JPS594433B2 - Manufacturing method of vitamin D - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing vitamin Ds.

More specifically, the present invention uses an acidic aqueous solution containing quinine, cupric sulfate, and nickel sulfate as a filter solution to irradiate provitamin D with ultraviolet rays, and then thermally isomerize the obtained previtamin D. Article 10 relates to a method for producing vitamin D, which comprises: The invention also relates to a filter solution consisting of an acidic aqueous solution containing quinine, cupric sulfate and nickel sulfate. In the present invention, vitamin Ds include vitamin D2 (ergocalciferol), vitamin D315 (cholecalciferol), and in addition to the hydroxyl group at the 3-position in their structure, for example, the hydroxyl group at the 1-position. , 2nd place, 24th place
Compounds having one or more hydroxyl groups at any position such as the 25-position, the 25-position, the 26-position, etc. (these are so-called "active vitamin D"), as well as compounds in which the hydroxyl group is It also refers to derivatives protected by protective groups.

Examples thereof include lα-hydroxycholecalciferol, 1α·25-dihydroxycholecalciferol, 1α·2α-hydroxycholecalciferol, 1α·24-dihydroxycholecalciferol, 24025-dihydroxycholecalciferol, Dihydroxycholecalciferol, 25-hydroxycholecalciferol, 1α・2
4,2530-trihydroxycholecalciferol,
1α.25.26-trihydroxycholecalciferol and their corresponding compounds of the D2 series and their hydroxyl-protected derivatives may be mentioned. 3
5 In the present invention, the provitamin Ds used as starting materials include 7-dehydrocholesterol, ergosterol, compounds having a hydroxyl group at the 1H position corresponding to the target product, and hydroxyl-protected derivatives thereof. Previtamin Ds refer to compounds in which the bonds at positions 9 and 10 of these provitamin Ds are cleaved.

It is well known that vitamin D is produced by irradiating provitamin D with ultraviolet light and subjecting the obtained previtamin D to thermal isomerization treatment, and this is applicable to the industrial production of vitamin D. has been done.

In the ultraviolet irradiation process, it is known that the wavelength of the irradiated ultraviolet rays has a large effect on the production of previtamin Ds. According to previous reports, the provitamin D used
Although it varies somewhat depending on conditions such as the type of solvent, irradiation time, temperature, etc., there is a tendency for the production of tachysterols to increase at short wavelengths, while the production of lumisterols and decomposition products increases at long wavelengths. UV radiation in the range of about 280-310 nm is generally preferred for the production of previtamin Ds. In the experiments we conducted, 29
Results have shown that a wavelength around 5 nm is most preferable for the production of previtamin D compounds. Ultraviolet irradiation is performed using a high-pressure, medium-pressure, or low-pressure mercury lamp as a light source, and in combination with various filters to select an effective wavelength. Conventionally, as a filter, Vycor (Vy
Glass filters such as cOr) filters or filter solutions containing various metal salts or organic substances are known. However, since the Vycor filter 1 transmits long wavelength ultraviolet rays, relatively large amounts of by-products are generated. As filter solutions containing metal salts, various aqueous solutions containing sodium nitrate, sodium bromide, copper sulfate, cobalt sulfate, nickel sulfate, silver sulfate, lead acetate, etc., singly or in combinations thereof, have been devised. [Rec. trav. Chim. 7
3, 393 (1954); 379392 (1960):
791012 (1960): Danryo 665 (1964)
,reference〕.

In these metal salt-containing filter solutions, 28
There are many products that effectively cut out light of 0 nm or less, but 310
There is nothing that can cut out the long wavelength side of 4 nm or less. Recently, D.H.R. BartOn et al. reported in JP-A-49-95956 that the ultraviolet irradiation wavelength of 1α-hydroxyprovitamin D3 was 275 to 30.
0 nm is preferred, and a methanol solution containing toluene and carbon disulfide is described as a suitable filter solution. According to our follow-up tests, the filter solution of Burton et al. is very preferable in terms of wavelength selectivity, transmitting light from 275 nm to 300 nm.
Within a very short period of time, the filter solution itself changes due to the irradiation light, and a brown, poorly soluble substance precipitates out, resulting in a significant decrease in light transmittance over all wavelengths. They become unable to perform their functions. Therefore, it cannot withstand multiple uses. Furthermore, since the filter solution is an organic solvent, cooling water must be used separately during ultraviolet irradiation. Therefore, the present inventors have discovered a filter solution that has extremely high transmittance to light at the above effective wavelengths compared to light transmittance at other wavelengths, and which is itself stable to light. As a result of conducting various studies to achieve this purpose, the present inventors discovered that an acidic aqueous solution containing quinine, cupric sulfate, and nickel sulfate was suitable for the purpose, and completed the present invention. The filter solution of the present invention is produced by adding quinine, cupric sulfate, and nickel sulfate to pre-acidified water and dissolving them, or by dissolving them in water and then adjusting the resulting aqueous solution to acidity. be done.

Quinine may be the free base itself, but acid addition salts such as sulfates, hydrochlorides, etc. are usually used. As the acid used for acidification, any acid can be used as long as it itself does not have absorption in the wavelength range of 280 to 310 nm, and examples thereof include hydrochloric acid, sulfuric acid, acetic acid, and the like. The pH of the acidification should be about 4.6 or less, and about 2 to about 3.3 is particularly preferred. The concentration of each component is appropriately selected so that the absorbance at the minimum absorption wavelength existing between 280 and 310 nm is about 0.7 or less, preferably about 0.6 or less. for example,
Quinine or its salts 1 (weight): CuSO4.5H
A combination of 2020 (weight): NiSO4.6H 202000 (weight): acid 40 (volume): water 10000 (volume) is used.

The ultraviolet irradiation process can be carried out under the same conditions as the conventional ultraviolet irradiation process, except that the above filter solution is used.

The thermal isomerization process of irradiation products, previtamin Ds, also
It can be carried out under the same conditions as the isomerization step in the conventional production of vitamin Ds.

The reaction between brevitamins D and vitamin D is a reversible thermal isomerization reaction, and at low temperatures, vitamin D is predominant, but it takes a long time to reach equilibrium; Although vitamin D is predominant, it is known that equilibrium is reached in a short time. Therefore, the thermal isomerization reaction is carried out by appropriately heating previtamin D dissolved in a suitable solvent such as alcohol, hydrocarbon, halogenated hydrocarbon, etc., leaving it at room temperature, or cooling it. The filter solution of the present invention has an absorption minimum near 280 nm, and has an absorption minimum of 270 nm or less and 310 nm, which is harmful to the production of previtamin Ds.
It effectively blocks light of nm or larger and is stable for long periods of time.

This is proven by the following experimental example. Example filter solution Total amount of distilled water is 51? shall be.

The above filter solution was irradiated with a 200W high-pressure mercury lamp while being cooled, and after a certain period of time, a portion of the solution was sampled and the ultraviolet absorption was measured.

The results are shown in Table 1 and FIG. 1 of the accompanying drawings. As shown in Table 1 and Figure 1, in the filter solution of the present invention, the absorption minimum gradually moves to the longer wavelength side with the passage of irradiation time, and the absorbance value tends to increase. The shift of the absorption minimum wavelength is in a favorable direction for the production of previtamin Ds, and the increase in absorbance value is also slight and does not pose an obstacle to the production of previtamins Ds.

Since the ultraviolet irradiation time required for one production of previtamin D is usually only a few minutes to several tens of minutes, the filter solution of the present invention can withstand repeated production of previtamin D several times.

Since the filter solution of the present invention is an aqueous solution, it can simultaneously serve as a cooling water in addition to the filter solution.

Therefore, it is not necessary to separately provide a filter solution part and a cooling solvent part in the ultraviolet irradiation apparatus, as is the case when an organic filter solution is used, and the apparatus can be simplified. ．． The invention will be explained in further detail in the following examples.

Example 1 Production of filter solution Quinine hydrochloride [C2OH24N2O2・HCl・2H2
0]2.07 was added to 101 ml of water, 200 ml of concentrated sulfuric acid was added, and the mixture was thoroughly shaken to obtain a uniform aqueous solution.

Next, copper sulfate (CuSO4.5H20) 40.0
7 and nickel sulfate (NiSO4.6H20) 4.0
After k9 was added and dissolved, water was added to adjust the total volume to 201, to obtain a filter solution. The pH of this filter solution was 1.5. Example 2 Production of filter solution Quinine sulfate [(C2OH24N2O2)2・H2SO4・2H20
') 2007 to 1000ml of water and 20ml of concentrated sulfuric acid.
was added and shaken well to form an aqueous solution.

Next, 47 y of copper sulfate (CuSO4.5H20) and 400 y of nickel sulfate (NiSO4.6H20) were added and dissolved, and then water was added to bring the total volume to 2000 ml.
A filter solution was obtained. The pH of this filter solution is 1
．． It was 1. Example 3 Ingredients for manufacturing filter solution Quinine hydrochloride 0.5t Copper sulfate 10y Nickel sulfate 1kg Mix and dissolve the above ingredients in an appropriate amount of water, and add 50% concentrated hydrochloric acid to this.
After adding ml, the total volume was adjusted to 51 with water.

The pH of the obtained filter solution was 1.1. Example 4 Ingredients for manufacturing filter solution Quinine hydrochloride 10 to Copper sulfate 0.27 Nickel sulfate 207 Glacial acetic acid 1 ml Make the total volume 100 ml with water.

A filter solution was prepared according to the method of Example 1 using the above ingredients.

The pH of this filter solution was 2.7. Example
5 Production of 1α-hydroxycholecalciferol (1) Ultraviolet irradiation reaction In this step, HL manufactured by Taishina Kogyo Co., Ltd.
- A type B irradiation device (200W high pressure mercury lamp) was used.

The filter solution 21 produced according to Example 1 was circulated through the outer part of the apparatus while being cooled in advance with Coolix (set temperature 5° C., filter solution temperature about 9° C.).

1α-Hydroxy J me[dehydrocholesterol 100
A solution of η dissolved in 400 d of ethanol was placed in an irradiation device, the outside was cooled with ice, and argon gas was introduced to remove oxygen.

A high-pressure mercury lamp (9) that has been lit and stabilized in advance.
0x2.2A) was put into the irradiation device and irradiation was started.

During the irradiation period, argon gas was passed through the bottom of the irradiation solution to maintain an inert atmosphere and to stir the solution.
Irradiation was carried out for 16 minutes, during which time the temperature of the reaction solution increased to 9
．． The temperature of the filter solution increased from 5°C to 10.5°C and from 9°C to 14°C. The same irradiation reaction was repeated seven more times.

For the final irradiation, 1α-hydroxy-J[dehydrocholesterol 103η was used. Therefore, the total amount of 1α-hydroxy-J medehydrocholesterol used for irradiation was 803η. Combine the irradiation solutions and remove the solvent under reduced pressure for 35 minutes.
It was distilled off at a temperature below ℃.

The resulting white residue was dissolved in about 40 ml of hexane acetone (7:3 volume), and this was added to a column (2.2 x 27.
0CTrL) and eluted with the same mixed solvent.
It was separated into one fraction each. One part of each fraction was measured for ultraviolet absorption, and fractions 5 to 12 having a maximum between 255 nm and 257 nm were combined (this contains approximately 445 η of 1α-hydroxy previtamin D3). ), was used in the following thermal isomerization reaction. (2) Thermal isomerization reaction The solvent was removed by evaporation from the combined solution of the above fractions 5 to 12, the resulting white residue was dissolved in 100 ml of dichloroethane, and this solution was heated under reflux on a water bath for 2 hours under argon gas. did.

The reaction solution was then concentrated under reduced pressure to obtain a yellow oily residue.
This residue was dissolved in chloroform-n-hexane (65:35 by volume) and added to Sephadex L.
H-20 (registered trademark) column (3.0 x 22.0 (
V7! ) and eluted with the same mixed solvent.

The eluate was separated into 15 ml fractions, the ultraviolet absorption of each fraction was measured, and fractions 20 to 25 showing maximum absorption at 265 nm were combined and concentrated under reduced pressure. The resulting residue (186
Tf19) was dissolved in n-hexane (7T1L) under argon gas.
Recrystallization from 1) gave 124 1α-hydroxy-cholecalciferol (yield 15% from 1α-hydroxy-cholecalciferol) as colorless fine needle-like crystals. Example 6 Production Example 2 of 1α-hydroxycholecalciferol
The filter solution 21 prepared according to the method is cooled and circulated through the jacket of the irradiation device.

1α-Hydroxy-J me[dehydrocholesterol (20
A solution of 01T19) in ethanol (400 ml) was ice-cooled, deoxidized by introducing argon gas, passed through a filter solution, and irradiated for 43 minutes, including the time required for stabilization of the light source.

The same irradiation reaction was carried out 5 times in total, and the total reaction solution (2000m0
were combined and concentrated to approximately 500 Tn1. The obtained concentrate was isomerized by heating at 75° C. for 2.5 hours in an argon gas stream, and then allowed to cool and then concentrated to obtain an oily residue. This oily residue was purified by column chromatography under the following conditions. Adsorbent: Kieselgel (Talc) 607 Column: φ
2.7×23.5? Developing solvent: Benzene/ethyl acetate (4:1V/) Fraction:
1 fraction on 30 m 10 thin layer chromatography
Fractions representing a single spot of α-hydroxycholecalciferol (black 39-52) were combined and concentrated.

The obtained oily residue was recrystallized from 15 ml of n-hexane to obtain 1α-hydroxycholecalciferol 231η as colorless fine needles. Example 7 Preparation of 25-hydroxycholecalciferol A solution containing 100 η of 25-hydroxy-J medehydrocholesterol in 200 ml of benzene and 200 ml of ethanol was irradiated with UV light as described in Example 5(1).

The irradiated solution was concentrated under reduced pressure below 35°C, and the resulting oily residue was washed with 35% ethyl acetate-n-hexane solution, and then filtered. The insoluble fraction contained unreacted raw materials, while the sap contained product. 15 ml of ethanol was added to the P solution and concentrated under reduced pressure to 5 TIL1. After heating this concentrated solution at 75°C for 2.5 hours under argon gas, the solvent was distilled off, and the residue was dissolved in 2 ml of benzene.
Purified by column chromatography on ieselgel) 20y using benzene monoethyl acetate (10:1/) as eluent. Fractions showing a single spot of 25-hydroxycholecalciferol were collected by thin layer chromatography [silica gel plate; benzene monoacetate (5:3 V/V); detection: UV 254 nm], and the solvent was removed. An oily residue 10Tn9 was obtained. This residue is λE in Uv
It showed a tOHmax of 265 nm, which corresponded to the standard of 25-hydroxycholecalciferol by thin layer chromatography.

Example 8 Production of ergocalciferol (vitamin D2) (1)
Ultraviolet irradiation reaction In this step, a photochemical reaction device (4
A 00W high-pressure mercury lamp) was used.

3.5 liters of the filter solution prepared according to Example 2 was circulated through the jacket of the device while being cooled beforehand with Coolix. Ergosterol 0.47 to ethanol 400
The solution dissolved in ml was placed in an apparatus and irradiated for 40 minutes under an argon gas flow.

The same reaction operation was repeated once more. Next, a solution of 0.27 ergosterol dissolved in 400 ml of ethanol was irradiated in the same manner as before, but in this case, the amount of filter solution used was 2.011, and the irradiation time was 22 minutes. In this way, a total amount of ergosterol of 1.07 was irradiated. (
2) Recovery of raw material ergosterol The irradiated solution from step (1) was combined, concentrated under reduced pressure at a temperature of 40°C or less to a volume of 50 ml, and left in a refrigerator overnight. 32η)
I got a lot of it.

The crystals were washed with 2 m2 of cold ethanol, and the washing solution was combined with solution f. (3) Thermal isomerization step The solution obtained in (2) was heat isomerized at 75° C. (bath temperature) for 2.5 hours under argon gas.

The reaction solution was then concentrated under reduced pressure to obtain a pale yellow oily residue. (4) Separation and purification step Dissolve the oily residue from step (3) in 5 ml of n-hexane,
This was applied to a column of silica gel [Kieselgel] 707 (φ
2.7X27.5c711), and
It was eluted with hexane (1:4 V/V) and fractionated into 15 ml fractions.

A portion of each fraction was detected by thin layer chromatography, and fractions (47-69) corresponding to ergocalciferol were collected, combined, and concentrated under reduced pressure to obtain an oily residue of 449η. This oily residue was dissolved in chloroform:n-hexane (6
5:35V/V) Dissolve in 3ml, Sephadex LH
-20 column (φ2.7×22.0Cr 1 L), eluted with chloroform:n-hexane (65:35V/), and fractionated into 7ml fractions.

As before, fraction 30- corresponding to ergocalciferol
34 were separated, combined, and the solvent removed under reduced pressure.
363 g of ergocalciferol (vitamin D2) (yield 36.3%) was obtained in the form of a pale yellow oil. This product became crystallized by standing or by crystallization from acetonitrile.

[Brief explanation of the drawing]

FIG. 1 shows an ultraviolet absorption curve of a filter solution of the present invention, where the vertical axis shows absorbance and the horizontal axis shows wavelength.

Claims (1)

[Claims] 1. A method for producing vitamin D, which comprises irradiating provitamin D with ultraviolet rays and thermally isomerizing the obtained previtamin D, comprising quinine or a salt thereof, cupric sulfate, and sulfuric acid. A method characterized in that the ultraviolet irradiation is performed using an acidic aqueous solution containing nickel as a filter solution. 2. The method according to paragraph 1, wherein the provitamin D is 1α-hydroxy-7-dehydrocholesterol. 3. The method according to paragraph 1, wherein the provitamin D is 25-hydroxy-7-dehydrocholesterol. 4. The method according to paragraph 1, wherein the provitamin D is ergosterol. 5. A process according to paragraph 1, comprising the addition of a step of chromatography of the thermally isomerized product on molecular sieve material or silica gel and/or recrystallization from n-hexane or acetonitrile.