JPS6251266B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing active vitamin D ₃ . More specifically, _three types of active vitamin D such as 1α-hydroxycholecalciferol, 1α,24-dihydroxycholecalciferol, and 1α,25-dihydroxycholecalciferol, whose hydroxyl groups are protected by specific protective groups, are using protected hydroxycholest-5-enes in high yield and efficiency.
The present invention relates to an industrially extremely advantageous manufacturing method.

1α-hydroxycholecalciferol, 1
Compounds such as α,24-dihydroxycholecalciferol are well known as active vitamin _D3 .

The method for producing active vitamin _D3 is as follows:
For example, hydroxycholest-5-ene with its hydroxyl group protected is treated with an allylic brominating agent, then reacted with a dehydrobrominating agent to obtain hydroxycholest-5,7-dienes, which are then irradiated with ultraviolet light. ,
A method for producing 1α-hydroxycholecalciferol by thermal isomerization and deprotection is known.

In this way, when producing active vitamin _D3 , hydroxycholest-5-enes are used, and this is subjected to allylic bromination and dehydrobromination reaction to produce hydroxycholest-5,7-diene. When using the method of obtaining active vitamin _D3 by irradiating it with ultraviolet rays and thermally isomerizing it, in the step of the allylic position bromination and dehydrobromination reaction,
In order to suppress side reactions and improve the yield, hydroxycholest-5-enes with protected hydroxyl groups were used to perform allylic bromination and dehydrobromination reactions to produce hydroxycholest-5,7-enes. -As a diene, it is necessary to produce active vitamin D ₃ by irradiating it with ultraviolet light, thermal isomerization, and deprotecting it.

For example, Japanese Patent Application Laid-Open No. 48-62750,
Tetrahedron Letters No.40, 4147-4150, 1972
etc., the hydroxyl group is protected with an acetyl group, 1α,3β-diacetoxycholest-5-ene, 1α,3β,24-triacetoxycholest-
Using 5-enes, hydroxycholest-5-enes are subjected to allylic bromination and dehydrobromination reaction to produce the corresponding hydroxycholest-5,7-dienes, which are irradiated with ultraviolet light. , thermal isomerization,
A method for producing active vitamin D ₃ by deprotection is described.

Also, Chem・Pharm・Bull・23, 695-697
(1975) etc., using hydroxycholest-5-enes protected with a benzoyl group, bromination at the allylic position and dehydrobromination reaction to produce hydroxycholest-5,7-dienes. A method for producing active vitamin D ₃ through ultraviolet irradiation and thermal isomerization is described.

However, these methods are limited to hydroxycholest-5-enes obtained by allylic bromination and dehydrobromination reactions.
The isolated yield of 5,7-dienes is only about 15 to 30%, and the reproducibility of the yield is poor. In addition, hydroxycholester-4,6-diene is produced as a by-product. This method cannot be said to be a satisfactory method for producing active vitamin D ₃ because it has the drawback of producing a high proportion of dienes.

On the other hand, the final step in the production of active vitamin _D3 , which involves ultraviolet irradiation and thermal isomerization, results in extremely low yields and is unsatisfactory according to conventional methods.

That is, for example, according to the example of JP-A No. 48-62750, 600 μg of 1α,3β-diacetoxycholesta-5,7-diene is irradiated with ultraviolet rays,
The yield of 1α,3β-diacetoxy previtamin D ₃ produced was only 120 μg, and
In the publication No. 110554, only 13 mg of 1α-hydroxycholecalciferol and 8 mg of 1α-hydroxyprevitamin D ₃ are obtained from 135 mg of 1α,3β-diacetoxycholeta-5,7-diene.

Also, JP-A-51-108050, JP-A-53-
In Publication No. 87344, hydroxycholester-5,7
- When irradiating dienes with ultraviolet rays, the irradiation time is stopped when the conversion rate of hydroxycholester-5,7-dienes is about 50%, and the corresponding previtamin D ₃ produced by ultraviolet irradiation is further Previtamin D 3 and unreacted hydroxycholester-5,7-dienes are separated from previtamin D ₃ and unreacted hydroxycholester-5,7-dienes after ultraviolet irradiation. A method is described in which hydroxycholester-5,7-dienes are recycled and reused, and previtamin D ₃ is further thermally isomerized to produce active vitamin D ₃ .

However, in such ultraviolet irradiation and thermal isomerization reactions, previtamin D ₃ after ultraviolet irradiation
The separation from unreacted hydroxycholester-5,7-dienes is carried out by high performance liquid chromatography, and previtamin D ₃ is unstable when using high performance liquid chromatography. Because of this, there is a risk of it being broken during chromatographic separation.
Furthermore, since a large amount of the compound cannot be processed at one time, it is disadvantageous for producing a large amount of the compound, and is not necessarily satisfactory as an industrial method for producing active vitamin _D3 .

The present inventors have discovered hydroxycholesto-5-ene, such as 1α,3β-dihydroxycholest-5-ene, 1α,3β,24-trihydroxycholest-5-ene, etc.
When we investigated a method for industrially advantageous production of active vitamin D ₃ in high yield using 5-enes, we found that the hydroxyl group of hydroxycholest-5-enes was In particular, if hydroxycholest-5-enes protected with lower alkoxycarbonyl groups such as ethoxycarbonyl groups are used, and this is subjected to allylic bromination and dehydrobromination reactions, extremely high yields can be obtained, and by-products can be produced. The production rate is low and hydroxycholester-5,7-dienes are obtained, and this hydroxycholester-5,7-diene is obtained.
7-dienes are irradiated with ultraviolet light at a low conversion rate, and the resulting mixture of previtamin D ₃ and terminally reacted hydroxycholester-5,7-dienes can be crystallized or rinsed without using high performance liquid chromatography. can be very easily separated into high-purity previtamin D ₃ and high-purity unreacted hydroxycholester-5,7-dienes, and the previtamin D ₃ obtained by separation is subjected to thermal isomerization, By subjecting to the deprotection reaction and recycling the unreacted hydroxycholester-5,7-dienes, active vitamin D ₃ can be obtained extremely efficiently and industrially advantageously. By using hydroxycholest-5-enes protected with a lower alkoxycarbonyl group, hydroxycholest-5,7-dienes can be obtained efficiently in high yields, and furthermore, they can be easily obtained through ultraviolet irradiation and thermal isomerization reactions. The inventors have discovered that this method can be carried out industrially with great advantage and high yield, and is extremely excellent as a method for producing active vitamin D ₃ , leading to the present invention.

That is, the present invention has the following formula [I] [In the formula, R ₁ and R ₂ represent a lower alkoxycarbonyl group, and R ₃ and R ₄ each independently represent a hydrogen atom or a lower alkoxycarbonyloxy group. ] Hydroxycholest-5-enes represented by the following formula [] are reacted with an allylic brominating agent and then a dehydrobrominating agent. [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. ] Hydroxycholester-5,7-dienes represented by the following formula [] [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. ] A mixture of previtamin D ₃ represented by the formula [ ] and unreacted hydroxycholester-5,7-diene represented by the above formula [] is produced, and then from this mixture, previtamin D ₃ and unreacted Separating hydroxycholester-5,7-dienes,
The following formula [] is characterized in that unreacted hydroxycholester-5,7-dienes are recycled and reused, and previtamin D ₃ is thermally isomerized and deprotected. [In the formula, R ₃ ′ and R ₄ ′ each independently represent a hydrogen atom or a hydroxyl group. ] This is a method for producing active vitamin D type ₃ expressed as follows.

The compound used as a starting material in the present invention is hydroxycholesto-5 represented by the above formula [I].
-It is an en-type. In the above formula [I], R ₁ and
R ₂ is a lower alkoxycarbonyl group, R ₃ ,
Each R ₄ is independently a hydrogen atom or a lower alkoxycarbonyloxy group. Examples of the lower alkoxycarbonyl group include lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, and among them, ethoxycarbonyl group is particularly preferred in the present invention. By using hydroxycholest-5-enes whose hydroxyl groups are protected with lower alkoxycarbonyl groups in this manner, hydroxycholesta-5,7-dienes can be obtained in extremely high yields.

Specific examples of the cholest-5-enes represented by the above formula [I] include the following.

(1) 1α,3β-diethoxycarbonyloxycholest-5-ene, (2) 1α,3β,24-triethoxycarbonyloxycholest-5-ene, (3) 1α,3β,25-triethoxycarbonyl Oxycholest-5-ene, (4) 1α,3β,24,25-tetraethoxycarbonyloxycholest-5-ene.

In order to produce such hydroxycholest-5-enes represented by the above formula [I], for example, hydroxycholesto-5-enes having a free hydroxyl group are used.
It can be easily produced by reacting enes with ethyl chloroformate in the presence of a tertiary amine catalyst such as 4-dimethylaminopyridine. The reaction proceeds at room temperature to 80°C. Note that ethyl chloroformate has a low boiling point, so the reaction must be carried out with caution;
It is advisable to take your time.

The thus obtained hydroxycholest-5-enes having a hydroxyl group protected by a lower alkoxycarbonyl group are reacted with an allylic brominating agent and then with a dehydrobrominating agent to obtain the desired hydroxycholest-5-ene. 5,7-dienes are obtained.

In the present invention, the allylic brominating agent includes:
Any compound that is normally used for bromination at the allyl position may be used, such as N-bromosuccinoimide, 1,
3-dibromo-5,5-dimethylhydantoin,
N-bromocaprolactam and the like are preferably used. These allylic brominating agents are usually used preferably in an amount of 1 to 2 times the amount of the hydroxycholest-5-ene of the general formula [] as a raw material.

In the reaction of the present invention, first, a hydroxycholest-5-ene of the general formula [] is reacted with an allylic brominating agent in an inert organic solvent. It is appropriate to do so.

As the inert organic solvent, one that does not react with the allylic brominating agent is used. For example, hexane, heptane, cyclohexane, ligroin, benzene, toluene, xylene, bromobenzene,
Chlorobenzene, nitrobenzene, carbon tetrachloride,
Hydrocarbons or halogenated hydrocarbons such as 1,2-dichloroethane and 1,2-dibromoethane are advantageously used.

Also, ethyl ether, tetrahydrofuran,
Ether solvents such as dioxane, methyl cellosolve, and phenyl cellosolve are also 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, depending on the reaction, the reaction may proceed even at temperatures lower than room temperature.
Furthermore, a small amount of a radical generator such as azobisisobutyronitrile, benzoyl peroxide, or cyclohexenyl hydroperoxide may be added.

Hydroxycholest obtained by the above reaction
The brominated 5-enes are then converted into hydroxycholester-5,7-dienes represented by the above formula [] by reacting with a dehydrobrominating agent.

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 used in the previous bromination reaction, so after the reaction solvent from the previous reaction is removed, 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 bromine compound produced in the previous bromination reaction, but the reaction rate or reaction yield may be preferable. In order to obtain the desired effect, it is usually preferable to use the bromine compound in a molar ratio of about 2 times or more relative to the bromine compound. 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-S-collidine system under reflux, the reaction is completed in a short time of about 20 minutes.

After completion of the reaction, separation and purification of the hydroxycholester-5,7-dienes, which are reaction products, can be easily carried out, for example, by expelling the reaction solvent and then performing recrystallization.

When producing hydroxycholest-5,7-dienes using hydroxycholest-5-enes in which the hydroxyl group is protected with a lower alkoxycarbonyl group as in the present invention, compared to the conventional method, The yield is high, the proportion of hydroxycholester-4,6-dienes produced as by-products is low, and in addition, the protective group for the lower alkoxycarbonyl group has the effect of increasing the crystallinity of the target product. Therefore, after the above-mentioned allylic bromination and dehydrobromination reactions, the hydroxycholester-5,7-dienes can be isolated and purified using a recrystallization method, which is an extremely simple method, to isolate a highly pure target product. have.

To perform recrystallization here, methanol, ethanol, n-propanol, iso-propanol,
Lower aliphatic alcohols such as n-butanol, methoxyethanol, n-hexanol, dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,
It is preferable to recrystallize by a known method using a mixed solvent with a lower aliphatic ether such as 2-dimethoxyethane.

The thus obtained hydroxycholester in which the hydroxyl group is protected with a lower alkoxycarbonyl group
5,7-dienes are irradiated with ultraviolet light to form the following formula [] [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. ] A mixture of previtamin D ₃ represented by the formula [ ] and unreacted hydroxycholester-5,7-diene represented by the above formula [] is produced, and then previtamin D ₃ and unreacted hydroxycholesterol are extracted from the mixture. Star-5,7-dienes are separated, unreacted hydroxycholester-5,7-dienes are recycled and reused, and previtamin D ₃ is thermally isomerized and deprotected to form active vitamin D _3. Manufacture types.

The ultraviolet rays used here are approximately 200~
It is known as a wavelength range of 360 nm, and a wavelength range of 260 to 310 nm is particularly preferably used.

Further, the reaction solvent is preferably an inert organic solvent,
For example, hexane, heptane, cyclohexane,
Ligroin, benzene, toluene, xylene, prombenzene, chlorobenzene, nitrobenzene, carbon tetrachloride, 1,2-dichloroethane, 1,
Hydrocarbons such as 2-dipromoethane, halogenated hydrocarbons, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, methyl cellosolve, phenyl cellosolve, methanol,
Alcohol solvents such as ethanol, propanol, hexanol, and cyclohexanol are often used as suitable solvents.

Particularly preferred are benzene, toluene, diethyl ether, methanol, ethanol, and the like alone or in combination.

The temperature during ultraviolet irradiation is -20℃ to 120℃, especially -
A range of 10°C to 20°C is preferred. Further, it is preferable to carry out the reaction in an inert atmosphere in which oxygen does not exist, such as an argon or nitrogen atmosphere.

In the present invention, it is preferable to stop the ultraviolet irradiation at a point when the conversion rate of hydroxycholester-5,7-dienes is low, especially when the conversion rate of hydroxycholester-5,7-dienes is low.
The conversion rate of dienes is preferably 0.1 to 50%, more preferably 10 to 40%, more preferably 10 to 30%, and the UV irradiation is preferably stopped. By stopping ultraviolet irradiation when the conversion rate is low, the previtamins expressed by the above formula [] produced by ultraviolet irradiation are further converted into other compounds, such as the corresponding lumisterol, taxerol, etc. It is possible to suppress the conversion and increase the production rate of the above-mentioned previtamin D ₃ types produced by ultraviolet irradiation.
D Type ₃ and unreacted hydroxycholesta-5,7-
The proportion of other compounds in the mixture with dienes can be lowered.

Next, from the thus obtained mixture of previtamin D ₃ and unreacted hydroxycholester-5,7-dienes, previtamin D ₃ and unreacted hydroxycholester-5,7-dienes were separated. To separate.

As in the present invention, by using hydroxycholester-5,7-dienes protected with a lower alkoxycarbonyl group, the previtamin D ₃ obtained by irradiating the same with the above-mentioned ultraviolet rays and unreacted hydroxycholester. Together with star-5,7-dienes,
It has a lower alkoxycarbonyl group as a protecting group for the hydroxyl group, and a mixture of the two can be prepared in an organic solvent using the difference in solubility between the two, such as by simple recrystallization or rinsing, without using high-performance liquid chromatography. Previtamin D ₃ and unreacted hydroxycholester-5,7
- It can be separated into dienes, and since both can be separated by extremely simple means, the method for producing active vitamin D ₃ of the present invention is industrially efficient. It becomes a manufacturing method.

When performing separation, after UV irradiation,
By partially distilling off the reaction solvent as described above and filtering the resulting solid matter or crystals by a conventional method, hydroxycholesterol is added to the crystal part.
5,7-diene is produced, and previtamin D ₃ is produced in the liquid part.

Alternatively, after irradiating with ultraviolet rays, the reaction solvent is distilled off, and the residue is an alcohol solvent such as methanol, ethanol, isopropanol, hexanol, cyclohexanol, or a mixed solvent of these alcohol solvents and an ether solvent such as diethyl ether or tetrahydrofuran. The previtamin D ₃ and unreacted hydroxycholester-5,7-dienes are separated by adding an organic solvent and subjecting the resulting solid or crystals to the same procedure as described above. Ru.

The unreacted hydroxycholester-5,7-dienes thus separated are recycled and reused as raw material compounds, and the previtamin D _3s are subsequently subjected to thermal isomerization and deprotection reactions.

The thermal isomerization reaction is preferably carried out in an inert organic solvent, such as
Preferred solvents include those similar to those used in the ultraviolet irradiation described above.

Thermal isomerization reaction is an equilibrium reaction between previtamin D ₃ and vitamin D ₃ , and the equilibrium value of both is:
It varies depending on the reaction temperature, and in general, the higher the isomerization reaction temperature, the faster the isomerization reaction rate from previtamin D ₃ to vitamin D ₃ , but the equilibrium value shifts to the side where vitamin D ₃ decreases. There is a tendency to

Considering these circumstances, the isomerization reaction is performed at 20 to 120
It is carried out at a temperature of preferably 40 to 100°C.

The active form of vitamin D ₃ protected by a lower alkoxycarbonyl group is obtained by the thermal isomerization reaction, and may then be separated and purified, or it may be subjected to a deprotection reaction following the thermal isomerization reaction. Ru.

Such deprotection reaction is a well-known reaction per se, and the protecting group can be easily removed by contacting with an alkali such as sodium hydroxide or potassium hydroxide.

The thus obtained active vitamin D ₃ can be purified by conventional manufacturing methods, such as extraction methods, recrystallization methods, column chromatography, thin layer chromatography, high performance liquid chromatography, and the like.

In addition, in the present invention, previtamin D ₃ produced by ultraviolet irradiation and unreacted hydroxycholesterol
In order to separate highly purified previtamin D ₃ from a mixture of 5,7-dienes, thermally isomerize and deprotect it, the separation and purification of the obtained active vitamin D ₃ is relatively simple. It is also possible to obtain highly pure active vitamin D ₃ by purification methods, extraction methods, recrystallization methods, chromatography methods, etc.

As described above, in the present invention, hydroxycholest-5-enes protected with a lower alkoxycarbonyl group such as an ethoxycarbonyl group are used, and by bromination at the allylic position and dehydrobromination reaction, In high yield, hydroxycholester-5,
7-dienes can be obtained easily and efficiently,
Hydroxycholester-5,7- thus obtained
Using dienes, this is irradiated with ultraviolet rays to obtain a mixture of the corresponding previtamin D ₃ and unreacted hydroxycholester-5,7-dienes, and from this mixture, crystallization, rinsing, etc. The unreacted hydroxycholester-5,7-dienes obtained are recycled and reused, and previtamin D ₃ is thermally isomerized and deprotected. , industrially advantageous and efficient production of large amounts of active vitamin D ₃ by extremely simple means.
can be obtained in high yield. As described above, the method for producing active vitamin D ₃ of the present invention is an industrially efficient and extremely advantageous process, and has great significance.

The present invention will be explained in more detail below using examples.

Example 1 (1) Synthesis of 1α,3β-diethoxycarbonyloxycholest-5-ene; 10gr of 1α-hydroxycholesterol and 4-
Dimethylaminopyridine 12gr to methylene chloride
Add to 100 ml and stir under nitrogen atmosphere to dissolve, then cool with ice water and add 47.5 ml of ethyl chlorocarbonate.
ml was added dropwise.

After dropping, the mixture was heated at a bath temperature of 60°C and stirred for 28 hours. The resulting reaction mixture was poured into ice water and extracted with methylene chloride. methylene chloride extract
2N-hydrochloric acid, then washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 13.34gr.
A residue was obtained.

By subjecting this residue to column chromatography (solvent benzene-ethyl acetate system) packed with 300 gr of silica gel, 12.6 gr of 1α,3β-diethoxycarbonyloxycholest-5-ene was obtained.
(93%).

(2) Synthesis of 1α,3β-diethoxycarbonyloxycholest-5,7-diene; 5.46g (10mmol) of 1α,3β-diethoxycarbonyloxycholest-5-ene in 100ml of n-hexane (Na dry) 1,3-dibromo 5,5 by heating in a 95°C oil bath and stirring.
-1.716gr (6mmol) of dimethylhydantoin was added and stirred for 15 minutes under infrared irradiation.

After cooling to room temperature, the precipitate was filtered and washed with n-hexane. The n-hexane solution and the washing solution were concentrated under reduced pressure at 40°C to obtain a concentrated residue.

25 ml of S-collidine dissolved in 33 ml of xylene (dried Na) was heated in an oil bath at 170°C, and a solution of the above concentrated residue (crude promide) dissolved in xylene was added dropwise with stirring. The addition funnel was further washed with xylene) and heated to reflux for 20 minutes. After cooling to room temperature, the precipitate was separated and washed with xylene.

The xylene liquid and washing liquid were concentrated under reduced pressure at 40°C to obtain a concentrated residue (mainly diene compound).

This product was dissolved in 200 ml of ethyl acetate and washed three times with 100 ml of 1N hydrochloric acid. The mixture was further washed successively with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.68 gr of a crude product.

(3) Isolation of 1α,3β-diethoxycarbonyloxycholesta-5,7-diene; The total amount of 6.68g of the crude product obtained in (2) above was added to a mixed solution of 170ml of methanol and 16ml of ether. The mixture was heated to reflux and dissolved at a bath temperature of 80°C. After cooling to room temperature for 2 and a half hours, it was left in a cool, dark place (5°C) overnight. The precipitated white needle crystals were collected, washed with cold methanol at -20°C, and dried under reduced pressure in a dark place to obtain 1α,3β-diethoxycarbonyloxycholesta-5,7-diene having the following properties.
3.41 gr (yield = 62.5%) was obtained.

Melting point (°C): 140.5-142 (ether-methanol reconsolidation) IR (KBr, cm ^-1 ): 2950, 2860, 1740, 1465, 1370 NMR (CDCl ₃ , δ (ppm)): 0.62 (3H, s, C-18-CH ₃ ) 0.86 (6H, d, C-26-27-CH ₃ ) 1.31 (6H, t, C-1 & 3-ethoxycarbonyl group CH ₃ ×2) 4.20 (4H, q, C-1 & 3- Ethoxycarbonyl group CH ₂ × 2) 4.86 (2H, b, C-1 & 3-H × 2) 5.37 and 5.67 (2H, b, C-6 & 7-H ×
2) UV (ethanol, λmax, nm): 293 (ε=6760), 281 (ε=11530) 271 (ε=10800), 262 (Shoulder ε=
7580) UV (ether, λmax, nm): 293 (ε = 7710), 281 (ε = 13010) 271 (ε = 12360), 262 (Shoulder ε = 8910) (4) 1α-Ethoxycarbonyloxy precholecalcifer Synthesis of role-3β-ethoxycarbonate A solution of 272 mg (0.5 mmol) of 1α,3β-diethoxycarbonyloxycholester-5,7-diene in 600 ml of ether was cooled and then placed under argon.
Irradiated for 5 minutes using a 200W Hanobia mercury lamp through a Vycor filter (conversion rate ≒ 28
%). After the reaction was completed, the solvent was removed under reduced pressure at room temperature. The obtained residue was slurried with 20 ml of methanol cooled to 0°C, filtered and
173 mg of α,3β-diethoxycarbonyloxycholesta-5,7-diene was recovered as crystals. This recovered 1α,3β-diethoxycarbonyloxycholesta-5,7-diene is
Can be recycled and used.

After filtration, the methanol solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate. Crude 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate was used as a raw material compound without being purified.

(5) Synthesis of 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate A solution of 100 ml of the above crude 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate in benzene was heated to bath temperature under an argon atmosphere. Heated at 50°C for 14 hours.

After the reaction was completed, the reaction solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate. Crude 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate was used as a raw material compound without purification.

(6) 1α-Hydroxycholecalciferol The above crude 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate was dissolved in 10 ml of methanol:benzene (1:1) mixture, and the mixture was stirred at room temperature. 2N−
5 ml of potassium hydroxide-methanol solution was added dropwise, and after the addition, the mixture was heated and stirred at 60°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 25°C.

Add 50 ml of water and 500 ml of ethyl acetate to the resulting residue.
was added to separate the layers, and the aqueous solution was further extracted three times with ethyl acetate. Combine the organic separation and ethyl acetate extract, add dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution,
After sequentially washing with saturated saline, drying with anhydrous sodium sulfate, filtering and concentrating, a viscous oil containing 1α-hydroxycholecalciferol76
I got mg. Add this to silica gel (Wakogel C-
1α-hydroxycholecalciferol 22 was subjected to column chromatography (solvent: benzene-acetone system) packed with
mg (yield=30%, based on 99 mg of 1α,3β-diethoxycarbonyloxycholester-5,7-diene consumed). The physical properties of this product were consistent with those of conventional 1α-hydroxycholecalciferol.

Example 2 (1) Synthesis of 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate (a) First reaction 1α,3β-diethoxycarbonyloxycholester-5 obtained in Example 1, After cooling a solution of 272 mg (0.5 mmol) of 7-diene in 600 ml of ether, it was passed through a Vycor filter under argon using a 200 W Hanobia mercury lamp.
Irradiated for minutes. After the reaction was completed, the solvent was removed under reduced pressure at room temperature.

Under the same conditions as above, 816 mg (1.5 mmol) of 1α,3β-diethoxycarbonyloxycholester-5,7-diene was further divided into three batches and reacted. Combine the obtained residues, 0
The mixture was slurried with 80 ml of methanol cooled to 0.degree. C. and filtered to recover 664 mg of 1α,3β-diethoxycarbonyloxycholester-5,7-diene as crystals.

After filtration, the methanol solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate. This crude 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate was designated as L-No.1.

(b) Second reaction 1α,3β-diethoxycarbonyloxycholester-5,7-diene recovered in (a) above
Dissolve 120mg of 664mg in 600ml of ether,
After cooling, it was irradiated for 25 minutes under argon using a 200W Hanobia mercury lamp through a Vycor filter.

After the reaction was completed, the solvent was removed under reduced pressure at room temperature. The remaining 544 mg of 1α,3β-diethoxycarbonyloxycholesta-5,7-diene was divided into two batches and reacted under the same conditions as in (a) above.

The resulting residues were combined, slurried with 50 ml of methanol cooled to 0°C, filtered, and
358 mg of α,3β-diethoxycarbonyloxycholester-5,7-diene was recovered as crystals.

After filtration, the methanol solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate. This crude 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate was designated as L-No.2.

(c) Third reaction 1α,3β-diethoxycarbonyloxycholester-5,7-diene recovered in (b) above
358 mg was dissolved in 600 ml of ether, and after cooling, it was irradiated for 5 minutes under argon using a 200 W Hanobia mercury lamp through a Vycor filter.

After the reaction was completed, the solvent was removed under reduced pressure at room temperature.

The obtained residue was slurried with 25 ml of methanol cooled to 0°C and filtered to obtain 1α, 3β.
-Diethoxycarbonyloxycholester-
224 mg of 5,7-diene was recovered as crystals.

After filtration, the methanol solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate. This crude 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate was designated as L-No.3.

(d) Fourth reaction 1α,3β-diethoxycarbonyloxycholester-5,7-diene recovered in (c) above
224 mg was dissolved in 600 ml of ether, and after cooling, it was irradiated for 10 minutes under argon using a 200 W Hanobia mercury lamp through a Vycor filter.

After the reaction is complete, the solvent is removed at room temperature under reduced pressure to obtain 1α-ethoxycarbonyloxyprecholecalciferol-3β.
A residue containing -ethoxy carbonate was obtained.
This crude 1α-ethoxycarbonyloxyprecholecalciferol-3β-ethoxycarbonate was designated as L-No.4.

(2) Synthesis of 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate; Crude 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate L-No. obtained in (1) above. Combine 1 to No. 4,
The solution was dissolved in 400 ml of benzene and heated at a bath temperature of 60°C for 7 hours under an argon atmosphere.

After the reaction was completed, the reaction solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate. Crude 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate was used as a raw material compound without purification.

(3) 1α-Hydroxycholecalciferol The crude 1α-ethoxycarbonyloxycholecalciferol-3β-ethoxycarbonate obtained in (2) above was mixed with methanol:benzene (1:
1) Dissolve in 40ml of mixed solution and add 20% of 2N potassium hydroxide-methanol solution to this mixed solution while stirring at room temperature.
ml was added dropwise, and after the dropwise addition, the mixture was heated and stirred at 60°C for 1 hour.

After the reaction was completed, the reaction solution was concentrated under reduced pressure at 25°C.

Add 200 ml of water and 200 ml of ethyl acetate to the resulting residue.
was added to separate the layers, and the aqueous solution was further extracted three times with ethyl acetate.

The organic liquid and ethyl acetate extract were combined, washed sequentially with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous solution containing 1α-hydroxycholecalciferol. 684 mg of oil was obtained.

684 mg of the above crude 1α-hydroxycholecalciferol was added to silica gel (Wakogel C-200).
275 mg of 1α-hydroxycholecalciferol was obtained by subjecting it to column chromatography packed with 60 gr (solvent benzene-acetone system).
(yield 34%). The physical properties of this product were as follows.

Melting point 141.5-142℃ (ether-pentane recrystallization: needle crystals) UV (ethanol, λmax, nm) 265 (ε
17200) High resolution mass spectrum (IV=75eV) M ⁺ 400.3358 (C ₂₇ H ₄₄ O ₂ ) Comparative example 1 (1) 1α,3β-diacetoxy cholester 5,7
- Synthesis of diene; 22.1 g (45.5 mmol) of 1α,3β-diacetoxycholest-5-ene was dissolved in 550 ml of n-hexane, and 1,3
-dibromo-5,5-dimethylhydantoin
Add 7.1g (24.8mmol) and add 20g under infrared irradiation.
Stir for a minute.

After the resulting reaction mixture was allowed to cool to room temperature, the precipitate was separated and washed with n-hexane. The liquid and washing liquid were combined and concentrated under reduced pressure at 40°C to obtain a residue (crude bromine compound).

A solution of s-collidine (114.4 ml) dissolved in 300 ml of xylene was heated to 170°C (bath temperature), and the crude bromine compound was added to the solution with stirring in 200 ml of xylene.
was added dropwise (the dropping funnel was further washed with 50 ml of xylene) and heated under reflux for 25 minutes.
After cooling to room temperature, 60 minutes without separating the precipitate.
It was concentrated under reduced pressure at °C.

150 ml of dimethylformamide was added to this residue, heated to 180°C (bath temperature), and stirred for 15 minutes. After cooling to room temperature, it was concentrated under reduced pressure at 60°C. Add 500ml of benzene to the residue and remove the precipitate (main component, s
-collidine/HBr salt) was separated, the liquid was concentrated under reduced pressure, and 1α,3β-diacetoxycholester
5,7-diene, 1α,3β-diacetoxycholest-4,6-diene, 1α,3β-diacetoxycholest-5-ene and 1α,-acetoxycholest-2,4,6-triene. A residue was obtained.

(2) 1α,3β-diacetoxycholester-5,7
- Isolation of diene: A column using 200 g of silica gel as a packing material was prepared (filling solvent: benzene), and the above residue was subjected to chromatography using benzene-ethyl acetate as a developing solvent. As the main component, 1
α,3β-diacetoxycholester-5,7-diene, 1α,3β-diacetoxycholester-
15.5 g of material was obtained containing 4,6-diene and 1α,3β-diacetoxycholest-5-ene.

Add this to 100ml of ethanol at 50°C.
(bath temperature) and left in a cool, dark place for 24 hours.

After separating the precipitate, it was washed with cold ethanol.
1α,3 showing melting point 113-115℃ (ethanol)
β-diacetoxycholester-5,7-diene
7.6 g (yield = 34.4%) was obtained.

(3) Synthesis of 1α-acetoxyprecholecalciferol-3β-acetate 1α,3β-diacetoxycholesta-5,7
- After cooling a solution of 242 mg (0.5 mmol) of diene in 600 ml of benzene, it was irradiated for 22 minutes under argon using a 200 W Hanobia mercury lamp through a Vycor filter (conversion rate ≒ 60%).

After the reaction was completed, the solvent was removed under reduced pressure at 25°C.

Under the same conditions as above, an additional 1.21 g of 1α,3β-diacetoxycholester-5,7-diene
(2.5 mmol) was divided into 5 batches and the reaction was carried out.

The obtained residue containing 1α-acetoxyprecholecalciferol-3β-acetate was used as a raw material compound without being purified.

(4) 1α-acetoxycholecalciferol-3
β-acetate 800 ml of a benzene solution of the crude 1α-acetoxyprecholecalciferol-3β-acetate obtained in (3) above was heated to bath temperature under an argon atmosphere.
Heated at 80°C for 2.5 hours.

After the reaction was completed, the reaction solution was concentrated under reduced pressure at 25°C to obtain a viscous oil containing 1α-acetoxycholecalciferol-3β-acetate.
Crude 1α-acetoxycholecalciferol-3
β-acetate was used as a raw material compound without purification.

(5) 1α-Hydroxycholecalciferol The crude 1α-acetoxycholecalciferol-3β-acetate obtained in (4) above was dissolved in 45 ml of methanol, and 11.3 ml of a 25% potassium hydroxide-methanol solution was stirred at room temperature. was dripped. After the addition, the mixture was heated and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 25°C. Water to the resulting residue
62 ml and 120 ml of ether were added to separate the layers, and the aqueous solution was further extracted twice with ether. The organic liquid and ether extract were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.1 g of a viscous oil containing 1α-hydroxycholecalciferol. Obtained residue 2.1g
233 mg of 1α-hydroxycholecalciferol (yield 19.5
%; 1α,3β-diacetoxycholester-5,
(based on 1.452 g of 7-diene) was obtained.

Claims (1)

[Claims] 1. The following formula [I] [In the formula, R ₁ and R ₂ represent a lower alkoxycarbonyl group, and R ₃ and R ₄ each independently represent a hydrogen atom or a lower alkoxycarbonyloxy group. ] Hydroxycholest-5-enes represented by the following formula [] are reacted with an allylic brominating agent and then a dehydrobrominating agent. [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. ] The hydroxycholester-5,7-dienes are irradiated with ultraviolet rays to form the following formula [] [In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. ] A mixture of previtamin D ₃ represented by the formula [ ] and unreacted hydroxycholester-5,7-diene represented by the above formula [] is produced, and then from this mixture, previtamin D ₃ and unreacted Separating hydroxycholester-5,7-dienes,
The following formula [] is characterized in that unreacted hydroxycholester-5,7-dienes are recycled and reused, and previtamin D ₃ is thermally isomerized and deprotected. [In the formula, R ₃ ′ and R ₄ ′ each independently represent a hydrogen atom or a hydroxyl group. ] A method for producing active vitamin D type ₃ represented by 2. The method for producing active vitamin D ₃ according to claim 1, wherein R ₁ and R ₂ in the hydroxycholest-5-ene represented by the above formula [I] are ethoxycarbonyl groups. 3. The activity according to claim 1 or 2, wherein R ₃ and R ₄ in the hydroxycholest-5-ene represented by the above formula [I] are each independently a hydrogen atom or an ethoxycarbonyloxy group. Method for producing type ₃ vitamin D. 4. Claims 1 to 4, in which ultraviolet irradiation is carried out until the conversion rate of the hydroxycholester-5,7-dienes represented by the above formula [] is 0.1 to 50%.
Active vitamin D ₃ according to any one of paragraph 3
manufacturing method of types. 5. According to any one of claims 1 to 4, wherein ultraviolet irradiation is performed until the conversion rate of the hydroxycholester-5,7-diene represented by the above formula [] is 10 to 40%. A method for producing active vitamin D type ₃ . 6 Previtamin D type ₃ and unreacted hydroxycholester-5,7-dienes are separated using an organic solvent by utilizing the solubility difference between the two. A method for producing active vitamin D type ₃ according to any one of the items. 7. The method for producing active vitamin D ₃ according to claim 6, in which previtamin D ₃ and unreacted hydroxycholester-5,7-dienes are separated by rinsing or crystallization. .