JPS6228785B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention provides 24,25-dihydroxyvitamin
D Concerning the manufacturing method of Category ₃ . For more details, see 24・25
-Active vitamin D _{3 such as dihydroxyvitamin D 3} and _1α・24・25-trihydroxyvitamin D ₃
24,25-dihydroxyvitamin, also known as
This is a method for producing _D3 in high yield.

According to the present invention, the following manufacturing method is provided. In other words, the following formula [] [In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group, and R ₂ represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. ] The following formula [] is characterized by subjecting 25-hydroxy-24-oxo vitamin D ₃ represented by the formula to a reduction reaction, and further removing the protecting group as necessary. [In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group, and R ₂ represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. ] 24・25-dihydroxyvitamin D ₃ expressed as
This is a similar manufacturing method.

In the 25-hydroxy-24-oxo vitamin D ₃ represented by the above formula [] used as a starting material in the present invention, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group.

Examples of such hydroxyl protecting groups include acetyl group, propanoyl group, butanoyl group, pentanoyl group, cyclohexanoyl group, chloroacetyl group, bromoacetyl group, benzoyl group, p-bromobenzoyl group, p-nitrobenzoyl group, and ethyl group. aliphatic or aromatic carboxylic acid residues having 1 to 12 carbon atoms such as benzoyl group and tolyl group, or their nitro-, halogen-, or alkoxy-substituted derivatives; or trialkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; Examples include 2-cyclic ether groups such as 2-tetrahydropyranyl group and 2-tetrahydrofuranyl group. R ² 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.

By subjecting the 25-hydroxy-24-oxo vitamin D ₃ represented by the above formula [] to a reduction reaction, the desired 24,25-dihydroxyvitamin D ₃ represented by the above formula [] can be obtained. can get.

The reduction reaction can be carried out under any reducing conditions that are selective to olefins. For example, Pondorf reduction conditions using aluminum alkoxide as a catalyst, Birch reduction conditions in which the reaction is carried out in liquid ammonia or primary amines using lithium or sodium, or hydrogen anions such as aluminum hydrides and borohydrides are provided. Examples include conditions using a reducing reagent.
Among these, conditions using reducing reagents such as aluminum hydrides and boron hydrides, which can be easily performed, are preferred.

As aluminum hydrides, for example, the following formula [] M ₁ (R ₄ ) _n AlH _o ... [] [In the formula, M ₁ is an alkali metal atom, R ₄ is a lower alkoxy group, and n is 1 to 4] integer, m is 0 to 3
is an integer. ] Aluminum metal hydride represented by these can be mentioned.

In the above formula [], M ₁ represents an alkali metal atom, such as lithium, sodium, etc. Further, R ₄ represents a lower alkoxy group, such as methoxy, ethoxy, t-butoxy, 2-methoxyethoxy group and the like. Specific examples of aluminum metal hydride include lithium aluminum hydride, sodium aluminum hydride, lithium tri-t-butoxyaluminum hydride,
Lithium triethoxyaluminum hydride, lithium trimethoxyaluminum hydride, lithium di-t-butoxyaluminum hydride, lithium diethoxyaluminum hydride, bis(2)
- methoxyethoxy) aluminum sodium,
Preferred examples include sodium triethoxyaluminum hydride. Further, as other aluminum hydrides, aluminum hydride, diisobutylaluminum hydride, aluminum hydride-triethylamine, etc. can also be used.

As boron hydrides, for example, the following formula [] M ₂ (R ₅ ) _n BH _o ...... [] [In the formula, M ₂ represents an alkali metal atom, R ₅ represents a lower alkyl group or a lower alkoxy group, n is 1 to 4
m is an integer of 0 to 3. ] Metal boron hydride represented by these can be mentioned.

In the above formula [], M ₂ represents an alkali metal atom, such as sodium, lithium, potassium, etc. Further, R ₅ represents a lower alkyl group or a lower alkoxy group, examples of the lower alkyl group include ethyl and Sec-butyl, and examples of the lower alkoxy group include methoxy and is. -propoxy group and the like. Specific examples of metal borohydride include sodium borohydride, lithium borohydride, lithium triethylborohydride,
Preferred examples include lithium tri-s-butylborohydride, sodium trimethoxyborohydride, potassium triisopropoxyborohydride, and the like.

Further, as other borohydrides, calcium borohydride and the like may also be used.

Among the above aluminum hydrides or borohydrides, lithium aluminum hydride, sodium borohydride, etc. are particularly preferably used.

Such reducing reagents such as aluminum hydrides and borohydrides are 25-
It is preferable to use excess mole per mole of hydroxy-24-oxovitamin D type ₃ , 1.5 to 4
Double molar ratio is particularly preferred.

In carrying out the reaction, it is advantageous to use an organic liquid medium as a solvent, and examples of such organic liquid medium include ether solvents such as diethyl ether and tetrahydrofuran, alcohol solvents such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, dimethyl Examples include solvents such as formamide and dimethyl sulfoxide.

In such a solvent, the 25-hydroxy-24-
Dissolving or suspending oxovitamin D ₃ ,
Adding the reducing agent little by little while stirring and stirring further after the addition will make the process proceed smoothly. When using an aprotic solvent, the reaction is completed by treating the reaction solution with water or alcohol.

The reaction temperature is either cooled only in the initial stage to suppress heat generation, or the reaction proceeds quantitatively under room temperature to heating conditions. The preferred range of reaction temperature is -60 to 50°C, and the reaction is completed in several hours.

Any conventional method can be used to isolate and purify the target compound from the reaction solution. That is, concentration, extraction, column chromatography, high performance liquid chromatography, recrystallization, etc. are used.

When a protecting group exists in the target compound, that is, at least one of OR ₁ , OR ₃ , and R ₂ in the 24,25-dihydroxyvitamin D ₃ represented by the above formula [] is a protected hydroxyl group. If necessary, the protecting group may be removed subsequent to the reaction or 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.

Therefore, according to the present invention, 24,25-dihydroxyvitamin D ₃ represented by the above formula [], that is, 24,25-dihydroxyvitamin D ₃ or its hydroxyl group-protected derivative when R ₂ is a hydrogen atom, R 1 where ₂ is a hydroxyl group or a protected hydroxyl group
α·24·25-dihydroxyvitamin D ₃ or its hydroxyl-protected derivative can be obtained in high yield.

Here, the 25-hydroxy-24-oxo vitamin D ₃ represented by the above formula [] used in the present invention can be produced in the following manner as previously proposed by the present inventors.

In other words, the following formula [] [In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group, and R ₂ represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. ] 25-hydroxy-24-oxoprevitamin D ₃ is produced by irradiating the 25-hydroxy-24-oxocholester-5,7-dienes represented by ultraviolet rays.
They can be produced by isomerizing them using thermal energy. Therefore, the present invention also provides the following manufacturing method.

That is, 25-hydroxy-24 represented by the above formula []
-Oxocholesta-5,7-dienes are irradiated with ultraviolet rays, and the generated 25-hydroxy-24-oxocholestavitamin D ₃ is isomerized by thermal energy, resulting in 25-hydroxy-24 represented by the above formula [] - Production of 24,25-dihydroxyvitamin D ₃ represented by the above formula [], which is characterized by preparing oxovitamin D ₃ , then subjecting it to a reduction reaction, and further removing protecting groups as necessary. It is the law.

25-hydroxy-24-oxocholester represented by the above formula [] used as a raw material compound
R ₁ , R ₂ and R ₃ in the 5,7-dienes are the same as defined above.

The 25-hydroxy-24-oxocholesta-5,7-dienes represented by the above formula [] are first irradiated with ultraviolet light to form the following formula ['] [In the formula, R ₁ , R ₂ and R ₃ are the same as defined above. ] It is converted to 25-hydroxy-24-oxobrevitamin D ₃ represented by

This conversion reaction is a cleavage reaction of the carbon-carbon bond at the 9th and 10th positions of the 25-hydroxy-24-oxocholesta-5,7-diene of the above formula [], and the type of protecting group for the hydroxyl group is directly involved in the reaction. No effect.

As the ultraviolet rays, those having a wavelength of approximately 200 to 360 nm, preferably those having a wavelength of 260 to 310 nm are used.

This conversion reaction is suitably carried out in an inert organic solvent. For example, hexane, heptane,
Hydrocarbons or halogenated hydrocarbons such as benzene, toluene, xylene, chlorobenzene, and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and alcohols such as methanol, ethanol, and propanol are preferably used.

In addition, the reaction temperature does not have a very important meaning for the conversion reaction, but it is usually -20℃ to 120℃, especially -
Since it is carried out at a temperature of 10 to 50°C, there is no problem industrially.

Next, the 25-hydroxy-24-oxo previtamin D ₃ represented by the above formula ['] produced as described above is converted into 25-hydroxy-24-oxo previtamin D represented by the above formula [] by thermal energy. D It is isomerized to type ₃ . This isomerization reaction is an equilibrium reaction between previtamin D ₃ of the above formula ['] and vitamin D ₃ of the above formula [], and the equilibrium value between the two differs depending on the reaction temperature.
This thermal equilibrium relationship between vitamin D ₃ and previtamin D ₃ has been known for a long time. Generally, the higher the isomerization reaction temperature is, the faster the isomerization reaction rate from previtamin D ₃ to vitamin D ₃ is, but the equilibrium value tends to shift to the side where vitamin D ₃ decreases.

In the present invention, considering these circumstances, the isomerization reaction is carried out at 20° to 120°C, preferably 40° to 100°C.
It will be held in Further, the isomerization reaction proceeds satisfactorily in the inert organic solvent used in the above conversion reaction.

Therefore, for example, when the conversion reaction to produce previtamin D ₃ is carried out at 40°C, the previtamin D ₃ produced at the same time as the conversion reaction progresses gradually becomes vitamin D in the reaction system.
A reaction of isomerization to D ₃ will occur. As is clear from the above, the isomerization reaction using thermal energy in the method of the present invention does not necessarily mean heating the reaction system.

In this way, 25-hydroxy-24-oxo vitamin D ₃ represented by the above formula [] is obtained, which is subjected to the reduction reaction as described above, and then, if necessary, a protecting group is removed by the method described above. By removing , 24,25-dihydroxyvitamin D ₃ can be obtained.

As detailed above, according to the present invention, 24・25−
Dihydroxyvitamin D ₃ can be obtained in good yield.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 (a) Synthesis of 25-hydroxy-24-oxovitamin D ₃ 157 mg of 3β·25-dihydroxy-24-oxocholesta-5·7-diene was dissolved in a mixed solution of 50 ml of deoxygenated ethanol and 500 ml of ether. I let it happen.

The resulting solution was irradiated using a 200 watt Hanobia lamp surrounded by a Vycor filter for 14 minutes under stirring at a controlled temperature of 5°C. This cold solution was concentrated under reduced pressure while controlling the temperature at 30°C. 250 ml of deoxygenated benzene was added to the resulting concentrated solution. The resulting benzene solution was heated under reflux for 2.5 hours to complete the reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure while controlling the temperature at 30°C. The obtained residue was subjected to silica gel thin layer chromatography (solvent system: chloroform-methanol system) and silica gel thin layer chromatography (solvent system: benzene-ethyl acetate system) treated with a 2% silver nitrate-acetonitrile solution. , 25-hydroxy-
8.7 mg of 24-oxo previtamin D ₃ and 14.8 mg of 25-hydroxy-24-oxo vitamin D ₃ were obtained.
The physical properties of this product were as follows.

Γ25-hydroxy-24-oxoprevitamin
D ₃ : UV (ethanol: λmax nm) 260 Γ25-hydroxy-24-oxo vitamin D ₃ : UV (ethanol: nm) λmax 264.5 (ε
= 15500) λmin228 (ε = 8400): IR (neat: cm ^-1 ) 3375, 2925, 2860,
1705, 13385, 1045: NMR (CDCl ₃ : δppm) 0.54 (3H.SC−18−CH ₃ ) 1.37 (6H.SC−26 & 27−CH ₃ ×2) 3.90 (1H.bC−3−H) 4.80, 5.03 (2H.mC−19−H×2) 6.01, 6.20 (2H.AB Quartet, J=
11.5C-6 & 7-H x 2): High resolution mass spectrum (IV = 75eV) M ⁺ = 414, 3131 (C ₂₇ H ₄₂ O ₃ ) (b) Synthesis of 24・25-dihydroxyvitamin D ₃ 25-hydroxy- 24-Oxovitamin D ₃ 4.9
mg was dissolved in 1 ml of methanol. 0.76 mg of sodium borohydride was added to the resulting solution. After addition, the reaction was completed by stirring at room temperature for 20 minutes. After the reaction was completed, the reaction solution was diluted with water and extracted with ether. The ether extract was washed with saturated brine and dried over anhydrous sodium sulfate. After drying, the ether extract is filtered and concentrated to produce 24/25-dihydroxyvitamin.
5 mg (quantitative) of _D3 was obtained. The obtained 24,25-dihydroxyvitamin D ₃ was subjected to thin layer chromatography (solvent system: benzene-ethyl acetate system, silica gel) and high performance liquid chromatography (2 bottles of Waters μ Porasil, solvent system: dichloromethane-methanol system). The results of the analysis were consistent with the standard sample.

The physical properties of this product were as follows.

Γ24・25-dihydroxyvitamin D ₃ : UV (ether: nm) λmax264 λmin228 : High resolution mass spectrum (IV=75eV) M ⁺ =416.3413 (C ₂₇ H ₄₄ O ₃ )

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group, and R ₂ represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. ] The following formula [] is characterized by subjecting 25-hydroxy-24-oxo vitamin D ₃ represented by the formula to a reduction reaction, and further removing the protecting group as necessary. [In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group, and R ₂ represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. ] 24・25-dihydroxyvitamin D ₃ expressed as
manufacturing method of types. 2 The following formula [] [In the formula, R ₁ and R ₃ each independently represent a hydrogen atom or a protecting group for a hydroxyl group, and R ₂ represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. ] The 25-hydroxy-24-oxocholesta-5,7-dienes represented by the following formula [] are irradiated with ultraviolet rays, and the generated 25-hydroxy-24-oxoprevitamins D are isomerized by thermal energy. [In the formula, R ₁ , R ₂ and R ₃ are the same as defined above. ] 25-hydroxy-24-oxovitamin D ₃ represented by the following formula [], which is then subjected to a reduction reaction and, if necessary, further removing protecting groups. [In the formula, R ₁ , R ₂ and R ₃ are the same as defined above. ] 24・25-dihydroxyvitamin D ₃ expressed as
manufacturing method of types.