JPS62181293A - Production of steroid derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material of vitamin D3 using a by-product as a raw material, by oxidizing cholesta-dien-ol to cholesta-dien-one, isomerizing in the presence of a basic catalyst and reducing the product. CONSTITUTION:The objective cholesta-5,7-dien-3-ol of formula IV can be produced by (1) oxidizing cholesta-4,6-dien-3-ol of formula I produced as a by- product with an oxidizing agent such as chromic acid, manganese dioxide, etc., to obtain cholesta-4,6-dien-3-one, (2) isomerizing the product to cholesta-5,7- dien-3-one in the presence of preferably 3-5 times equivalent of a basic catalyst (e.g. sodium methoxide) and (3) reducing the isomerized product with a reducing agent such as sodium borohydride.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a process for producing cholesta-5,7-dien-3-ol. More specifically, it relates to a method for producing cholesta-5,7-dien-3-ol tlA using cholesta-4,6-dien-3-ol as a starting material.

(Prior art) Cholestar-5,7 used as a raw material for vitamin D5
-dien-3-ol (7-dihydrocholesterol,
Below 1'-7-DHC! (abbreviated as J) is produced by dehydrobromide oxidation of 7-bromocholesterol obtained by brominating cholesterol (K, Ziegl).
er, Justug Liebig's Ann.

Chew, Bi, 80 (1942)).

(Problems to be Solved by the Invention) In this conventional method, the desired product 7-D
)! In addition to O, the isomer of 7-DHO, cholesta-4,6-')en-3-olka phase M it, is produced as a by-product and interferes with the purification of 7-DHO, so removal of the by-product is a problem. (Refer to Japanese Patent Application Laid-open Nos. 51-15661 and 51-145656).

Therefore, this by-product cholester 4,6-dinine-3-
Various methods for synthesizing 7-DHO for the purpose of suppressing the by-product of ol have been reported (for example,

Y, Tachibana, [Bull, Chem, So
c, Jpn, J51, 3085 (1978):
W., G., Salmond at al., [Tetr.
ahearon Lett, Jl 977, 1685;
P, N, Confalone et al.

(-J, ○rg, ohem, J46, 1030 (198
1)), but all of these methods require a longer number of steps than the conventional methods mentioned above, and the overall 7-DHO
There is no improvement in the yield of .

Furthermore, the by-product cholester 4,6-dinin-3-ol has not found any use.

(Means for solving the problem) For the above-mentioned reasons, Cholesta-4 and 6 have conventionally been considered only as by-products and treated as useless.
-'; If en-3-ol can be used effectively, it is considered to be of industrial significance. As a result of intensive research in order to solve this problem, the present inventors have discovered that 7-DH using the conventional method
Cholesta-4, which is produced as a by-product during the synthesis of O,
Using 6-dien-5-ol as a starting material, finally 7
- Found a method to produce DHCt.

That is, 1 the present invention provides cholesta-4,6-dien-6-ol (1
) is subjected to an oxidation reaction to produce cholesta-4,6-dien-5-one (Ill), and by subjecting (■) to an isomerization reaction in the presence of a base catalyst, the formula (110% formula% (110) was then subjected to a total reduction reaction to give the formula (IV) 5.7-' en-3-ol (
7-DHC).

Cholesta-4,6-diene-3, the starting material of the present invention
-ol (1) can be easily obtained from the crystal mother liquor from which 7-DHC is isolated, as described above. Others, eg, Bernstet et al.

[J, Org, ChemJ14, 465 (1949),
R, Jaworekaat al “Tetrahelr.
on Lett, 1968.4541 and Japanese Patent Application Publication No. 1983.
It can be obtained by the method described in Japanese Patent Application No.-124800.

As the oxidizing agent that can be used, there is used one that does not react with the double bond or the produced cholesta-4,6-dien-3-one (10).

For example, Jones reagent: Collins (c
reagents; chromic acids such as pyridinium dichromate (PDO) and pyridinium chlorochromate (POO), manganese compounds such as manganese dioxide, activated manganese dioxide and permanganic acid, ruthenium tetroxide and ruthenium dioxide-sodium periodate, etc. Metal oxides such as ruthenium oxide; DMS used for Swern oxidation
Oxidizing agents used in O-(0001,) 2 :0 ppenauer oxidation; DDQ and diethyl azodicarboxylate (DFIAD) as dehydrogenating agents can be used, but are not limited thereto. These may be used alone or as a mixture of two or more as necessary.

In the +11& reaction, generally a solvent stable to the above-mentioned oxidizing agent, such as a halogen-based M medium such as chloroform, dichloromethane, and trichlene; an aromatic solvent such as benzene and toluene; and an ether-based solvent such as dioxane, diethyl ether, and tetrahydrofuran. Solvents; alcoholic solvents such as methanol and ethanol can also be used, and water can also be used as a solvent. These solvents are appropriately selected depending on the type of the oxidizing agent and used alone or as a mixture of two or more. The above-mentioned oxidizing agent is usually 1% relative to cholesta-4,6-dien-6-ol (1).
It is used in a range of 20 to 20 times the molar amount.

The oxidation reaction proceeds rapidly at a temperature from -20°C to the solvent reflux temperature, preferably in the range of 10°C to 40°C. After the oxidation reaction is completed, cholesta-4,6-dien-3-one (n) can be obtained by distilling off the solvent, subjecting the residue to silica gel chromatography, and then crystallizing it. Incidentally, after the oxidation reaction is completed, the obtained reaction mixture may be used as it is in the next isomerization step.

cholesta-4,6-dien-6-one (If) to cholesta-5,7-;en-6-one (as a base catalyst used in the isomerization reaction to llD) IJ ummethoxide, potassium methoxide , sodium ethoxide,
There are strong bases such as potassium ethoxide and potassium (-)butoxide, and cholesta-4,6-dien-3-one (
It is used in an amount of 0.1 to 10 times, preferably 3 to 5 times, relative to It).

Although the reaction can generally be carried out in an organic solvent, polar solvents are most suitable, especially dimethylformamide and dimethylsulfoxide (DMSO). The reaction is carried out at room temperature to 10
It can be carried out in the range of 0℃, but the temperature range is 40℃ to 60℃.
C is preferred.

Cholesta-5,7-dien-3-ol (in the synthesis of M, cholesta-5,7-dien-3-one (1u)
Because of the instability of the compound (Inl = kN), the reduction reaction is generally carried out without preparing the compound (Inl = k
NaBH4), lithium aluminum hydride r7
iAlH4), calcium boron hytride (Oa(
BF2)2), zinc boron hydride (Zn(BF2)
)2)s Sodium bis(2-methoxyethoxy)aluminum hydride ((G(5ccH2a(2o)2
AIH2)Na etc. can be used, Corestar-5,
7-dien-6-one (conveniently used in an amount of 1 to 20 times the equivalent of
Aromatic hydrocarbons such as IE, Hensen, and toluene, or ether solvents such as tetrahydrofuran and diethyl ether are suitable. These organic solvents can be appropriately selected depending on the type of reducing agent described above and used alone or as a mixture. The reaction is carried out at a temperature ranging from -50°C to 1°C, where decomposition of the reducing agent does not occur, preferably -30°C.
Proceeds smoothly at room temperature to room temperature.

After the reaction was completed, the solvent was distilled off from the reaction mixture.

The target compound can be obtained by crystallizing the residue.

It has been confirmed that the steric configuration of the hydroxyl group at the 3-position of cholesta-5,7-dien-3-ol (M) produced in this reduction reaction is all in the β-form, and that the α-form is not produced at all.

Next, the present invention will be explained in more detail with reference to one typical example, but the present invention is not limited thereto.

(Example) Synthesis example of cholesta-4,6-';en-6-one Cholesta-4,6-dien-3-ol (1) (3,8
j.

1 pmmol) was dissolved in 20-dichloromethane.

then pyridium dichromate) (4,5p, 12r
rmol) and stirred at room temperature for 6 hours. After the reaction, dichloromethane was distilled off, and the residue was chromatographed on silica gel (isopropyl ether/hexane = 2/8 (
v/v)) to obtain 3.79 of crude cholesta-4,6-dien-3-one (II). Then, crystallization was performed in acetone to obtain (■) in 3. OP was obtained (melting point 81-82°C). The yield was 80%.

Example 2 Cholesta-4,6-dien-3-ol (1) (3,8
p% 10 mmol) and DDQ (2,7jl, 12
mmol) to 25111ffi of dioxane,
Stirred at room temperature for 8 hours. After filtering the generated hydroquinone and concentrating the F solution.

Chromatography on silica gel and crystallization were carried out in the same manner as in Example 1 to obtain 3.39 g of cholesta-4,6-dien-S-one (II). The yield was 85 cm.

Example 3 Cholesta-4,6-dien-3-ol (1) (5,8
9,10 mmol1) was dissolved in 30 mmol of toluene, and then p-benzquinone (10,8F%100 mmol1)%
Aluminum isopropoxide (3,19% 15mm
o1) was added and heated under reflux for 2 hours. After the reaction, toluene was distilled off and the residue was extracted with hexane. ! After reduction, silica gel chromatography and crystallization were performed in the same manner as in Example 1 to obtain cholesta-4,6-dien-3-one (If
) was obtained for 2.99. The yield was 75 cm.

Example 4 Cholesta-4,6-dien-3-ol (1) (3,
8p%10mmo1) and ruthenium dioxide (0A59
．． 1 mmol) was added to Trichlene 50-, then 32 ml (15 mmol) of a 10% aqueous solution of sodium periodate was added to
) was added dropwise at room temperature. Next, 20 g of methanol was added and the mixture was stirred at room temperature for 20 hours. After reaction.

Trichlene and methanol were distilled off, and the aqueous layer was extracted with ethyl acetate. After drying the ethyl acetate layer, ethyl acetate was distilled off, and silica gel chromatography and crystallization were performed in the same manner as in Example 1 to obtain cholesta-4,6-dien-5-one (I
I) was obtained at 2.5F.

The yield was 65%.

Cholesta-5,7-'; En-6-olno Synthesis Example 5 Sodium methoxide (Mθ0Na) (2,29,4 pmmol) was added to 20 ml of dimethyl sulfoxide.

Heated to 60°C. Next, a DM80 solution 1 of cholesta-4,6-dien-3-one (n) heated to 60°C:
2.39 (6mmol), DMSO: 25m
) was added dropwise for 10 minutes. After reacting at 60°C for 15 minutes, the reaction was stopped by pouring into a 2M aqueous acetic acid solution (approximately 40041). The generated solid was extracted with ether and dried (Na
2SO4) and concentrated to approximately 5 pml.

Calcium chloride (2.2F, 20 mmol) was dissolved in 30 methanol and cooled to -5°C. Furthermore, sodium borohydride (0,81,20 mmol)
Add dropwise an ethanol solution (20 ml) of
The temperature was maintained at ℃KAC1. Then, an ether solution of cholesta-5,7-dien-3-one ((2)) was heated at 0°C to -5°C.
The mixture was gradually added dropwise and left overnight at the same temperature.

After adding 50% acetic acid aqueous solution until it becomes a homogeneous solution.

Extracted with ether. Dry the ether layer (Na2SO4
), the ether was distilled off. The residue was purified by silica gel chromatography (ethyl acetate/hexane = 1/4).
V)) After purification, crystallization was performed in acetone-methanol. Kolester 5.7-:5x:y
-5-,t-ru(!'1Q(7-DHO) f: 1.
I got 41. The yield was 60%. Melting point 140℃~1
41 °C (ε = 10.800, EtOH).

Exactly the same method could be used when using other baths, bases, and reducing agents. The results are shown in Table 1.

Table 1 Production of cholesta-5,7-dien-3-ol by rearrangement and reduction of cholesta-4,6-dien-3-one 1) MeONa DMSOZn(BI3)2 T
HF 51MeONa DMSOLiA
1) (4 ether 20KtONa DMS
OCa(BI3)2 Methanol/Ethanol 4
1t-BuOK DMSOC1a (BI3)2 Methanol/Ethanol 35MeONa DMF
6) Ca(BI3)2 methanol/ethanol
37MeONa DMSONaBH4 ether
321) Cholesta-4,6-diene-3-
On: 6 mmol'1 2) Base: 40 mmol 3) Solvent for rearrangement reaction 4) Reducing agent: 2Q mmol 5) Solvent for reducing agent 6) Dimethylformamide

Claims (1)

[Claims] oxidizing cholesta-4,6-dien-3-ol,
Cholesta-5, which is characterized in that the obtained cholesta-4,6-dien-5-one is isomerized to cholesta-5,7-dien-3-one in the presence of a base catalyst, and then reduced.
, 7-dien-5-ol manufacturing method.