JPS623840B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel compound, 25-hydroxy-24
-Relating to oxocholesterol derivatives and methods for producing the same. More specifically, various active forms of vitamin D ₃
A novel compound extremely useful as a manufacturing intermediate, 25-
The present invention relates to a hydroxy-24-oxocholesterol derivative and a method for producing the same. The 25-hydroxy-24-oxocholesterol derivative provided by the present invention and the method for producing the same have not been previously known. The 25-hydroxy-24-oxocholesterol derivative of the present invention has the following formula [] [In the formula, R ¹ and R ⁵ are hydrogen atoms or hydroxyl group protecting groups, R ² is hydrogen atoms, hydroxyl groups, or protected hydroxyl groups, R ³ and R ⁴ are hydrogen atoms, or R ³ and R ⁴ are combined Represents a carbon-carbon bond. ] It is expressed as . In Japanese Patent Application Laid-open No. 50-140436, the following formula [] Cholesta-1,4,6-triene-3-
A method for producing one derivatives is described, and the name 24-keto-25-hydroxycholesterol is disclosed as one of the cholesterol derivatives represented by the above formula []. However, the above-mentioned publication does not describe a specific method for producing 24-keto-25-hydroxycholesterol, examples using this compound, or its physical properties. Therefore, the 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] provided by the present invention is a novel compound produced for the first time by the present inventors. R ¹ in the novel compound 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] provided by the present invention is a hydrogen atom or a hydroxyl group-protecting group. Examples of such hydroxyl protecting groups include acetyl group, propanoyl group, butanoyl group, pivaloyl group, pentanoyl group, cyclohexanoyl group, chloroacetyl group, bromoacetyl group, benzoyl group, p-bromobenzoyl group, p-nitrobenzoyl group. aliphatic or aromatic carboxylic acid residues having 1 to 12 carbon atoms, such as ethylbenzoyl group, toluyl group, or their nitro-, halogen-, or alkoxy-substituted derivatives, or trialkyl group, such as trimethylsilyl group, dimethyl-t-butylsilyl group, etc. 2 such as silyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, etc.
- A cyclic ether group, etc. can be mentioned. ^R2
represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. Examples of such protected hydroxyl groups include hydroxyl groups protected with the above-mentioned protecting groups. R ³ and R ⁴ represent a hydrogen atom or R ³ and R ⁴ together represent a carbon-carbon bond. Therefore, according to the present invention, 25-hydroxy-24-oxocholesterols in which R ² , R ³ and R ⁴ are hydrogen atoms, R ² is a hydroxyl group or a protected hydroxyl group,
1α・3β・25-trihydroxy-24-oxocholest-5-enes in which R ³ and R ⁴ are hydrogen atoms, R ² is a hydrogen atom, and R ³ and R ⁴ together form a carbon-carbon bond 3β・25-dihydroxy-24-
Oxocholesta-5,7-dienes, 1α,3β-25-trihydroxy-24-oxocholesta-5, where R ² is a hydroxyl group or a protected hydroxyl group, and R ³ and R ⁴ together form a carbon-carbon bond. 25-hydroxy-24-oxocholesterol derivatives such as 7-dienes are provided. Examples of such 25-hydroxy-24-oxocholesterol derivatives include the following. That is, for example, (1) 3β·25-dihydroxy-24-oxocholest-5-ene (2) 3β·25-dihydroxy-24-oxocholest-5-ene-3-acetate (3) 3β·25-dihydroxy-24- Oxocholest-5-ene-3-benzoate (4) 25-hydroxy-24-oxocholest-5-
En-3,2'-tetrahydropyranyl ether (5) 25-hydroxy-24-oxocholest-5-
En-3-trimethylsilyl ether (6) 25-hydroxy-24-oxocholesterols such as 3β・25-dihydroxy-24-oxocholest-5-ene-3-p-toluenesulfonate, (7) 1α,・3β・25 -Trihydroxy-24-oxocholest-5-ene (8) 1α, 3β, 25-trihydroxy-24-oxocholest-5-ene-1, 3-diacetate (9) 1α, 3β, 25-trihydroxy-24 -Oxocholest-5-ene-1,3-dibenzoate (10) 25-hydroxy-24-oxocholest-5-
1α, 3β, 25-trihydroxy-24-oxocholest-5-enes such as ene-1, 2', 3, 2'-ditetrahydropyranyl ether, (11) 3β, 25-dihydroxy-24-oxocholest-5・7-Diene (12) 3β・25-dihydroxy-24-oxocholesta-5,7-dienes such as 3β・25-dihydroxy-24-oxocholesta-5,7-diene-3-acetate, (13) 1α・3β·25-trihydroxy-24-oxocholesta-5,7-diene (14) 1α·3β· such as 1α·3β·25-trihydroxy-24-oxocholesta-5·7-diene-1·3-diacetate Examples include 25-trihydroxy-24-oxocholester-5,7-dienes. Therefore, according to the present invention, a method for producing a novel 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] is also provided. In other words, the following formula [] [In the formula, R ₁ is a hydrogen atom or a protecting group for a hydroxyl group, R ² is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R ³ and R ⁴ are hydrogen atoms, or R ³ and R ⁴ taken together form a carbon-carbon Represents a bond. ] A 24-oxocholesterol derivative represented by is subjected to an oxygen oxidation reaction in the presence of a basic compound,
This is a method for producing a 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] by removing the protecting group or protecting the hydroxyl group, if necessary. R ¹ , R ² , R ³ and R ⁴ in the above formula [] are the same as in the above formula []. Therefore,
Examples of 24-oxocholesterol derivatives include 24-oxocholesterols, 1α/3β-dihydroxy-24oxocholest-5-enes, 3β-hydroxy-24-oxocholest-5,7-dienes, 1α/3β-dihydroxy-24- Examples include 24-oxocholesterol derivatives such as oxocholesta-5,7-dienes. In the present invention, represented by the above formula []
By subjecting a 24-oxocholesterol derivative to an oxygen oxidation reaction in the presence of a basic compound, the following formula [] [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as defined in the above formula []. It is believed that a 25-peroxy-24-oxocholesterol derivative represented by the following is produced, and then a 25-hydroxy-24-oxocholesterol derivative of the present invention represented by the above formula [] is produced from the derivative. Examples of basic compounds used here include alkali metals or alkaline earth metals such as lithium, sodium, and potassium, metal oxides such as barium oxide and silver oxide, sodium hydroxide, calcium hydroxide, sodium carbonate, and hydrogen carbonate. Hydroxides, carbonates, bicarbonates of alkali metals or alkaline earth metals such as sodium, sodium methoxide, potassium t-butoxide, sodium-
Lower alkyl alkoxides such as t-pentyl oxide, phenolates such as potassium phenolate and sodium phenolate, triethylamine, s
Examples include amines such as collidine, glymes, complex compounds of reaction compounds of cyclic glymes and alkali metals called crown compounds, and quaternary bases such as benzyltrimethylammonium hydroxide. Among these, lower alkyl alkoxides such as sodium t-butoxide, potassium t-butoxide, and sodium t-pentyl oxide are preferred. The amount of the basic compound to be used is preferably in the range of 0.1 to 100 mol per 1 mol of the 24-oxocholesterol derivative represented by the above formula [].
A range of ~10 moles is preferred. In carrying out the reaction, it is advantageous to use an organic liquid solvent as a solvent, such as aliphatic hydrocarbons such as hexane and heptane, alicyclic hydrocarbons such as cyclopentane and cyclohexane, benzene and toluene. , aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as chlorobenzene and carbon tetrachloride, methanol, ethanol,
Alcohol solvents such as propanol and t-butanol, diethyl ether, tetrahydrofuran,
Ethers such as dioxane and diglyme, ester solvents such as methyl acetate and ethyl acetate, sulfur-containing compounds such as diethylthioether and dimethyl sulfoxide, amines such as triethylamine and pyridine, nitro compounds such as nitrobenzene and dinitrobenzene, and acetonitrile. Examples include amides such as cyano compounds, dimethylformamide, tetramethylurea, and N-methylpyrrolidone. Among these, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and diglyme, alcohol solvents such as propanol and t-butanol, and mixed solvents of combinations thereof are particularly preferred. When performing oxygen oxidation in such a solvent in the presence of the basic compound, oxygen is added per mole of the 24-oxocholesterol derivative represented by the above formula [] while stirring the reaction solution in a closed system.
This can be achieved by absorbing 0.5 to 2 moles. The reaction temperature is preferably in the range of -40° to 100°C,
Particularly preferred is a temperature range of -20° to 20°C. The reaction time varies depending on the compound used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 10 hours, and the reaction time is preferably determined by the amount of oxygen absorbed. Any conventional method can be used to isolate and purify the target compound from the reaction mixture. That is, extraction, column chromatography, high performance liquid chromatography, and recrystallization methods are used. When a protecting group exists in the target compound, that is, in the 25-hydroxy-24-oxocholesterol derivative represented by the above formula [],
When at least one of OR ¹ and R ² is a protected hydroxyl group, the protecting group is added following the reaction,
Alternatively, it may be removed after isolation and purification. This elimination reaction of the protecting group is a known reaction per se. For example, when the protecting group is an acyl group, it can be easily removed by bringing it into contact with an acid or an alkali. Further, for example, when the protecting group is bonded to the oxygen atom of the hydroxyl group to form an ether group, it can be easily removed reductively or by contacting with an acid or an alkali. Furthermore, when a hydroxyl-protecting group is introduced into the target compound, the hydroxyl group can be protected subsequent to the reaction or after isolation and purification.
This hydroxyl group protection reaction is a known reaction per se. For example, when the protecting group is an acyl group, the protecting group can be easily introduced by reacting an acid halide or acid anhydride with pyridine. Further, when the protecting group is a trialkylsilyl group, the protecting group can be easily introduced by reacting a trialkylsilyl halide with imidazole. As detailed above, according to the present invention, it is represented by the above formula []. A 25-hydroxy-24-oxocholesterol derivative is obtained. Among these compounds, compounds in which R ³ and R ⁴ together represent a carbon-carbon bond are left as is, while compounds in which R ₃ and R ⁴ represent a hydrogen atom are removed at the 7-position using a conventional method such as hydrobromic acid. is halogenated, then subjected to dehydrohalogenation reaction to form a compound in which R ³ and R ⁴ together represent a carbon-carbon bond, and then subjected to photoirradiation and thermal isomerization reactions known per se. can lead to active vitamin _D3 such as 24-oxo-25-hydroxyvitamin _D3 . Therefore, the compounds of the present invention are extremely useful as intermediates for the production of active vitamin _D3 . The present invention will be explained in more detail below using examples. Example 1 3β-[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-24-one
1452 mg (3 mmol) and 504.5 mg (4.5 mmol) of potassium t-butoxide were added to a mixed solution of t-butanol and diglyme (1:1), and the bath temperature was 40°C.
The mixture was heated and stirred at ℃ to dissolve it. While controlling the temperature of the resulting solution at 20°C, 72 c.c. of oxygen was absorbed while stirring to complete the reaction. After the reaction was completed, appropriate amounts of water and ether were added to separate the layers, and the aqueous solution was extracted with ether. The ether separation and ether extract were combined, washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was subjected to column chromatography packed with silica gel (solvent: benzene-ethyl acetate system) to obtain 25-hydroxy-3β-[(tetrahydro-2H-pyran-2-yl)oxy]-cholesto-5. 291.5 mg of -en-24-one was obtained. The physical properties of this product were as follows. Melting point: 146-148°C (n-hexane) IR (KBr; cm ^-1 ); 3450, 2940, 1708, 1060, 1030 NMR (CDCl ₃ ; δppm); 0.68 (3H, s, C-18-CH ₃ ) , 1.01 (3H,
3H, s, C-19-CH ₃ ) 1.38 (6H, s, C-26 & 27-CH ₃ ×2) 3.78 (1H, s, C-25-OH), 3.92 (1H,
bm, C-3-H) 4.70 (1H, bm, C-2'-H), 5.32 (1H, bd,
C-6-H) Example 2 24-oxocholesterol-3-acetate
Add 1702 mg (3.85 mmol) and 647 mg (5.77 mmol) of potassium t-butoxide to a mixed solution of t-butanol and diglyme (1:1), and leave the bath at a temperature of 40°C.
The mixture was heated and stirred at ℃ to dissolve it. While controlling the temperature of the obtained solution at 20°C, 88 c.c. of oxygen was absorbed while stirring to complete the reaction. After the reaction is complete, add an appropriate amount of water and ether, separate the liquid,
The aqueous solution was extracted with ether. The ether separation and ether extract were combined, washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was subjected to column chromatography packed with silica gel (solvent benzene-ethyl acetate system) to obtain 72 mg of 25-hydroxy-24-oxocholesterol-3-acetate and 299 mg of 25-hydroxy-24-oxocholesterol. Ta. The physical properties of this product were as follows. :25-hydroxy-24-oxocholesterol-
3-acetate melting point; 141-143°C (n-hexane: needle crystals) IR (KBr; cm ^-1 ); 3430, 2940, 1730, 1710, 1465, 1365, 1248,
1035 NMR ( _CDCl3 ; δppm); 0.68 (3H, s, C-18- _CH3 ) 1.01 (3H, s, C-19- _CH3 ) 1.38 (6H, s, C-26&27-CH3 x ₂ ) 2.02 (3H, s,

[Formula]) 4.60 (1H, bm, C-3-H) 5.36 (1H, bd, C-6-H) High resolution mass spectrum (IV = 75eV); M ⁺ -AcOH 398.3182 (C ₂₇ H ₄₂ O ₂ ): 25-hydroxy-24-oxocholesterol Melting point; 168-170°C (benzene) IR (KBr; cm ^-1 ); 3425, 2925, 1708, 1460, 1370, 1050 NMR (CDCl ₃ ; δppm); 0.68 (3H , s, C-18-CH ₃ ) 1.01 (3H, s-C-19-CH ₃ ) 1.38 (6H, s, C-26 & 27-CH ₃ ×2) 3.60 (1H, bm, C-3-H) 5.34 (1H, bd, C-6-H) High resolution mass spectrum (IV = 75eV); M ⁺ 416.3380 (C ₂₇ H ₄₄ O ₃ ) Raw material compounds used in Examples 1 and 2, 24-oxocholesterols At the same time, 1α, 3β-dihydroxy-24-oxocholest-5-enes, 3β-hydroxy-24-oxocholest-5, 7-dienes, 1α, 3β-dihydroxy-24-oxocholesta-5, 7- are used as raw material compounds. Even when dienes or the like are used, a 25-hydroxy-24-oxocholesterol derivative having a hydroxyl group introduced at the 25th position is produced. Example 3 3β-hydroxy-24-oxocholesta-5.
290 mg (0.73 mM) of 7-diene and 122.5 mg (1.1 mM) of t-butoxypotassium were added to 20 ml of a mixed solvent of t-butanol and diglyme (1:1), and dissolved with stirring at a bath temperature of 40°C. The reaction was completed by absorbing 8 c.c. of oxygen while stirring the resulting solution while controlling the temperature to 0°C. After the reaction was completed, an appropriate amount of water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dilute hydrochloric acid, and a saturated aqueous sodium bicarbonate solution, and then dried over Glauber's salt. The concentrated residue obtained by concentrating after filtration was mixed with benzene 5
ml and add 48mg of triphenylphosphine,
Stirred at room temperature for 30 minutes. The concentrated residue obtained by concentration was purified by silica gel thin layer chromatography (solvent: benzene-ethyl acetate system) to obtain 85 mg of 3β.25-dihydroxy-24-oxocholester-5.7-diene. The physical properties of this product were as follows. Melting point: 150-152℃ (ethyl acetate) IR (KBr, cm ^-1 ): 3400, 2940, 1710, 1460, 1375, 1060, 1035 NMR (CDCl ₃ : δppm) 0.63 (3H, s), 0.95 (3H, s), 1.38 (6H,
s), 3.4-3.7 (1H, brm), 5.3-5.66 (2H,
brm) UV (EtOH: λmax nm) 294 (ε=6470), 282 (ε=11270) 271 (ε=10760), 262 (sh, ε=7840) High resolution mass spectrum (IV=75eV) M ⁺ :414.3201 (C ₂₇ H ₄₂ O ₃ ) Example 4 1α・3β-diethoxycarbonyloxy-24
-Oxocholesta-5,7-diene 1.425g
(2.55mM) and t-butoxypotassium 2.86g (25.5mM
M) with 40ml of t-butanol and diglyme (1:
The mixed solvent of 1) was added, and the mixture was stirred at 40°C for 30 minutes under a nitrogen stream. Next, after cooling to -20°C, the mixture was replaced with oxygen and stirring was continued until almost the theoretical amount of oxygen (60 ml) was absorbed. Add triphenylphosphine, then ethyl acetate,
1N-HCl was added to adjust the pH to ~7, followed by extraction. 1N−
After sequentially washing with HCl, saturated aqueous sodium bicarbonate solution, and saturated brine, it was dried with sodium sulfate. The crude product obtained after filtration and concentration was purified using a silica gel column.
325 mg (yield 30.1%) of α·3β·25-trihydroxy-24-oxocholesta-5·7-diene was obtained. The physical properties of this product were as follows. IR (KBr, cm ^-1 ): 3400, 2945, 1710 NMR (CDCl ₃ : δppm) 0.629 (3H, s), 0.947 (3H, s), 1.386
(6H, s) 3.65-4.25 (2H, brm), 5.44 (1H, m), 5.78 (1H, m) UV (EtOH: λmax nm) 294, 282, 271, 262 MS: 430 (M ⁺ ), 412 , 394, 371, 251 Example 5 10 g of 24-oxo-25-hydroxycholesterol (24 mM) with a mixture of 122.6 g of acetic anhydride (1.2 M) and 171.0 g of pyridine (2.2 M)
The mixture was heated and stirred at 90°C for 24 hours. Acetic anhydride was concentrated under reduced pressure, and ethyl acetate 11 was added for extraction. 1N−HCl200
ml 3 times, 200 ml of saturated sodium bicarbonate aqueous solution
The mixture was washed twice with brine and twice with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was subjected to column chromatography using 200 g of silica gel, and 7.5 g was eluted with benzene-ethyl acetate system.
24-,oxo-3β·25-diacetoxycholest-5-ene was obtained. IR (KBr, cm ^-1 ) 1725, 1740 NMR (CDCl ₃ : δppm) 0.70 (3H, s), 1.05 (3H, s), 1.50 (6H,
s), 2.05 (3H, s), 2.12 (3H, s), 4.6
(1H, m), 5.4 (1H, m)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ and R ⁵ are hydrogen atoms or hydroxyl group protecting groups, R ² is hydrogen atoms, hydroxyl groups, or protected hydroxyl groups, R ³ and R ⁴ are hydrogen atoms, or R ³ and R ⁴ are combined Represents a carbon-carbon bond. ] A 25-hydroxy-24-oxocholesterol derivative represented by: 2 The following formula [] [In the formula, R ¹ is a hydrogen atom or a protecting group for a hydroxyl group, R ² is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R ³ and R ⁴ are hydrogen atoms, or R ³ and R ⁴ together form a carbon-carbon Represents a bond. ] The following formula [′] is characterized in that the 24-oxocholesterol derivative represented by is subjected to an oxygen oxidation reaction in the presence of a basic compound. [In the formula, R ¹ is a hydrogen atom or a protecting group for a hydroxyl group, R ² is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R ³ and R ⁴ are hydrogen atoms, or R ³ and R ⁴ together form a carbon-carbon Represents a bond. ] A method for producing a 25-hydroxy-24-oxocholesterol derivative represented by: