JPS6258352B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel compounds, 1α,25-dihydroxy-24-oxocholecalciferols, and a method for producing the same.

1α,25-dihydroxy- provided by the present invention
24-oxocholecalciferols have the following formula [] [In the formula, R ¹ , R ² , and R ³ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] It is expressed as . In the above formula [], especially
1α,25-dihydroxy-24-oxocholecalciferol, in which R ¹ , R ² and R ³ are hydrogen atoms, is fully expected to be a pharmacologically active compound that exhibits the same pharmacological effects as vitamin D ₃ series compounds. It is something that

Furthermore, the 1α,25-dihydroxy-24-
Oxocholecalciferols are 1α, 24, 25-
It is also extremely useful as an intermediate for the production of trihydroxyvitamin _D3 .

Examples of the protecting group for the hydroxyl group in the above formula [] include acetyl group, propanoyl group, butanoyl group, pentanoyl group, cyclohexanoyl group,
C1-C12 aliphatic or aromatic carboxylic acid residues such as chloroacetyl group, bromoacetyl group, benzoyl group, p-bromobenzoyl group, p-nitrobenzoyl group, ethylbenzoyl group, toluyl group, or their nitro , halogen, alkoxy substituted derivative, or trimethylsilyl group, t-
Examples include trialkylsilyl groups such as butyldimethylsilyl groups, and 2-cyclic ether groups such as 2-tetrahydropyranyl groups and 2-tetrahydrofuranyl groups.

Therefore, specific examples of the compound represented by the above formula [] include (1) 1α,25-dihydroxy-24-oxovitamin D ₃ , (2) 1α,25-dihydroxy-24-oxovitamin D ₃ − 1,3-Diacetate (3) 1α,25-dihydroxy-24-oxovitamin D ₃ -1,3,25-triacetate (4) 1α,25-dihydroxy-24-oxovitamin D ₃ -1,3,25 -Tribenzoate (5) Compounds such as 1α,25-dihydroxy-24-oxovitamin D ₃ -1,2',3,2',25,2'-tritetrahydropyranyl ether are mentioned.

According to the method of the present invention, a novel 1α,25-dihydroxy-24-
Also provided are methods of producing oxovitamin D _III .

In other words, the following formula [] [In the formula, R ¹ , R ² , and R ³ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] 1α,25-dihydroxy-24-oxocholester-5,7-dienes represented by are irradiated with ultraviolet rays, and the generated 1α,25-dihydroxy-24-oxoprevitamin D ₃ is isomerized by thermal energy, This is a method for producing 1α,25-dihydroxy-24-oxovitamin D ₃ represented by the above formula [] by removing the hydroxyl protecting group as necessary.

The raw material compound represented by the above formula [] for producing the target product represented by the above formula [] is:
First, after being irradiated with ultraviolet light, the following formula [′] [In the formula, R ¹ , R ₂ , and R ₃ are the same as defined above. ] It is converted to 1α,25-dihydroxy-24-oxoprevitamin D ₃ represented by

As the ultraviolet rays, those having a wavelength of 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, 1α,25-dihydroxy-24 represented by the above formula [′] produced as above
-Oxoprevitamin D ₃ is isomerized by thermal energy to 1α,25-dihydroxy-24-oxovitamin D ₃ represented by the above formula []. This isomerization reaction is an equilibrium reaction between the previtamin D ₃ of the above formula [′] and the vitamin D ₃ of the above formula [], and the equilibrium value of both 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°C to 120°C, preferably 40°C to 100°C.
It will be held in Further, this 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 simultaneously with the progress of the conversion reaction gradually becomes vitamin D ₃ in the reaction system.
An isomerization reaction 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.

Thus, according to the present invention, 1α,25-dihydroxy-24-oxovitamin D ₃ represented by the above formula [] is obtained, but in order to isolate it from the reaction mixture, for example, column chromatography, diluted By layer chromatography, high performance liquid chromatography, recrystallization, etc.

When removing the hydroxyl-protecting groups of R ¹ , R ² , and R ₃ , the hydroxyl-protecting groups should be removed following the conversion reaction using ultraviolet rays and the isomerization reaction using thermal energy, or after isolation and purification. Can be done. This elimination reaction of the hydroxyl group is a known reaction per se. For example, when the protecting group is an acyl group, it is treated in an alkaline solution of a lower aliphatic alcohol such as methanol or ethanol, or treated in an alkaline solution of a lower aliphatic alcohol such as LiAlH ₄ in ether. It can be treated with metal hydride. The temperature may be -10°C to 50°C. 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 by reduction or by contacting with an acid or an alkali.

As detailed above, according to the present invention, 1α,25-dihydroxy-24 represented by the above formula []
- Oxovitamin D ₃ class is obtained, and such a compound is fully expected to be a compound showing pharmacological activity similar to vitamin D ₃ , and by reducing the oxo group at the 24-position, 1α,24,25-trihydroxy Vitamin D ₃ is obtained, and therefore it is also useful as an intermediate for the production of active vitamin D ₃ such as 1α, 24, 25 trihydroxyvitamin D ₃ .

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

Example 1 a Synthesis of 24-ethylenedioxy-1α-hydroxycholesterol 1α-hydroxy-24-oxocholesterol
1.36 g was dissolved in 36 ml of anhydrous benzene. 9 ml of ethylene glycol and 18 mg of p-toluenesulfonic acid were added to the obtained solution, and the mixture was reacted for 20 hours with stirring at a bath temperature of 105° C. in a reaction vessel containing a molecular sieve and equipped with a moisture meter.

After the reaction was completed, the mixture was diluted with an appropriate amount of water and separated. The resulting aqueous solution was extracted with ethyl acetate, and the benzene separation and ethyl acetate extract were combined and washed with a 5% aqueous sodium hydrogen carbonate solution and saturated brine.

The resulting benzene-ethyl acetate mixed solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 970 mg of 24-ethylenedioxy-1α-hydroxycholesterol.

b Synthesis of 24-ethylenedioxy-1α-hydroxycholesterol-1,3-diacetate 970 mg of 24-ethylenedioxy-1α-hydroxycholesterol was dissolved in 3.3 ml of pyridine.
Add 1.76 ml of acetic anhydride to the resulting solution and bring the bath temperature to 80°C.
The acetylation reaction was carried out for 3 hours while heating and stirring at °C.
After the reaction was completed, the mixture was diluted with an appropriate amount of water and extracted with ether.

The ether extract was washed with 2N hydrochloric acid, 5% aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated to give 24-ethylenedioxy-1α-hydroxycholesterol-1,3- 1.02 g of diacetate was obtained.

c Synthesis of 1α,3β-dihydroxy-24-oxocholesta-5,7-diene 1.02 g of 24-ethylenedioxy-1α-hydroxycholesterol-1,3-diacetate was dissolved in 30 ml of hexane. Bath temperature of the obtained solution is 95℃.
While heating and stirring under a nitrogen atmosphere, 322 mg of 1,3-dibromo-5,5-dimethylhydantoin was added. After the addition, the mixture was vigorously heated under reflux and stirred while being irradiated with an infrared lamp, and the bromination reaction was carried out for 15 minutes. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a concentrated residue containing the 7-bromine compound of 24-ethylenedioxy-1α-hydroxycholesterol-1,3-diacetate.

The obtained residue was dissolved in 13 ml of xylene, and added dropwise to a mixed solution of 25 ml of xylene and 3.85 ml of s-collidine while heating and stirring at a bath temperature of 165°C. After dripping, further
The reaction was completed by heating and stirring for 20 minutes.

After the reaction was completed, the reaction solution was filtered and concentrated to obtain a concentrated residue containing 1α,3β-diacetoxy-24-ethylenedioxycholesta-5,7-diene.

The resulting residue was dissolved in 61 ml of acetone, and 357 mg of p-toluenesulfonic acid was added. After the addition, the mixture was stirred at room temperature for 2.5 hours to complete the deketaling reaction.

After the reaction, the reaction solution was concentrated. An appropriate amount of 5% aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the obtained concentrated residue, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with a 5% aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1α,3β-diacetoxy-24
A concentrated residue containing -oxocholester-5,7-diene was obtained.

The obtained concentrated residue was dissolved in 46 ml of a benzene-methanol (1:1) mixed solution. 27.5 ml of 2N potassium hydroxide methanol solution was added to the obtained mixed solution, and the mixture was heated and stirred at a bath temperature of 60°C for 3 hours to carry out a deacetylation reaction.

After the reaction was completed, the reaction solution was concentrated, diluted with an appropriate amount of water, and extracted with ethyl acetate. The ethyl acetate extract was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.

The obtained concentrated residue was subjected to silica gel thin layer chromatography treated with a 2% silver nitrate-acetonitrile solution (solvent dichloromethane-methanol system) to obtain 1α,3β-dihydroxy-24
312 mg of -oxocholesta-5,7-diene was obtained.

The physical properties of this product were as follows.

IR (KBr: cm ^-1 ) 3450, 2960, 1718, 1475,
1387 NMR (CDCl ₃ : δ (ppm)) 0.62 (3H, s, c-18-CH ₃ ) 0.93 (3H, s, c-19-CH ₃ ) 1.08 (6H, d, J=6Hz, C-26&27 _−CH3
×2) 3.74, 4.06 (each 1H, bm, c-1-H&c-
3-H) 5.36, 5.68 (each 1H+bm+c-6-H&c-
7-H) d Synthesis of 1α,3β,25-trihydroxy-24-oxocholesta-5,7-diene 248 mg (0.6 mmol) of 1α,3β-dihydroxy-24-oxocholesta-5,7-diene and potassium-t- Butoxide 101mg (0.9mmol) t
- It was added to a mixed solution of butanol and diglyme (1:1) and dissolved by heating and stirring at a bath temperature of 40°C.

While controlling the resulting solution at 0°C,
While stirring, 7 cc of oxygen was absorbed to complete the reaction.

After the reaction was completed, the mixture was diluted with an appropriate amount of water and extracted with acetic acid. The ethyl acetate extract was washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was dissolved in 6 ml of a mixed solution of benzene and ethyl acetate (5:1). 40 mg of triphenylphosphine was added to the obtained solution, and the mixture was reacted for 30 minutes with stirring at room temperature. After the reaction was completed, the reaction solution was concentrated.

The concentrated residue was subjected to silica gel thin layer chromatography (solvent: benzene-acetone system) to obtain 88 mg of 1α,3β,25-trihydroxy-24-oxocholesta-5,7-diene.

The physical properties of this product were as follows.

Melting point: 162.5-164℃ (methanol) IR (KBr: cm ^-1 ): 3450, 2975, 1715, 1468,
1382, 1060, 1045 NMR (CDCl ₃ : δppm) 0.63 (3H, s, c-18-CH ₃ ) 0.94 (3H, s, c-19-CH ₃ ) 1.38 (6H, s, c-26 & 27-CH ₃ ×2) 3.74, 4.06 (each 1H, bm, c-1-H&c-
3-H) 5.36, 5.68 (each 1H, bm, c-6-H&c-
7-H) UV (ethanol: λmax nm) 294 (ε=6160), 282 (ε=10550), 271 (ε=9810), 263 (Shoulder ε=
6840) High resolution mass spectrum (IV=75eV) M ⁺ :430,3122( _C27H42O4 )e Synthesis of 1α,25-dihydroxy-24 _- oxovitamin _D3 1α,3β,25 _- trihydroxy-24 -70 mg of oxocholester-5,7-diene was dissolved in a mixed solution of 50 ml of deoxygenated ethanol and 500 ml of ether. The resulting solution was irradiated using a 200 watt Hanobia lamp surrounded by a Vycor filter for 6 minutes while stirring at a controlled temperature of 10-20°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: chloroform-methanol system) and silica gel thin layer chromatography (solvent: benzene-acetone system) treated with a 2% silver nitrate-acetonitrile solution to obtain 1α, 10.8 mg of 25-dihydroxy-24-oxo vitamin D ₃ was obtained.

The physical properties of this product were as follows.

Melting point: 91-93.5℃ IR (KBr: cm ^-1 ): 3450, 2960, 1715, 1390,
1055 NMR (CDCl ₃ : δppm): 0.55 (3H, s, c-18-CH ₃ ) 1.37 (6H, s, c-26 & 27-CH ₃ ×2) 4.98, 5.30 (2H, m, c-19-H ×2) 6.18 (2H, AB-quartet, J=11.5Hz)
c-6&7-H×2) UV (ether: nm) λmax264.5, λ
min228.6 High resolution mass spectrum (IV=75eV) M ⁺ :430,3116 (C ₂₇ H ₄₂ O ₄ )

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ , R ² , and R ³ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] 1α,25-dihydroxy-24-oxocholecalciferols represented by: 2 The following formula [] [In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom or protection of a hydroxyl group. ] Irradiating the 1α,25-dihydroxy-24-oxocholesta-5,7-dienes represented by ultraviolet rays and isomerizing the generated 1α,25-dihydroxy-24-oxoprevitamin D ₃ using thermal energy. The following formula [] is characterized by [In the formula, R ¹ , R ² , and R ³ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ] A method for producing 1α,25-dihydroxy-24-oxocholecalciferols represented by: