24 expressed by the above formula [] thus obtained
The isolation and purification of (R) or 24(S)-hydroxycholesterols is carried out after the completion of the above reduction reaction by crushing the excess reducing agent with alcohol and water, extracting with an organic solvent, drying, concentrating, distilling, and column column. This can be carried out by conventional methods such as chromatography.
24(S)-hydroxycholesterol of the above formula [] is 24(R) or 24(S)-hydroxycholecalciferol, 1α,24(R) or 1α,24(S)-
Active forms such as dihydroxycholecalciferol
It can be used as a synthetic intermediate for not only VD ₃ but also various other active forms of VD ₃ . In the present invention, 24(R) or 24(S)-hydroxycholesterol having a double bond at the 25th position represented by the above formula [] is further subjected to catalytic reduction, which is a known reaction per se. , 24(R) or 24(S)-hydroxycholesterol represented by the above formula [] is obtained. When carrying out catalytic reduction, it is preferable to carry out in the above-mentioned inert organic solvent, and in particular, for example, alcohols such as methanol and ethanol, hydrocarbons such as benzene and cyclohexane, diethyl ether, dioxane, tetrahydrofuran, etc. Ethers are preferably used. If desired, two or more of these may be used in combination. Any catalyst may be used as long as it is commonly used in this type of catalytic reduction reaction, but particularly preferred are palladium catalysts, platinum catalysts, and the like. For example, 5% palladium on carbon is particularly preferably used. The amount of catalyst used is, for example, 50 mg to 10 g, preferably 50 mg to 1 g, per 1 g of raw material. The reaction usually proceeds easily under mild conditions, and conditions of room temperature and 1 atm are sufficient, but if desired, it may be carried out at a temperature of -60°C to 150°C and under pressure. The reaction time depends on the amount of catalyst used, the concentration of raw materials,
Although it varies depending on other reaction conditions, the reaction ends when equimolar amounts of hydrogen are absorbed, and the desired 24(R)- or 24(S)-hydroxycholesterol represented by the above formula [] is obtained. After the reaction is completed, the compound represented by the above formula [] is separated and purified, for example, as follows. The catalyst in the reaction mixture is separated, thoroughly washed with an organic solvent, and the organic layer is concentrated under reduced pressure to obtain a product. Purification of the product is achieved by further performing separation operations such as column chromatography, thin layer chromatography, and distillation. Thus obtained, expressed by the above formula []
The 24(R) or 24(S)-hydroxycholesterol is then subjected to acid or alkali hydrolysis or reductive decomposition, which is known per se, to remove the protecting groups of the protected hydroxyl groups it has. , can be formed into a hydroxyl group. Alternatively, the hydroxyl group may be further protected if necessary. In order to protect a hydroxyl group, for example, when the protecting group is an acyl group, by reacting an acid halide or an acid anhydride with pyridine, and when the protecting group is a trialkylsilyl group, by reacting the acid halide or acid anhydride with pyridine, This reaction is carried out by reacting a silyl halide with imidazole, and when the protecting group is tetrahydropyranyl, by contacting dihydropyran in the presence of an acidic catalyst such as para-toluenesulfonic acid. Such removal or introduction of the protecting group can also be carried out after reduction with aluminum hydride in the presence of the above-mentioned 2,2'-dihydroxy-1,1'-binaphthyl and lower aliphatic alcohols. Thus, according to the invention, 24-oxo-△ ²⁵ −
24(R) with extremely high yield compared to cholesterols.
or 24(S)-hydroxycholesterols, such as 24(R)-hydroxycholesterol, 24(S)
-Hydroxycholesterol, 1α,24(R)-dihydroxycholesterol, 1α,24(S)-dihydroxycholesterol, 24(R)-hydroxy-
△ ²⁵ -cholesterol, 24(S)-hydroxy-△
²⁵ -cholesterol, 1α,24(R)-dihydroxy-Δ ²⁵ -cholesterol, 1α,24(S)-dihydroxy-Δ ²⁵ -cholesterol, etc. are obtained. Hereinafter, the present invention will be explained in more detail with reference to Examples. Reference example (i) Synthesis of cholesta-5,25-diene-3β,24-diol-3-tetrahydropyranyl ether A mixture of 0.109 g of magnesium and 3 ml of tetrahydrofuran (THF) was stirred, and 0.45 ml of propenyl bromite was added to the mixture for 30 min. It was dripped in minutes. In addition, 3β-hydroxy-col-5-ene-24
A solution of -R in 3 ml of THF was added, and the mixture was further stirred for 3 hours. Ether was added to the resulting reaction solution, washed with an aqueous ammonium chloride solution, dried over magnesium sulfate, and then the ether was distilled off to obtain 1.4 g of a product. This product was used in the next reaction without being purified. In addition, in order to obtain a sample for analysis, a part of the above product was subjected to silica gel column chromatography (benzene: ethyl acetate = 50:1),
A sample for analysis was obtained. The spectral data of this product were as follows. Melting point: 289-290℃ NMR ( _CDCl3 , δ (ppm)): 0.67 (3H, s, 13
−CH ₃ ), 0.94 (3H, d, J=6Hz, 20−CH ₃ ), 1.02 (3H, s, 10−CH ₃ ), 1.72 (3H, s, 25
_-CH3 ), 3.5 (2H, m, THP proton), 3.8-4.1 (2H, m, 3α-H, 24-H), 4.70 (1H, br, THP proton), 4.8, 4.9 (26- _H2 ), 5.33 (1H, br, 6-H). (ii) 24-oxo-cholesta-5,25-diene-
Synthesis of 3β-ol-3-tetrahydropyranyl ether Cholesta-5,25-diene obtained in (i)
1.4 g of 3β,24-diol-3-tetrahydropyranyl ether was dissolved in 30 ml of dichloromethane-dimethylformamide (1:1), 3 g of pyridinium dichromate was added, and the mixture was stirred at room temperature for 3 hours. 250 ml of ether was added to the reaction solution, and the solution was passed through a Florisil column, then washed with 2N hydrochloric acid and sodium hydrogen carbonate solution, dried over magnesium sulfate, and the ether was distilled off to obtain 1300 g of a crude product. This was purified by silica gel column chromatography (benzene) to obtain the desired 24-oxo-cholester-5,25-diene-
1.1 g of 3β-ol-3-tetrahydropyranyl ether was obtained. Melting point: 136-138℃ NMR ( _CDCl3 , δ (ppm)): 0.68 (3H, s, 13
_-CH3 ), 0.94 (3H, d, J=6Hz, 20- _CH3 ), 1.02 (3H, s, 10- _CH3 ), 1.87 (3H, s, 25- _CH3 ), 3.4 (2H, m , proton of THP), 3.9 (1H, m, 3α-H), 4.68 (1H, br, proton of THP), 5.3 (1H, br, 6-H), 5.7, 5.9 (26-H ₂ ). Example 1 (24R)-24-hydroxy-cholesto-5,25
-Synthesis of diene-3β-ol 114mg of lithium aluminum hydride
Suspend in 1.5 ml of THF, and add 1.5 ml of a 2 molar ethanol solution of tetrahydrolafuran at 0°C. After 10 minutes, 5 ml of a THF solution of R-(+)-2,2'-dihydroxy-1,1'-binaphthyl was added at 0°C, and the mixture was stirred at room temperature for 1 hour. This solution was cooled to -80 to -85°C with dry ice-ether to obtain 24-oxo-cholester-5,25 obtained in reference example (ii).
A solution of 430 mg of -diene-3β-ol-3-tetrahydropyranyl ether in 5 ml of THF was added. Stirred for an additional 18 hours at -80 to -85°C. Add water and ammonium chloride solution, extract with ethyl acetate, treat the extracted solution in the usual manner, and perform silica gel chromatography (benzene: ethyl acetate = 100:1).
This was purified to obtain 300 mg of 24-OH compound. Melting point: 118-120°C NMR ( _CDCl3 , δ (ppm): 0.68 (3H, s, 13- _CH3 ), 0.95 (3H, d, J=6Hz, 20- _CH3 ), 1.01 (3H, s, 10− _CH3 ), 1.73(3H, s, 25−
_CH3 ), 3.5 (2H, m, protons of THP), 3.8-4.1 (2H, m, 3α-H, 24-H), 4.7 (1H, m, protons of THP), 4.81, 4.90 (2H, brs , 26-H ₂ ), 5.32 (1H, m, 6-H). The above 24-OH form was treated with HCl in the usual manner and 3
The tetrahydropyranyl group at the position was removed and then reacted with benzoyl chloride to give 24-hydroxy-Δ ²⁵ -cholesterol-3β,24-dibenzoate. This was dissolved in an ethanol-tetrahydrofuran solution and catalytically reduced with 5% PD-C.
24-hydroxycholesterol-3β,24-dibenzoate was obtained. This compound is HPLC
The retention time and 13C−nmr are shown in the literature (Tetrahe
24(R)-hydroxycholesterol-3β, described in dron Letters No. 26, 2203-2206, 1975.
It was in good agreement with that of 24-dibenzoate. According to HPLC analysis results, approximately 5% of 24
Although it contains (S)-hydroxycholesterol-3β,24-dibenzoate, the above compound is almost pure 24(R)-hydroxycholesterol-3β,24-dibenzoate.
It was 3β,24-dibenzoate. Example 2 Instead of using R-(+)-2,2'-dihydroxy-1,1'-binaphthyl, S-(-)-2,2'-
Using dihydroxy-1,1′-binaphthyl, 24
-Oxo-cholesta-5,25-dien-3β-ol-3-tetrahydropyranyl ether was reduced in the same manner as in Example 1, and 24-hydroxy-cholesta-5,25-dien-3β-ol-3
-Tetrahydropyranyl ether (melting point: 112~
114° C.), which was treated with HCl to remove the tetrahydropyranyl group at position 3, leading to 24-hydroxycholest-5-en-3β-ol, and then reacted with benzoyl chloride. 24-hydroxy-Δ ²⁵ -cholesterol-3β,24-dibenzoate was prepared, and this was catalytically reduced to obtain 24-hydroxycholesterol-3β,24-dibenzoate. This compound has HPLC retention time and
The 13C-nmr was in good agreement with that of 24(S)-hydroxycholesterol-3β,24-dibenzoate described in the literature.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ₁ represents a hydrogen atom or a protecting group, and R ₂ represents a hydrogen atom. ] 24-oxo-△ ²⁵ -cholesterol represented by optically active 2,2'-dihydroxy-1,
The following formula is characterized by reduction with lithium aluminum hydride in an inert organic solvent in the presence of 1'-binaphthyl and a lower aliphatic alcohol [] [In the formula, R ₁ represents a hydrogen atom or a protecting group, and R ₂ represents a hydrogen atom. ] A method for producing 24(R) or 24(S)-hydroxycholesterol represented by: