JPS5821919B2 - 3 Beta, 24 (S) - Diacyloxycholesta -5,7- Dienno Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 3β·24(S)-cyasyloxycholester-5
-Relating to a method for producing 7-diene.

In more detail, 3β24 is an intermediate that can lead to 24(S)-hydroxycholecalciferol, which has been shown to have the same ability to absorb calcium from a vial as 25-hydroxycholecalciferol. The present invention relates to a method for producing (S)-siasiloxycholester-5,7-diene.

Conventionally, 3β・24-dibenzoyloxycholest-5-
It is known that 24(S) and 24(R) are separated [Journal of the American Chemical Society (J.

Am, Cbem, Soc, ) 75 3284 (195
See 3)].

However, the corresponding 5,7-diene form, 3β24(3
)-dibenzoyloxycholesta-5,7-diene and 3β,24(R)-dibenzoyloxycholesta-5
- There is no known method for producing 7-ginine.

The present invention discloses novel compounds such as 3β.24(S)-dibenzoyloxycholester-5.7-diene, which are useful intermediates that can be derived from the novel compound 24(S)-hydroxycholecalciferol. 3β·2 obtained by separating 3β·24(S)-cyasyloxycholest-5,7-diene from 3β·24-cyasyloxycholest-5-ene
The object of the present invention is to provide a method for advantageously producing it from 4(S)-cyasiloxycholest-5-ene in a good yield.

That is, the present invention provides 3β·24(S)-cyasyloxycholest-5-ene represented by the following formula [■] [wherein R1 and R2 represent an acyl group] with an allylic brominating agent. 3β24(S)- represented by the following formula (n) [wherein R, and R2 are the same as in the above formula], which is characterized by reacting in an active organic solvent and then reacting with a dehydrobrominating agent. This is a method for producing siasiloxycholester-5,7-diene.

3β24 (S
)-siasiloxycholest-5-ene is represented by the above formula [I].

In the formula, R1 and R2 are the same or different acyl groups.

Examples of the acyl group include benzoyl group, 7sef)R
4,7'ropionyl group, p-bromobenzoyl group, p-
A nitrobenzoyl group, a chloroacetyl group, and the like are preferably used, but the group is not particularly limited thereto.

These raw materials include, for example, 3β·2 obtained by benzoylating 3β·24-dihydroxycholest-5-ene.
4-Dibenzoyloxycholest-5-ene can be easily obtained by recrystallizing it several times with acetone or chromatographically separating it with n-hexane and benzene.

3β・24(S)-dibenzoyloxycholest-5-
In the case of ene, the melting point is 144-146.5℃ in this way.
A product with high purity can be obtained.

By the way, one epimer, 3β・24 (R)-
The melting point of dibenzoyloxycholest-5-ene is 182
~184°C.

As the allylic position brominating agent, for example, N-promosuccinimide, 1.3-dibromo-5.5-dimethylhydantoin, etc. are particularly preferably used.

These are preferably 1 to 1.5 with respect to the 5-ene form of the raw material.
It is usually used at a ratio of twice the equivalent amount.

The reaction is usually carried out by first treating 3β·24(S)-cyacyloxycholest-5-ene as described above with an allylic brominating agent as described above in an inert organic solvent at a temperature of room temperature to 140°C. preferably done.

As the inert organic solvent, one that does not react with the allylic brominating agent is used.

For example, hexane, heptane, cyclohexane, refloin, benzene, toluene, xylene, frombenzene, chlorobenzene, nitrobenzene, carbon tetrachloride,
Hydrocarbons or halogenated hydrocarbons such as 2-dichloroethane and 1.2-dichloroethane are advantageously used.

Ether solvents such as ethyl ether, tetrahydrofuran, dioxane, methyl cellosolve, and phenyl cellosolve can also be used.

These inert organic solvents may be used alone or as a mixture.

Further, although the reaction proceeds at the above-mentioned temperature, actinic light having a wavelength of infrared to ultraviolet rays may be irradiated at that time.

In this case, since the reaction can proceed even at a relatively low temperature, the reaction can proceed even at a temperature lower than room temperature depending on the case.

The 3β·24(S)-cyasyloxycholest-5-ene obtained by the above reaction was then reacted with a dehydrobrominating agent to form a 3β·24( S)-cyasyloxycholester-5.
7-Jininni conversion sale.

This reaction does not necessarily require the presence of a reaction solvent.

This is because the dehydrogenating agent can also be used as it is as a reaction solvent.

When using a reaction solvent, the suitable reaction solvent is not necessarily the same as the solvent for the previous bromination reaction, so after expelling the reaction solvent from the previous reaction, a new reaction solvent suitable for this reaction is used. A method in which an additional reaction is carried out is usually employed.

Thus, examples of suitable reaction solvents include xylene, bromobenzene, chlorobenzene, hexamethylphosphoramide, dimethylformamide, dimethylacetamide, and the like.

Further, as the dehydrogenating agent, for example, trimethyl phosphite, s-collidine, diethylaniline, etc. are particularly preferably used.

These can be used in combination, and theoretically the reaction will proceed sufficiently if the moles are equal to the prohuman body produced in the previous bromination reaction, but the reaction rate or reaction yield may be preferable. Generally, about 2% of the bromine body is
It is preferable to use it in a molar ratio or more.

As mentioned above, since the dehydrobromating agent also acts as a reaction solvent, there is no particular upper limit to the amount used.

The reaction normally proceeds suitably at a temperature of 100 to 180°C.

The reaction time varies depending on the dehydrogenating agent or reaction solvent used, but for example, in a preferred embodiment in which the reaction is carried out in a xylene-8-collidine system under reflux, the reaction is completed in a short time of about 20 minutes.

After completion of the reaction, the reaction product 3β·24(S)-siasiloxycholester-5·7-diene can be separated and purified, for example, by expelling the reaction solvent and then recrystallizing it with a recrystallization solvent such as acetone. This can be easily done by doing the following.

Separation and purification can also be suitably carried out, for example, by column chromatography using benzene-n-hexane as a solvent and silica gel as a filler.

Obtained 3β・24(S)-siasiloxycholester-5
・7-diene can be thermally isomerized after irradiation with light, and then the acyl group can be removed by a method such as hydrolysis, thereby improving the physiological activity of 25-hydroxycholecalciferol ·of·
Sciences, USA (Pooceedings o
f the National Academy
of 5 sciences, USA) 61 1503
As a result of the research conducted by the present inventors, it was revealed that the calcium absorption ability from the small intestine is almost the same as that shown in [Reference]24
It is a useful intermediate that can be converted into (S)-hydroxycholecalciferol, and is of great significance to the present invention.

EXAMPLES Hereinafter, the present invention will be specifically described in detail with reference to Examples.

Example (1) Production of 3β24(S)-dibenzoyloxycholest-5-ene Fucosterol acetate, which is abundant in brown algae, is ozonolyzed to produce 24-ketocholesteryl acetate, which is then treated with LiAlH4. 1.779 ml of 24-hydroxycholesterol produced by reduction was dissolved in 5 ml of pyridine, and 2 rrLl of benzoyl chloride was added thereto.

After heating on a 60° C. water bath for 2 hours, 10 ml of water was added, stirred, and left overnight.

The precipitate was collected by filtration and washed with boiling water.

269 g of crude product was obtained.

This crude product was recrystallized with acetone, and the mother liquor was recrystallized three times with n-hexane.

A purified product of 497 ml having a melting point of 144-145°C was obtained.

When this product was analyzed by high performance liquid chromatography, a single peak was obtained.

Furthermore, by comparing the melting point of this substance with the melting point of a standard product described in the literature, it was confirmed that it was 3β24(S)-shihensoyloxycholest-5-ene [Journal of American Chemical Society (
J-Am・Chem-8oc6,)75 3284(1
954)].

(2) Process for producing 3β·24(S)-dibenzoyloxycholest-5,7-diene 401.8 rv of 3β·24(S)-dibenzoyloxycholest-5-ene obtained as described above was carbon tetrachloride 2
120 ml of N-promosuccinimide in 4 ml
The mixture was heated under reflux for 15 minutes.

After cooling, excess N-promosuccinimide was removed by filtration, the lachrymal fluid was concentrated, and 8.5 ml of xylene was added to the residue to form a solution.

This solution was mixed with 8 ml of xylene containing 0.4 ml of trimethyl phosphite. was added dropwise to the refluxing solution, and the mixture was further refluxed for 90 minutes.

Thereafter, the reaction system was concentrated at a temperature of 75°C or lower, and the residue was recrystallized by accent to obtain a purified product of 129.6 da (yield: 32.4%) having a melting point of 155-157°C.

This product showed the following properties.

N, M, R (CDCI 3, δ (ppm)):
5.8 (IH, d, J=5Hz, c-6 or C-7),
5.6 (] H, d, J=5Hz, c-7 or c-6
), 4.7 (2H, m, c-3, c-24), UV (C2H50H1λmax (nm)): 230.2
71.282 294 From the above properties, 3β·24(S)-dibensoyloxycholester 5·7-dininto was identified.

Claims (1)

[Claims] 1 3β·24(S)-siasiloxycholest-5-ene represented by the following formula CI) [wherein R1 and R2 represent an acyl group] is used as an allylic brominating agent. 3β24(S) represented by the following formula [■] [wherein R1 and R2 are the same as the above formula], which is characterized by reacting in an inert organic solvent and then reacting with a dehydrobrominating agent. -Production method of cyasiloxycholester-5,7-diene.