JPS5828280B2 - Steroids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to active vitamin Ds having a hydroxyl group at the 1α position, which have attracted attention as pharmaceuticals in recent years, such as lα-hydroxycholecalciferol, 1α·25-dihydroxycholecalciferol, and 1α·24 -Important as a synthetic intermediate for dihydroxycholecalciferol, etc. 1.
The present invention relates to a novel and useful method for producing 4,6-triene-3-one steroids.

Cholesterol, fucosterol, and the like have been known as starting materials for producing various active vitamin Ds, particularly active vitamin Ds having a hydroxyl group in the side chain.

However, although fucosterol is useful as a raw material for products such as 1α,24-dihydroxycholecalciferol, its production relies entirely on extraction from plants, making it extremely difficult to obtain as a raw material. Unfavorable for industrial production.

Furthermore, when producing 1α,25-dihydroxycholecalciferol using cholesterol, 25
In order to introduce a hydroxyl group into this position, a long process and complicated treatment methods were required.

In other words, Mazur is a useful method for introducing hydroxyl groups into the side chains of cholestane steroids.
) [Journal on the Chemical Society Chemical Communication (J, C, S,
Chem, Comm) 1974, p. 15] cannot be applied directly to compounds with double bonds, such as cholesterol, because it involves an unfavorable side reaction of double bond cleavage; A method is essential, the number of steps becomes long, and a decrease in yield is unavoidable.

According to the present invention, cholestanol and lithocholic acid (1ithocholic acid), which are easily available raw materials but could not be easily used for the synthesis of active vitamin D
lic acid).

That is, the present invention relates to the general formula (I) (wherein R1 and R3 are the same or different, and each is a hydrogen atom,
2,3-dichloro-5・General formula characterized by treatment with chloranil in the presence of 6-dicyazhydroquinone (
H) (In the formula, R1, R2, and R3 have the same meanings as above.) The present invention relates to a method for producing a 1.4.E-)genone body.

Specific examples of the 1,4,6-drienone obtained by the method of the present invention include 25hydroxy-cholestat 4,6-) IJ en-3-one, cholesta-
1,4,6-triene-3one, cholestar-14,6-
) 'Jen-3,24-dione, 24-hydroxy-cholester-1,4,6-drien-3-one, etc., and these can be prepared by known methods such as JP-A-50-84555 and JP-A-50-84560. The corresponding active vitamin Ds can be easily obtained according to the method described in No. 1, etc.

In the method of the present invention, the compound represented by the general formula (I) can be easily obtained by subjecting the corresponding cholestanol such as 25-hydroxycholestanol, 24-hydroxycholestanol, etc. to the method of Japanese Patent Publication No. 39-6672. can be obtained.

By using the method of the present invention, the complicated means of protecting the double bond at the 5-position, such as when using cholesterol, is eliminated, and by using lithocholic acid as a raw material, it is difficult to obtain raw materials such as fucosterol. The problem was also resolved.

The present invention is a novel and useful method for obtaining cholestat 4,6-trienones represented by general formula (■) in high yield in one step using cholestate 4-genones represented by general formula (I) as a starting material. This is a great method.

For reference, an example of a method for synthesizing 1α,24-dihydrocalciferol using the method of the present invention using lithocholic acid as a raw material is shown below.

By the method of the present invention, compound (I) is converted into 2,3-dichloro-5.
Compound (II) is obtained by treatment with Floranil in the presence of 6-dicyazhydroquinone.

At this time, the reaction is preferably carried out in a solvent, and examples of solvents that can be used include dioxane and higher alcohols such as n-amyl alcohol and 5ee-amyl alcohol.

The reaction temperature is preferably the reflux temperature of the solvent used.

The reaction time usually requires several tens of hours, but the reaction time can be shortened by lowering the ratio of solvent to compound (I).

The additive 2,3-dichloro-5,6-diciazhydroquinone is 1 molar equivalent or more relative to compound (I),
Floranil is required in an amount of 1 molar equivalent or more.

Compound (n) is isolated from the reaction mixture by a conventional method, for example, by distilling off the solvent and subjecting the residue to a means such as column chromatography. Reference Example 1 (a) Magnesium turnings 7.27f? was suspended in 200 ml of dry ether, and a solution of 28.1 ml of isopropyl bromide dissolved in 100 rnl of dry ether was added dropwise under stirring at room temperature. After the dropwise addition, the mixture was boiled for 30 minutes to completely dissolve the magnesium.

After cooling, 43.56'y of anhydrous cadmium bromide powder is gradually added.

After boiling for 1 hour, the ether was distilled off, and dry benzene was added to replace the solvent (until the boiling point reached 80°C).

On the other hand, acetyl lithocholic acid 101 and thionyl chloride 100
A solution was prepared by dissolving acetyl lithocholic acid chloride in dry benzene, which was prepared by dissolving the acetyl lithocholic acid chloride prepared by dissolving it in dry benzene and leaving it at room temperature for 2 hours, and then distilling off excess thionyl chloride under reduced pressure. Add dropwise at 7°C with vigorous stirring.

After 5 to 10 minutes of dropping, add cold water and 5% hydrochloric acid to decompose the reagent, then add new benzene, wash the benzene layer with water,
Dry over magnesium sulfate and evaporate the solvent to a volume of about 300 ml.

Add to this 100ml of a methanol solution of 1N potassium hydroxide.
1 was added, left overnight at room temperature, and extracted with ether.

After washing with water and drying the upper layer, the solvent is distilled off to precipitate crystals.

Washing with petroleum ether gives 4.661 (48.4%) of 5β-cholestan-24-one-3α-ol.

Melting point: 123.5-125°C.

Mass spectrum: m/e 402 (M+), 394
379 (b) 5β-cholestan-24-one-3α-ol 1
87゜3m9 was dissolved in methanol, a solution of 90cm of sodium borohydride dissolved in methanol was added under water cooling, and 1
The mixture is stirred for an hour, acidified with hydrochloric acid, extracted with ether, washed with water, washed with sodium bicarbonate solution, further washed with water, dried over magnesium sulfate, and evaporated.

Needle crystals of 5β-cholestane-3α·24-diol 185#j (98.3%) are obtained from methanol.

Elemental analysis value: H as C2□H4802 Theoretical value (%) 80.14 11.96 Actual value (%)
80.02 12.01 The 24-epimer can be easily separated by repeating recrystallization with methanol or by subjecting it to column chromatography packed with alumina (solvent: chloroform).

5β-Cholestane-3α・24ξ1-diol White needle crystals (1ess polar) Melting point 123-124.5℃
5β-Cholestane-3α・24ξ2-diol White needle crystals (more polar) Melting point 143.5-144.5
°C Reference Example 2 (a) 25-hydroxy-5α-cholestanol 319
■30m1 of dioxane! 2,3cyclo5,6-dicyazbenzoquinone (624.28cm) was added.
The mixture was heated under reflux for 19 hours.

After cooling, precipitated crystals (2,3-dichloro-5,6-dicyazhydroquinone) are removed and washed with dioxane.

The r liquid is dried under reduced pressure and subjected to alumina column chromatography.

First benzene then 10% chloroform-benzene, 2
From the part that flows out with 0% chloroform-benzene and further with 30% chloroform-benzene, the target 25
-hydroxy-cholestat 4-dien-3-one 18
I got 0■.

This substance has a melting point of 151-15 when recrystallized from ether.
It is 3℃.

, EtoH UV spectrum, λ 247 (log ε = aX 4.23) Mass spectrum m/e: 398 (M+), 38
0 Reference example 3 5α-cholestanol 1? was dissolved in 70 ml of dioxane, 2.41 ml of 2,3-dichloro-5,6-dicyazbenzoquinone was added, and the mixture was heated under reflux for 27 hours.

After cooling, filter and concentrate the F solution. The residue is subjected to column chromatography packed with alumina 40f.

From the part that flows out with benzene and shows 246 nm in the UV spectrum, crude cholestat 4-dien-3-one 526
get.

This substance has a melting point of 109.5 when recrystallized from methanol.
~111''C.

Reference example 4 5β-cholestan-24-one-3α-ol 9.29
'y' was dissolved in 173ml of dry dioxane and 2.3-
Dichloro-5,6-dicyazbenzoquinone 17.29P
and heated under reflux for 20 hours.

After cooling, the sparingly soluble 2,3-dichloro-5,6-dicyazhydroquinone is removed from each room, thoroughly washed with dioxane, the lachrymal fluid is concentrated, and subjected to column chromatography packed with alumina 801.

Elution with chloroform, concentration of the effluent to dryness, and crystallization from methanol yielded Cholestat 4-S-r-7-3-24-dio:/3.39 with a melting point of 142-144.5°C.
f? (37,0%).

Mass spectrum: m/e 396 (M+) NMR
Spectrum (CDC13): δ (ppm) 6.10 (I
H, d), 6.1 s (tH, dd), 7.06 (
IH, d) Reference example 5 5β-cholestane-3α・24-dio-/1/117m
9 was dissolved in 2 ml of dry dioxane, and 2,3 dichloro-
Add 217 cm of 5,6-dicyazbenzoquinone and heat under reflux for 20 hours.

Treated in the same manner as in Reference Example 4, oily 24-hydroxy-cholester-1,4-dien-3-one 44cm (38.2%
).

UV spectrum: λEt0H243nrrLaX NMR spectrum: δ (ppm) 3.1-3.5
(I Hlm), 6.09 (LH, d), 6.19 (
IH, dd), 7.07 (IH, d) Mass spectrum: m/e 398 (M+), 380
Example 1 25-hydroxy-cholestat 4-dien 3-one 5
9rv in 5ml of dioxane, Floranil 4
41n9 and 20 μm of 2,3-dichloro-5,6-dicyazhydroquinone were added, and after heating on a boiling water bath for 24 hours,
Further, 30 ml of 2,3-dichloro5,6-dichiazhydroquinone was added, and another 50 m9 was added, and heating was continued for a total of 5 days.

At this stage, the UV spectrum showed absorption mostly of the trienone form.

After distilling off the solvent, the residue is subjected to alumina column chromatography.

Initially, a small amount of unreacted Floranil flowed out from the part where benzene flowed out, and chloroform-methanol-100:5
50 μm of crystals were obtained from the outflowing portion.

When this crystal is recrystallized from ether, the melting point is 180-18
3° C., and no decrease in melting point was observed even when mixed with 25-hydroxy-cholestat 4,6-drien-3-one, which was prepared separately.

toH UV spectrum: λ 225.257, aX 02 Example 2 500 μ of cholestat 4-dien-3-one was dissolved in 45 ml of dioxane, and 374 μ of Floranil and 2,3-dichloro-5,6-dicyazine were dissolved in this. Add 170 μm of hydroquinone, heat under reflux for 42 hours, and then add 50 mF of 2,3-dichloro-5,6-dicyazhydroquinone. and heated under reflux for a total of 61 hours.

After cooling, filter the solution, concentrate the p solution, and apply the residue to column chromatography packed with alumina 23f.

A small amount of Floranil flows out from the part where benzene flows out first, and then crude trienone 421 (confirmed by UV) flows out.

When this is again subjected to column chromatography packed with alumina 301 (solvent: n-hexane), cholestat 4.6-) IJ enone 3-one is obtained.

This substance has a melting point of 82.5~ when recrystallized from methanol.
It shows 83.5°C.

toH UV spectrum: λ 229.251, aX 98 Example 3 24-hydroxy-cholestat 4-dien 3-one 4
00■ in 35ml of dioxane, Floranil 3
00rv and 150 μl of 2,3-dichloro5,6-dicyazhydroquinone were added, and the mixture was heated under reflux for 40 hours.

Thereafter, treatment was carried out in the same manner as in Example 1 to obtain 240 ml of 24-hydroxy-cholestat 4.6-trien-3-one.

toH UV spectrum: λ 299.257, aX 43nm

Claims (1)

[Claims] 1 General formula (wherein R1 and R3 are the same or different, each represents a hydrogen atom,
2,3-dichloro-5・General formula characterized by treatment with Floranil in the presence of 6-dicyazhydroquinone (in the formula, R1, R2, and R3 have the same meanings as above)
A method for producing a 1,4,6-drienone compound shown in