JPS61189294A - Production of 25-hydroxycholesterol compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for the production of activated vitamin D3, etc., economically on an industrial scale, by treating a specific 24-halogenated cholesterol with a base, and treating the resultant 24,25-epoxycholesterol with a reducing agent. CONSTITUTION:The 24-halogenated cholesterol of formula I [R1 and R2 are H or protecting group; R3 is H or (protected) hydroxyl group; X is Br, Cl or I] (e.g. 24-bromo-3beta,25-dihydroxycholest-5-ene) is treated with a base (e.g. sodium bicarbonate), and the resultant 24,25-epoxycholesterol of formula II is treated with a reducing agent (e.g. aluminum lithium hydride) to obtain the objective compound of formula III.

Description

[Detailed description of the invention] 〔Technical field〕 The present invention is 25-hydroxycholeste 9-/L.

and 24-halogenated cholesterol. More specifically, the present invention relates to 24-1-rogonated cholesterols in which the 24th position is substituted with a bromine atom, etc., and 24-
The present invention relates to a method for producing 25-hydroxycholesterol from rhodanated cholesterol. The 25-hydroxycholesterols produced in the present invention include 25-hydroxyvitamin D, lα, 25-dihydroxyvitamin D
It is a compound useful as an intermediate for active vitamin D, such as No. 3.

[Prior art]

Conventional methods for producing 25-hydroxycholesterols include a method using 25-homocholenic acid ester as a raw material (5teroids, vo113*567 (196
9) Method using + desmostyrol (Special Publication 1972-
18700, Special Publication No. 52-31871),
Method using pregnenolone (%Koshō 56-14680
Publication No.).

Method using stigmasterol (Special Publication 56-14
679), a method using cholenic acid (Japanese Unexamined Patent Publication No. 1983-
5500 Publication) are known, and in addition to this,
JP-A-51-70759, JP-A-55-6660
Publication No. 0 describes its manufacturing method. However, 25 using 24-halogenated cholesterol as raw material
-No known method for producing hydroxycholesterols.

[Purpose of the invention]

As a result of detailed study on the method for producing 25-hydroxycholesterols, the present inventors found that 24-halogenated cholesterols are treated with a base to obtain 24.25-epoxycholesterols, and then treated with a reducing agent. The present invention was achieved by discovering that the desired 25-hydroxycholesterols can be produced industrially and advantageously in high yield.

Therefore, an object of the present invention is to provide an industrially advantageous method for producing 25-hydroxycholesterols and 24-halogenated cholesterols that can be used as raw materials for 25-hydroxycholesterols.

[Structure and effects of the invention]

According to the present invention, 24-halogenated cholesterol represented by the following formula [D] is treated with a base to give 24. A method for producing 25-hydroxycholesterols represented by the following formula [wherein R1, R, are the same as defined above], which comprises obtaining 25-epoxycholesterols and then treating them with a reducing agent. The raw material, the above formula [24-)10-genated cholesterol represented by D, is provided.

The raw material compound of the above formula CDK(*teR1) represents a hydrogen atom or a protective group. Examples of such a protective group include the following groups.

(1) Acyl group such as acetyl group, pro/(noyl group, butanoyl group,
Pentanoyl group, cabroyl group, cyclohexanoyl group, chloroacetyl g, , /q moacetyl group, benzoyl group.

01 to C1t aliphatic or aromatic carboxylic acid residues such as p-bupmobenzoyl group, p-nitrobenzoyl group, ethylbenzoyl group, toluyl group, or their nide g+)
10 gen.

Alkoxy substituted derivatives and the like are preferably used.

Among them, an acetyl group is particularly preferred.

These include benzoyl group, 7° lovanoyl group, etc.

(2) A group that forms an ether bond with a hydroxyl group, such as a trimethylsilyl group, a trialkylsilyl group such as a dimethyl-t-butyl-silyl group, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, etc. 2-cyclic ether group; methoxymethyl group, I-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2
-propyl group.

(2-methoxyethoxy)methyl group, methylthiomethyl group, etc. can be added.

(3) Alkoxycarbonyl group! Examples of A include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, 9-phthoxycarbonyl group, and pentoxycarbonyl group.

Among the above protecting groups, acyl groups are particularly preferred.

It is an alkoxycarbonyl group, but is not limited to these.

R8 is a hydrogen atom or a protective group. Such a protecting group must be a protecting group that can be deprotected by treatment with a base in the next step, and examples of such protecting groups include the aforementioned 7-syl group and alkoxycarbonyl group. can.

R3 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. When R8 is a protected hydroxyl group, the protecting group is R
Protecting groups similar to the protecting group of 1 can be mentioned.

Or represents a bromine atom, chlorine atom, or iodine atom.

Specific examples of 24-halogenated chole 1-length stickers represented by the above formula include 24-bromo lα, 3β, 25-trihydroxychole St-5-ene 24-bromo 3β, 25-diacetoxycholest-5
-ene24-bromo-3β-methoxymethoxy-25-hydroxycholest-5-ene24-riqI:I-3β,25-dihydroxycholest-5-ene24-ty E-1α, 3
β,25-trihydroxycholest-5-enei4-chloro-3β,25-diacetoxyprest-5
-ene24-iobi3β,25-dihydroxycholesto-5
-ene24-iodo lα,3β,25-) dihydroxyfrest-5-ene24-iodine3β,25-diacetoxyfrest-5
-En, etc. can be mentioned.

Such 24-hapgated cholesterols represented by the above formula [1] are treated with a base to convert them into 24,25-epoxykol-blind n-resdel cholesterols represented by the above formula (2). The base used here is, for example, potassium hydroxide.

Examples include sodium hydroxide, calcium carbonate, sodium methoxide, sodium ethylate, potassium t-butoxide, and sodium hydride. Among these, potassium hydroxide and sodium ethylate are preferable, and it is preferable to use one such base in excess by molar amount relative to the raw material compound. The solvent may be any organic solvent that is inert to bases. Preferred examples include tetrahydrofuran, methanol, ethanol, t-butanol, etc., and these solvents may also be used together.The reaction time and reaction temperature can be adjusted as appropriate depending on the raw materials and type of base used. , 30 minutes to l in the temperature range of 06 to 100℃
The reaction is completed at O time.

Conventional methods are used to isolate and purify the target product from the reaction solution. In other words, concentration and extraction.

Means such as recrystallization, column chromatography, and high performance liquid chromatography are used.

24.2 expressed by the above formula l obtained in this way
In 5-epoxycholesterols, R1 represents a hydrogen atom or a protecting group.

R8 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. Here, when R8 is a protecting group and R3 is a protected hydroxyl group, examples of the protecting group include the same protecting groups as in the case of the above formula [D].

Next, by treating the 24.25-epoxycholesterol represented by the above formula with a reducing agent, 25-hydroxycholesterol represented by the above formula is provided.

The reducing agent °C is, for example, lithium aluminum hydride,
Examples include lithium triethylborohydride, lithium trimethoxyaluminum hydride=lithium triptoxyaluminum hydride, aluminum hydride, poran, and 9-borabicyclononane.

The reducing agent is preferably used in an amount of 0.25 to 4 times the mole of the raw material compound.

Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran, and the like. The reaction temperature may be in the range of θ°C to 80°C, and the reaction is completed in several hours to 24 hours.

Conventional methods are used to isolate and purify the target product from the reaction solution. In other words, concentration and extraction.

Means such as recrystallization, column chromatography, and high performance liquid chromatography are used.

Thus, according to the manufacturing method of the present invention, 2 represented by the above symbol
5-hydroxycholesterols are obtained.

25-hydroxycholesterols are 25-hydroxyvitamin D, lαt25-';'hydroxyvitamin Ds+24+25-dihydroxyvitamin D1,25
．． It is an extremely useful compound as a synthetic intermediate for active vitamin D3s such as 26-dihydroxyvitamin D3.

According to the present invention, 24-halogenated cholesterol represented by the following formula [■] is provided.

Such 24-halogenated cholesterols can be synthesized, for example, by halogenating 24-hydroxycholesterols represented by the following formula (R1+RtyRs is the same as defined above).

As for the p-genization method, any commonly used method may be used, for example, the following five methods may be used. Namely, methods using phosphorus halides such as phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, and phosphorus triiodide; methods using a triphenyl-iodine combination; methods using thionyl halides such as thionyl chloride and thionyl bromide. etc.

Reaction solvent 9 Reaction time and temperature are f of the halogenating agent used.
It is possible to react appropriately according to Category 1, but when phosphorus tribromide is used as the halogenating agent, it is preferable to use carbon tetrachloride as the solvent and react at room temperature for 30 minutes to 1 hour to give preferable results. Isolation and purification of the target product from the reaction mixture can be carried out by conventional methods, such as concentration, extraction, recrystallization, column chromatography, and high-performance liquid chromatography.

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

101 24-oxo-25-hydroxycholesteq-
(24 mmol) was mixed with 122.6 g of acetic anhydride (1
,2 mol) and pyridine (2,2 mol) and 171.0 F.
The mixture was heated and stirred at 90° C. for 24 hours. Acetic anhydride was concentrated under reduced pressure, and extracted with 1 liter of ethyl acetate. ZN-f (CA!) was washed three times at 200 m, twice with 200 ml of saturated aqueous sodium bicarbonate solution, and twice with 200 ml of saturated brine, dried over hot sodium sulfate, and concentrated. The product is silica gel 200
Column chromatography using I and elution with benzene-ethyl acetate system yielded 7.511 24-ochine-3β.

The physical properties of the 25-diacetoxycholest-5-methane obtained were as follows.

IR(KBr): 1725.1740-v-”NM
RCCDCtl&l: δ0.70 (S13HIC-18
-I(L 1.05(813H, C-19-HL 1.
50 (s, 6H, C-26, 27-H), 2.05 (
s+3H,acetyl), 2.12(s,3H+a
cctyl) + 4.6 (m, IH, 3αH) + 5
．． 4(m+IHtc 61[()5y 24-oxo-
3β,25-diacetoxycholest-5-ene (10 m
mol) methanol 50d, tetrahydrofuran 2
0.7611% water-accumulated sodium boronate (20 mmol) was added while stirring under water cooling. After the addition, the mixture was stirred at room temperature for 1 hour, and the reaction solution was poured into 5 ml of ice water and extracted twice with 200 MLI of ethyl acetate.

After washing twice with saturated brine, it was dried over anhydrous sodium sulfate and concentrated. 4. The obtained crude product was purified using a silica gel column (solvent: benzene-ethyl acetate system).
5 g of 24-hydroxy-3β,25-diacetoxycholest-5-ene was obtained. The physical properties of this product were as follows.

IR (KBr): 3525, 17301 1710
c! IL-1 MR (CDIJ, ): δ
o, 8o(s+3H+c-18-HL 1.03(s
, 3H, C-19-H), 1.20(s, 6H,
C-26,27-H) t2.02(s+3H,aee
tyl), 2.14(s+3)1. acetyl)
4.8(m, 21(,3α-H, C-24-H),
5.35(m,IH,6-H)II of 24-hydroxy-3β,25acetoxyprest-5-ene (2mmo
1) was dissolved in 30 g of carbon tetrachloride, and while stirring under a nitrogen stream, 0.181 (0.66 mmol) of phosphorus tribromide was added.
was dripped.

After the completion of the dropwise addition, stirring was continued for 30 minutes, and the reaction solution was poured into a 500-ml solution and extracted three times with 10014 methylene chloride. The mixture was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was purified using a silica gel column (solvent: benzene) to obtain 1.0 g of 24-bromo-3β,25-diacetoxycholest-5.
-I got en. The physical properties of this product were as follows.

IR (KBr): 1730 cra”N (CDC
ls)” δ 0.70(s, 3H, C-18-HL
LO5(s+3H+c-+9-H)+1.60(s
+6H+c-26+27-H)+4.6(m, 2H, 3
α-I(+C24H), Ri, 4(rn+IH9C6
H) MS: 5061504.424.364.25
3*tllr Example 2 24.25-Epoxy Freshero-
Soil synthesis 24-promo 3β, 25-diacetoxycholest-5
-En1. Loom Og (1,77 mmol)
/ dissolved in 10% potassium hydroxide-methanol solution,
The mixture was stirred at 60° C. for 1 hour under a nitrogen stream. Methanol was removed under reduced pressure, 100 d of water was added, and the mixture was extracted twice with 100 d of rolloform.

After washing with 1N-HCI and saturated saline, it was dried over anhydrous sodium sulfate. - The crude product obtained after overconcentration was purified using a silica gel column (solvent: benzene-ethyl acetate system) to obtain 684 μ of 24125-epoxycholesterol. The physical properties of this product were as follows.

IR (KBr): 3450 cyt-”NMR (C
DCI, ): δ0.70 (a+3H+c-18-HL
1.05(s, 3H, C-19-H)t 1,21(
s, 3H, C-26-H), 1.31 (s+3H, C
-27-I(), 3.45(m, II(,3α-H)
, 5.34 (m, IH, C-C-6-H): 400 (Eng. +), 382.367, 27
1.255mm lithium aluminum hydride 60119 (1,6mm
ol) was suspended in 2-tetrahydrofuran.

A solution prepared by dissolving 9 (0.25 mmol) in 24.25-epoxy cholesterol 10011 in 1 rnl of tetrahydrofuran was added dropwise to this suspension at room temperature under a nitrogen stream. The mixture was stirred for an additional 24 hours at room temperature. The mixture was poured into 200 ml of ice water and extracted twice with 100 ml of ethyl acetate. I N-HCl
and saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was concentrated and dried with anhydrous sodium chloride. The obtained product was purified using a silica gel column (solvent: benzene-ethyl acetate system) to obtain 76 ml of the desired product. The property value of this property was as follows.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a protective group, and R_3 is hydrogen represents an atom, a hydroxyl group or a protected hydroxyl group, and X represents a bromine atom, a chlorine atom or an iodine atom. ] 24-halogenated cholesterol represented by is treated with a base to form the following formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼...[II] [In the formula, R_ I and R_3 are the same as the above definitions. 24,25-epoxycholesterols represented by the following formula [I] are obtained and then treated with a reducing agent.
II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] A method for producing 25-hydroxycholesterols represented by [In the formula, R_1 and R_3 are the same as defined above]. 2. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a protective group, and R_3 is a hydrogen atom hydroxyl group or a protected hydroxyl group. and X represents a bromine atom, a chlorine atom or an iodine atom. 24-halogenated cholesterol represented by