JPS6049640B2 - Method for producing cholesta-5,23,24-trien-3β-ols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides cholester 5,23,24-triene-3β
-Relating to a method for producing oars.

More specifically, the present invention relates to a method for producing cholester 5,23,24-trien-3β-ols useful as insect sterol metabolism inhibitors. Cholester 5,23,24-triene-3β-ol has the effect of inhibiting the metabolism of cholesterol contained in plants or animals that insects consume as food into ecdysone, thereby inhibiting normal development. It is expected to be used as a pesticide, etc.

The present inventors have proposed that Kolester 5-en-23-in-3
Cholester 5,23,24-triene, which is made from β,25-diols and furthermore bisnorcol-5-ene-3β,22-diols, is expected to be used as an insect cholesterol metabolism inhibitor and as agrochemicals such as insecticides. 3β-
The method of the present invention was arrived at as a result of intensive research aimed at developing an industrially easy method for producing oars.

That is, the present invention provides cholest 5 represented by the following formula [■] [wherein R1 and R2 are the same or different hydrogen atoms, lower alkyl groups, higher alkyl groups, oxygen-containing atom ring 7 alkyl groups, or acyl groups] -en-23-yne-3β,25-diols, LiAlH
Cholester 5,23,24-triene-3 represented by the following formula [■] [wherein R1 is the same as defined above], characterized by reacting with 4 and AlCl3.
Process for producing β-ols, and cholest-5-en-23-yne-3β,25-diols represented by the above formula [■] can be prepared by the following formula [1a] [where R1 is a hydrogen atom,
Bisnorkol-5-ene-3β,22-diols represented by a lower alkyl group, a higher alkyl group, an oxygen-containing cyclic alkyl group, or an acyl group, R3 is a hydrogen atom or a protecting group for a hydroxyl group that is easily eliminated, can be expressed by the following formula: [Ib] [In the formula,
R2 hydrogen atom, lower alkyl group, higher alkyl group, oxygen-containing cyclic alkyl group, or acyl group]
From the compounds represented by the above formulas [1a] and [Ib] produced by reaction with methyl-3-butyn-2-ols, the cholester 5 represented by the above formula [■] is produced through the compound represented by the above formula [■]. , 23,24-trien-3β-ols.

Cholesto 5-en-2 used in the method of the present invention
3-yne-3β,25-diols are represented by the above formula [formula], where R1 and R2 are the same or different hydrogen atoms, lower alkyl groups, higher alkyl groups, oxygen-containing cyclic alkyl groups, or acyl. It is the basis.

Examples include lower alkyl groups such as methyl, ethyl and propyl, higher alkyl groups such as octyl and decyl, oxygen-containing cyclic alkyl groups such as tetrahydropyranyl and ethoxyethyl, and acyl groups such as acetyl and benzoyl. I'll come. That is, specific examples of such compounds include cholest-5-en-23-yne-3β
, 25-diol, cholest 5-en-23-yne-3β,25-diol 3-acetate, cholest 5-
These include en-23-yne-3β,25-diol ditetrahydropyranyl ether, cholestol-5-en-23-yne-3β,25-diol diacetate, and the like. Such a compound is bisnorco-5 represented by the above formula [1a].
-en-3β,22-diol (BisnOrchOl
-5-En-3β,22-DiOl), and is produced from the compound represented by the above formula [1a] and 3-acetoxybisnorcholenic acid through five steps.

Colesto 5-en-23- represented by the above formula [■]
Produced by reacting yne-3β,25-diols with bisnorkol-5-ene-3β,22-diols represented by the above formula [1a] and 2-methyl-3-butyn-2-ols represented by the above formula [Ib]. For example, 22-tosyloxybisnorkol-5-ene-3β-
This is carried out by reacting about 4 equivalents of 2-methyl-3-butyn-2-ol tetrahydropyranyl ether per mole of all-tetrahydropyranyl ether in an inert medium such as dioxane under heating.

The yield of the target product reaches 70%. The reaction product can be separated from the reaction system by treating the crude product in a mixed solvent of methanol and tetrahydrofuran acidified with hydrochloric acid, operating in a conventional manner, and then performing silica gel column chromatography.

The product was confirmed by melting point, ultraviolet absorption spectrum, NMR, etc. The above formula thus obtained [■
] Cholesto-5-ene-23-yne-3β
, 25-diols are then induced to convert into cholester 5,23,24-trien-3β-ols represented by the above formula [■] by reacting with lithium aluminum hydride and aluminum chloride. This method has not been previously known, and most preferably, cholest-5-en-23-yne-3β,25-diol or its diacetate, in which R1 and R2 in the above formula [■] are both hydrogen atoms or acetyl groups, or its diacetate is prepared on AlCl3. This is a method of reducing the amount in the system. The reaction solvent is preferably an inert ether type, and dioxane, ether, tetrahydrofuran, diglyme, etc. are particularly preferably used. The reaction temperature is preferably 100 to 100'C, particularly preferably 20 to 70C. The reaction time varies from several hours depending on the reaction temperature, etc.
It lasts for an hour. The ratio of lithium aluminum hydride to aluminum chloride is 1:10 to 10:1 by weight.
Particularly preferred is a molar ratio of 1:4 to 4:1, and more preferably 4:1 to 3:1. After the reaction is complete, remove the excess reagent by carefully adding water or aqueous alkali solution, extract with a suitable solvent such as dichloromethane or methylene chloride, wash with water, and remove the solvent under reduced pressure. The resulting mixture was then subjected to silica gel column chromatography and developed with a solvent such as n-hexane, benzene, ethyl acetate, etc. to obtain purified cholester represented by the above formula) [■]. 5,23,24-trien-3β-ols can be obtained. The product was confirmed by melting point, infrared absorption spectrum, NMR, etc. According to the method of the present invention, as described above, cholester 5,23,24-triene-3β, which is used as an insect sterol metabolism inhibitor,
-Ols can be produced industrially advantageously.

Hereinafter, the method of the present invention will be described in detail with reference to Examples.

The method of the present invention is not limited to these methods. Example 1 (1) 3β-acetoxycholenic acid methyl ester (10
Add 44.3 ml of 5% caustic potassium solution of 3:1 mixed solvent of methanol and water to 400 ml of ethanol solution of y).
added.

The mixture was stirred at room temperature for 3 hours. After neutralization by adding 1N HCl, the mixture was concentrated under reduced pressure and poured into ice water.

After collecting the precipitate by offshore filtering, it is washed with water and dried under reduced pressure, and the recrystallized product from methanol has a melting point of 138-141℃.
MethylbisnOrchOl-5-En-
3β-01-22-0ate was obtained. This is 400m1
of methylene chloride and 4.5 ml of dihydropyran and a catalytic amount of p-toluenesulfonic acid were added. Add this solution to 1. Stir for hours. The reaction mixture was treated in a conventional manner and extracted with methylene chloride to obtain the corresponding 3-tetrahydropyranyl ether having a melting point of 137.5 DEG -138.5 DEG C. when recrystallized from a methanol-acetone mixed system. (2) 200 m of this tetrahydropyranyl ether body 8.7y
To a solution of 1 dry ether was added 2.09 LiAlH4 suspended in 100 ml dry ether at 0°C.

The mixture was stirred at room temperature for 1 hour. After addition of 1N NaOH, the mixture was subjected to ether extraction.

Treated using conventional methods to obtain the following properties! Bisnorkol-5-ene-3,22-diol-3-tetrahydropyranyl ether 7.9V was obtained. Melting point: 148.5-15
0°C (from methanol) NMR (δ (Ppm)): 0
．． 67(3FI,.S118-3CH3), 1.00(
3H,. S119-CH3), 3.1-4.2, 4.7
5 (6H, .m122 Ichito, 2″-H of 3α-H1 tetrahydropyranyl group), 5.4 (1H1m16-H),
Elemental analysis: Cl78. O2;HllO. 83; (Cl
477.83:HllO. 65 theoretical value C27l (440
3) Furthermore, by treating this product with p-toluenesulfonyl chloride in pyridine, a corresponding 22-tosylate compound having the following properties was obtained.

Melting point: 143-1452C (from acetone-methanol mixture) NMR (δ (Ppm)): 0.65 (3H.
．． S118-Cll3), 1.00 (3H.S, 19-
CH3), 2.45 (311..S1 aromatic CH3),
3.2-4.2, 4.73 (6H..m122-H2,
7-H of the tetrahydropyranyl group), 5.35 (1H.
．． m16-H), 7.6 (4H.m1 aromatic ring H4), elemental analysis: Cl7l. 46; Hl8.96 (Cl7l.5
7; Hl8.83 theoretical value C34H5OO. as S),
Example 2: 1) 15y 2-methyl-3-butyne-2-
The mixture was stirred at 0° C. with 60 mt of methylene chloride, 27y of dihydropyran, and a catalytic amount of p-toluenesulfonic acid.

To this solution, 5 ml of saturated NaHCO3 was added and stirring was continued. This mixture was extracted with methylene chloride,
After washing the organic layer with water, it was dried over MgSO4, and the solvent was distilled off at room temperature. The oily residue was purified by fractional distillation to obtain 26.9 g (yield: 90%) of 2-methyl-3-butyn-2-ol tetrahydropyranyl ether having the following properties.
Boiling point: 71C/11T0nHg (literature value 30-33℃
/0.5 Hg), NMR (δ(Ppm)): 1.43
, 1.46(6H..S1(CH3)2), 2.35(
1H. ．． S... HC...C), 5.05 (1H..bs1
2″-H) of tetrahydropyranyl group, elemental analysis: Cl
7l. 42; Hl9.58 (Cl7l.39; H, 9.
59 theoretical value ClOl (as 1602), ? )1.34
n of m-butyllithium (87Tt.m01) was added to a mixture of q of 2-methyl-3-butyn-2-ol tetrahydropyranyl ether and 10rrLL of dry dioxane.
- The hexane solution was cooled under an argon atmosphere and added under stirring.

3-tetrahydropyranyl ether of bisnorkol-5-ene-3,22-diol, 22-p, dissolved in 20 ml of dry dioxane after stirring for 3 C at room temperature.
- Added tosylate. The mixture was refluxed overnight. After extraction with ether in a conventional manner, a brown oily residue was obtained.
This was obtained by chromatography on silica gel.
The fraction of benzene distillate was reconsolidated with methanol to obtain cholest 5-ene-23-yne-3β, which has the following properties.
25-diol ditetrahydropyranyl ether 1.
01g (yield 75%) was obtained. Melting point: 100-105℃
NMR (δ(Ppm)): 0.68 (3H..S118
-CH3), 1.00 (3HNS119-CH3), 1
.

45, 1.49 (6H..S126,27-(CH3)
2), 4.71 (1H..?, 2″-H of the 3-position tetrahydropyranyl group), 5.06 (1H..Y:F5, 2″-H of the 2-mosquito tetrahydropyranyl group), element Analysis: Cl
78.5nuHllO. 47 (Cl78.42, HllO
．． 3l theoretical value C37H58O4) Example 3 1.35 produced in the same manner as the method of Example 2 (2)
The crude product of y, i.e. 2-methyl-3-butyne-2-
All-tetrahydropyranyl ether and 3-tetrahydropyranyl ether of bisnorkol-5-ene-3,22-diol, 22-p tosylate were reacted in the same manner as in Example 2 (2), and the reaction product was extracted with ether by a conventional method. The 1.35y crude product obtained later was
Drops of 1N HCl and methanol (20T!IL)
After treatment with a mixture of tetrahydrofuran (10 mL) and conventional treatment, chromatography on silica gel yielded bisnorcol-5-ene-3, which showed the following properties from the benzene-ethyl ether (150:1) fraction.
97 m9 of 22-diol-22-tosylate (yield 1
0%) obtained.

Melting point: 103-104C (from methanol) NMR (
δ (Ppm)). 0.65 (3FI.S, 181C
Fl3), 0.99(31(,S,19-CFI3),
2.48 (3H, S, aromatic ring CH3), 3.5-4.1
(311.m122-H2, 3α-H), 5.35(1
H. ．． m16-H) Also, benzene-ethyl acetate (
Cholesto 5- exhibiting the following properties from the fraction of 100:1)
560 m9 of en-23-yne-3β,25-diol
(yield 70%).

Melting point: 154-1565C (acetone-methanol) Infrared (νMax (Cm-1)): 360 to 345 to 225
0NMR (δ (Ppm)): 0.68 (3H..S1
18-CH3), 1.00(3Shi H,.Sll9-CH
3), 1.50 (6H..S126,27-(CH3)
2), 3.5 (1H..m13α-H), 5.35 (1
H. ．． m16-H), elemental analysis: Cl8l. 5O; Hl
lO. 78 (Cl8l.35; HllO.62 theoretical value C
23H42O.

), Mass (ditrimethylsilyl), m/e
:542 (M), benzene-ethyl acetate (5
0:1), 66 mg (yield: 10%) of bisnorkol-5-ene-3,22-diol having a melting point of 206 to 206.5°C as an ethyl acetate recrystallized product was obtained.

Example 4 Cholest 5-ene-23-yne-3β,25
A mixture of 160 mg of -diol, 1 mt of pyridine, and 1 ml of acetic anhydride was left at room temperature overnight to obtain 140 m9 of cholest-5-en-23-yne-3β,25-diol 3-acetate (yield: 805C) having the following properties.

Melting point: 173-175.5°C (from methanol) NMR
(δ (Ppm)): 0.69(31(, Sll8-C
H3), 1.02 (3H..S, 19-CH3), 1.
49 (6H1S126,27-(CH3)2), 2.0
2(3)1. ．． S1 acetyl), 4.6 (IH..ml
3α-H), 5.4 (1H1m16-H), elemental analysis:
Cl78.92:HllO. l4(Cl79.O4:H
llO. As O7 theoretical value C29H44O3) Example 5
A mixture of 400 mg of cholest 5-en-23-yne-3β,25-diol, 3 ml of pyridine and 3 mt of acetic anhydride was heated at 120'C for 2 hours to obtain cholest 5-en-23-yne-3β,25-diol acetate having the following properties. 415m9 (yield 86%) was obtained.

Melting point: 99-10rc (from methanol) NMR (δ
(Ppm)):0.70(31(,S..l8-CH3
), 1.02 (3F[, Sll9-CH3), 1.63
(6H1S126,27-(CH3)2), 2.00~
2.03 (6H1S12-acetyl), 4.6 (1H,
．． m13α-H), 5.4 (1H..m16-H), elemental analysis: Cl77. l6; Hl9.77 (Cl77.l
3:H, 9.61 theoretical value C3lH4GO4) Example 6 Bisnorkol-5-ene-3,22-diol 40
Dissolve 0mg in dry THFlOml, LiAlH4l
Dry T8l containing 54y and AlCl3l33TfLg
Added in Oml.

After refluxing for 1 ctf in an argon atmosphere, the reaction solution was ice-cooled and water was added to decompose unreacted substances. After filtration, the filtrate was extracted with ether, and the extract was washed with water, dried over MgSO4, and concentrated. The resulting residue was purified by silica gel column chromatography (benzene ethyl diacetate 150:1) to obtain 50 m9 (13%) of cholester 5,23,24-trien-3β-ol. Melting point: 109-111-C (
methanol) Vmax (CCl4): 362 to 335 1970cTn-1 NMR (δ (Ppm)): 0.69
(3FI..s118-Me), 1.00 (3H..s
119-Me), 1.65 (6H..d,.J3Hz1
26.27-Me2), 3.5(1H,.n132-H
), 4.85 (1H..m123.H), 5.4 (1H.
、． m16-H).

Claims (1)

[Claims] 1 The following general formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ [In the formula, R^1 and R^2 are the same or different hydrogen atoms, lower alkyl groups, higher alkyl groups, Cholest-5-en-23-yne-3β,25-diols represented by [oxygen atom cyclic alkyl group or acyl group], LiAl
Corestar-5,23,24-, which is characterized by reacting with H_4 and AlCl_3, is represented by the following formula [III] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is the same as the above definition] triene-3
Method for producing β-ols. 2 The following formula [I a] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I
a] [wherein R^1 is a hydrogen atom, a lower alkyl group, a higher alkyl group, an oxygen-containing cyclic alkyl group, or an acyl group,
Bisnorkol-5-ene-3β,22-diols represented by R^3 is a hydrogen atom or a protecting group for a hydroxyl group that is easily eliminated] are represented by the following formula [I b]▲ There are mathematical formulas, chemical formulas, tables, etc.▼... ...[I b] 2-methyl-3- represented by [in the formula, R^2 hydrogen atom, lower alkyl group, higher alkyl group, oxygen-containing atom cyclic alkyl group or acyl group]
By reacting with butyn-2-ols, the following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II] [In the formula, R^1 and R^2 are the same as the above definition]. The cholest-5-en-23-yn-3β,25-diols shown below are formed, and then the cholest-5-en-23-
The following formula is characterized by reacting in-3β,25-diols with LiAlH_4 and AlCl_3 [
III〕▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・
[III] [In the formula, R^1 is the same as defined above] Cholesta-5,23,24-triene-3
Method for producing β-ols.