JPH07233192A - Production of 24,25-dihydroxysteroid - Google Patents

Abstract

PURPOSE:To readily and efficiently produce an optically active 24,25- dihydroxysteroid through one step in high yield by conducting a high-selective asymmetric diol formation reaction of a specified cholesterol derivative through an oxidation reaction in the presence of a stereoselective catalyst and subsequantly deprotecting it. CONSTITUTION:This optically active 24,25-dihydroxycholesterol derivative represented by formula IV can be readily synthesized through one step in high yield by conducting an oxidation reaction of a cholesterol derivative (e.g. desmosterol benzoate) represented by formula I [R<1> and R<2> are H, (substituted) hydroxyl group, (protected) hydroxyl group] with an oxidizing agent composed of, e.g. an osmium compound such as osmium tetraoxide and an inorganic salt such as potassium carbonate in the presence of a stero-selective catalyst composed of a dihydroquinine compound expressed by formula II (R<3> is hydroxyl group, a group of formula III, 4-chlorobenzoyl group, etc.), etc., in a solvent such as methylsulfonamide to high selectively form its asymmetric diol and subsequently deprotecting the hydroxyl groups as necessary.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

FIELD OF THE INVENTION The present invention relates to a novel process for producing an optically active 24,25-dihydroxysteroid using an excellent highly selective asymmetric diolation reaction.

[0003]

2. Description of the Related Art Synthesis of 24,25-dihydroxysteroid: (1) Japanese Patent Laid-Open No. 58-8099; A method for synthesizing a 24,25-dihydroxycholesterol derivative from methylhyodeoxycholate is described. However, the synthesis requires multiple steps, and only a mixture of 24S and 24R forms can be synthesized.

(2) Japanese Unexamined Patent Publication No. 54-130549: Using desmosterol as a starting compound, diacetoxy-3β-24-hydroxy-25-cholestene-
Although a synthetic method in which 5 is used as an intermediate is disclosed, the synthesis requires multiple steps, and only a mixture of 24S and 24R can be synthesized.

(3) US Pat. No. 3,994,878, US Pat. No. 4,028,349, US Pat. No. 4,038,272, and Journal of.
American Chemical Society, page 3739 (1976); The above-mentioned document describes a stereoselective synthesis method of 24S and 24R isomers, but the synthesis requires multiple steps and the total yield is poor. .

(4) Journal of Chemical Society Perkin Transcription I, 1
401 (1983) and Journal of Chemical Society, Chemical Communication, 115 (1981); the above document describes the stereoselective synthesis method of 24S and 24R bodies by the present inventors. However, the synthesis requires multiple steps and the total yield is poor.

As described above, 24S is simple and has a high yield.
It is not known about the highly selective production method of the R-form and the 24R-form.

For stereoselective catalysts:

[0009]

[Chemical 3]

(Wherein R ³ represents a hydroxyl group, a group having the formula (III), a group having the formula (IV), a group having the formula (V) or a 4-chlorobenzoyl group), etc. Is known as an oxidizing agent for Sharpless, and is described, for example, in Science, Vol. 259, p. 64 (1993).

[0011]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive research over a long period of time on a novel method for producing an optically active 24,25-dihydroxysteroid, and as a result, are completely different from known synthesis methods. The present invention has been completed by finding that it can be carried out in one step by a novel production method using an excellent highly selective asymmetric diol formation reaction, is simple and has a high yield.

[0012]

[Constitution of the invention]

[0013]

The present invention has the general formula

[0014]

[Chemical 4]

[In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a hydroxyl group, a substituted hydroxyl group or a protected hydroxyl group. ] The cholesterol derivative represented by] is oxidized in the presence of a stereoselective catalyst to remove the protecting group of the protected hydroxyl group, if desired.
General formula

[0016]

[Chemical 5]

[In the formula, R ¹ and R ² have the same meanings as described above. ] A novel highly selective method for producing an optically active 24,25-dihydroxycholesterol derivative represented by the above formula. Further, in the above case, when a dihydroquinine compound is used as a stereoselective catalyst, (24S)- Two
It is a novel highly selective method for producing a 4,25-dihydroxycholesterol derivative, and when a dihydroquinidine compound is used as a stereoselective catalyst, (24R)
A novel highly selective method for producing a -24,25-dihydroxycholesterol derivative.

In the above general formula (I), the "substituent" of the "substituted hydroxyl group" in the definition of R ¹ and R ² is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl. , Lower alkyl group such as t-butyl, pentyl, hexyl; “lower alkanesulfonyloxy group” such as methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy; trifluoromethanesulfonyloxy, pentafluoroethanesulfonyl "A fluorinated lower alkanesulfonyloxy group" such as oxy or "aryl-lower alkanesulfonyloxy group" such as benzenesulfonyloxy, p-toluenesulfonyloxy.
And a “lower alkyl group” is preferable.

The "protecting group" of "protected hydroxyl group" in the definition of R ¹ and R ² means "in the reaction which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. "Protecting group" is shown. Examples of such "protecting group in reaction" include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl. , 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl,
Tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,
Alkylcarbonyl groups such as 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl and henaicosanoyl, succinoyl, Carboxylated alkylcarbonyl groups such as glutaroyl and adipoyl, halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, (E) -2 “Aliphatic acyl group” such as unsaturated alkylcarbonyl group such as -methyl-2-butenoyl; arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, 2 Halogenoarylcarbonyl groups such as -bromobenzoyl, 4-chlorobenzoyl,
2,4,6-Trimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, 2-carboxybenzoyl, 3-carboxybenzoyl, 4 -Carboxylated arylcarbonyl groups such as carboxybenzoyl, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated aryl groups such as 2- (methoxycarbonyl) benzoyl. Lecarbonyl group, 4-
"Aromatic acyl groups" such as arylated arylcarbonyl groups such as phenylbenzoyl; tetrahydropyran-
2-yl, 3-bromotetrahydropyran-2-yl,
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydro "Tetrahydrofuranyl or tetrahydrothiofuranyl group" such as thiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
Tri-lower alkylsilyl groups such as methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, and one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl. “Silyl group” such as substituted tri-lower alkylsilyl group; lower such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl Alkoxymethyl group, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, halogeno lower alkoxymethyl group such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, etc. Kokishimechiru group "; 1-ethoxyethyl, 1- (isopropoxy) lower alkoxylated ethyl group such as ethyl," substituted ethyl group such as a halogenated ethyl group such as 2,2,2-trichloroethyl; "
Benzyl, α-naphthylmethyl, β-naphthylmethyl,
Lower alkyl groups substituted with 1 to 3 aryl groups such as diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-
Methylbenzyl, 2,4,6-trimethylbenzyl,
Of 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, piperonyl "Aralkyl group" such as lower alkyl, lower alkoxy, halogen, lower alkyl group substituted with 1 to 3 aryl groups substituted with aryl ring by cyano group; methoxycarbonyl, ethoxycarbonyl, lower alkoxycarbonyl groups such as t-butoxycarbonyl and isobutoxycarbonyl, 2,2,2
“Alkoxycarbonyl group” such as lower alkoxycarbonyl group substituted with halogen such as trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or tri-lower alkylsilyl group; “alkenyloxycarbonyl” such as vinyloxycarbonyl, allyloxycarbonyl Group "; benzyloxycarbonyl, 4
The aryl ring is substituted with 1 to 2 lower alkoxy or nitro groups such as -methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl. "Aralkyloxycarbonyl group" which may be present, and preferably "aliphatic acyl group", "aromatic acyl group", "tetrahydropyranyl or tetrahydrothiopyranyl group", "silyl group" Or “aralkyl group”, more preferably “aliphatic acyl group”, “aromatic acyl group”, “tetrahydropyranyl group” and “silyl group”, and most preferably
An "aromatic acyl group" and a "tetrahydropyranyl group".

A stereoselective catalyst is a catalyst used in Sharpless oxidation and has the formula

[0021]

[Chemical 6]

[In the formula, R ³ represents a hydroxyl group. ] Dihydroquinine (DHQ) or dihydroquinidine (DH
There is no particular limitation as long as it is a catalyst having QD) in its molecule, but preferably the above dihydroquinine, the above dihydroquinidine, or the general formula

[0023]

[Chemical 7]

[In the formula, R ⁵ represents the following formula (DHQ) or formula (DHQD). ] Having a

[0025]

[Chemical 8]

Dihydroquinine compounds such as dihydroquinine 4-chlorobenzoate, dihydroquinidine 4-chlorobenzoate, pyridyl dihydroquinine, pyridyl dihydroquinidine and dihydroquinidine compounds may be mentioned, and more preferably, the general formula

[0027]

[Chemical 9]

[In the formula, R ⁵ has the same meaning as described above. ]
Most preferably, the compound having the general formula (V
II) (wherein R ⁵ has the same meaning as described above) [hereinafter, referred to as (DHQ) ₂ -PHAL and (DHQD) ₂ -PHAL, respectively. ].

The "oxidation" is not particularly limited as long as it is an oxidation reaction using an osmium compound, and is carried out in a solvent in the presence of the above stereoselective catalyst and an inorganic base.

The reaction is N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-). Dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N,
N-diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8
-In the presence of an organic base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or a lower alkyl sulfonamide such as methyl sulfonamide, ethyl sulfonamide, propyl sulfonamide The reaction is preferably accelerated, more preferably in the presence of lower alkyl sulfonamides, and most preferably in the presence of methyl sulfonamide.

“Oxidation reaction using osmium compound”
The "osmium compound" in is preferably an osmium tetroxide, an octavalent osmium such as K ₂ OsO ₂ (OH) ₄ , Na ₂ OsO ₂ (OH) ₄ , or an octavalent osmium in the reaction solution. It is an osmium compound that can be oxidized to.

Incidentally, sodium chlorate, potassium chlorate,
Chlorates such as barium chlorate and silver chlorate; hydrogen peroxide; t-butyl hydroperoxide; triethylamine-N-oxide, N-methylmorpholine-N-oxide, tripropylamine-N-oxide, tributylamine- N-oxide, diisopropylethylamine-N
-Oxide, dicyclohexylamine-N-oxide,
N-oxides of tertiary amines such as N-methylpiperidine-N-oxide; chloramine T; or alkali metal ferricyanides such as potassium ferricyanide and sodium ferricyanide as oxidants with osmium compounds. A preferable reaction is achieved by using an osmium compound alone as an oxidizing agent, and more preferably, N-oxides of a tertiary amine or alkali metal ferricyanide is used together with an osmium compound. Used as an oxidant, most preferably alkali metal ferricyanides are used as an oxidant with an osmium compound.

As the "inorganic base" used in the reaction,
Usually, it is not particularly limited as long as it is used as a base, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate. Alkali metal hydrogen carbonates such as; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide Inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide, etc. Alkali metal alkoxides; sodium methyl mercaptan , Mercaptan alkali metals such as ethyl mercaptan sodium, and more preferably alkali metal carbonates.

The "solvent" used in the reaction is not particularly limited as long as it is usually used as a solvent, but a biphasic solvent is preferable, and a solvent immiscible with water,
A biphasic solvent such as water or a mixed solvent of water and an organic solvent miscible with water is used. Solvents that are immiscible with water include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride and dichloroethane. Such halogenated hydrocarbons; esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethylene glycol dimethyl ether; n-butanol, isobutanol, t-butanol , Isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, and other alcohols. Examples of the water-miscible organic solvent include diethyl ether, diisopropyl ether, and tetrahydrofuran. , Of dioxane Such ethers; ketones such as acetone; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphorotriamide Examples thereof include sulfoxides such as dimethyl sulfoxide and sulfolane.

The reaction temperature is -30 ° C to 100 ° C, preferably -10 ° C to 50 ° C. The reaction time mainly depends on the reaction temperature, the starting compound, the reaction reagent, the stereoselective catalyst or the type of solvent used,
Usually, it is 3 hours to 5 days, preferably 5 hours to 3 days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after stopping the oxidation reaction, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water or the like. After washing, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization,
Reprecipitation or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, and magnesium-silica gel florisil; Sephadex LH
-20 (Pharmacia), Amberlite XAD-
11 (made by Rohm and Haas), Diaion H
A method using a synthetic adsorbent such as partition column chromatography using a carrier such as P-20 (manufactured by Mitsubishi Kasei),
Elution with a suitable eluent by appropriately combining a method using ion exchange chromatography or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably high performance liquid chromatography). Can be separated and purified by.

Desired step, "protected hydroxyl group"
The removal of the protecting group of (4) depends on its type, but is generally carried out as follows by a method well known in the art.

When a silyl group is used as a hydroxyl group-protecting group, it is usually treated with a compound which produces a fluorine anion such as tetrabutylammonium fluoride or hydrofluoric acid, or methanesulfonic acid, It can be removed by treating with an organic acid such as paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid.
In the case of removing with fluorine anion, formic acid, acetic acid,
The reaction may be accelerated by adding an organic acid such as propionic acid. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol. Examples thereof include ethers such as dimethyl ether; nitriles such as acetonitrile and isobutyronitrile. The reaction temperature and the reaction time are not particularly limited, but are usually 0 ° C. to 50 ° C. (preferably room temperature) and 2 to 24.
Will be carried out for hours.

When the hydroxyl-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by bringing it into contact with a reducing agent in a solvent (preferably, catalytic reduction at room temperature under a catalyst). The method is preferred. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol and isopropanol.
Ethers, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, ethyl acetate and propyl acetate. Preferred are such esters, formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, amides such as hexamethylphosphorotriamide, fatty acids such as formic acid and acetic acid, water, or a mixed solvent thereof. And more preferably alcohols,
It is a mixed solvent of fatty acids, alcohols and ethers, a mixed solvent of alcohols and water, or a mixed solvent of fatty acids and water.

The catalyst used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, Rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used. The pressure is not particularly limited, but is usually 1 to 10 atm. The reaction temperature and the reaction time will differ depending on the types of starting materials, solvents, catalysts, etc., but are usually 0 ° C. to 100 ° C. (preferably 20 ° C. to 70 ° C.), 5 minutes to 48 hours (preferably 1 Time to 2
4 hours).

Also, in liquid ammonia or in methanol.
-78 in alcohols such as alcohol and ethanol
It can also be removed by reacting an alkali metal such as metallic lithium or metallic sodium at from -20 ° C.

Further, it can be removed by using aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide in a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, but preferably, nitriles such as acetonitrile, methylene chloride, halogenated hydrocarbons such as chloroform, or a mixed solvent thereof. Is used. The reaction temperature and the reaction time will differ depending on the starting materials, solvent, etc., but are usually 0 to 50 ° C., and 5 minutes to 3 minutes.
It is carried out for a day.

When the reaction substrate has a sulfur atom,
Aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treatment with a base in a solvent.

The base used is not particularly limited as long as it does not affect other parts of the compound, but metal alkoxides such as sodium methoxide; sodium carbonate, potassium carbonate, carbonic acid are preferred. Alkali metal carbonate such as lithium; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or ammonia water, ammonia such as concentrated ammonia-methanol . The solvent used is not particularly limited as long as it can be used in a usual hydrolysis reaction, and water; methanol, ethanol
Preference is given to organic solvents such as alcohols such as alcohol and n-propanol, organic solvents such as ethers such as tetrahydrofuran and dioxane, or mixed solvents of the above organic solvents with water. The reaction temperature and the reaction time vary depending on the starting material, the solvent, the base used, etc. and are not particularly limited. However, in order to suppress side reactions, it is usually carried out at 0 to 150 ° C. for 1 to 10 hours.

The hydroxyl-protecting group is an alkoxymethyl group,
In the case of a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, it is usually removed by treating with an acid in a solvent. The acid used is not particularly limited as long as it is usually used as a Bronsted acid or a Lewis acid, and preferably,
Hydrogen chloride; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid; or Bronsted acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid: Lewis acids such as boron trifluoride However, Dowex 5
Strongly acidic cation exchange resins such as 0 W can also be used. The solvent used does not inhibit the reaction,
There is no particular limitation as long as it dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene. Methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate,
Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methanol;
, Ethanol, n-propanol, isopropanol,
Alcohols such as n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone , Ketones such as cyclohexanone; water, or a mixed solvent thereof is preferable, and halogenated hydrocarbons, esters or ethers are more preferable. The reaction temperature and the reaction time will differ depending on the starting materials, the solvent, the type and concentration of the acid used, etc., but are usually −10 to 100 ° C. (preferably −5 to 50 ° C.), and 5 minutes to 48 hours. (Preferably 30 minutes to 10 hours).

When the hydroxyl-protecting group is an alkenyloxycarbonyl group, it is usually the same as the conditions for the removal reaction when the hydroxyl-protecting group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. And is treated with a base.

In the case of allyloxycarbonyl, the method of removing it particularly using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

The compound having the general formula (I) as a starting material compound is desmosterol, 1-hydroxydesmosterol or a compound which can be easily derived from them by a conventional method, and is all known compounds, such as desmosterol and 1- Hydroxydesmosterol is easier to obtain than natural.

[0050]

The novel optically active 24,25- of the present invention
The production method of dihydroxy steroid is a novel production method using an excellent highly selective asymmetric diol formation reaction, and the optically active substance which is the target substance can be produced easily and in high yield in one step.

[0051]

Example 1 Cholest-5-ene-3β, 24,25-triol
In a 3-benzoate flask, t-butanol (1 ml), water (0.5 m
l), (DHQ) ₂ -PHAL (2.0 mg, 2.5 μ
M), potassium carbonate (21 mg, 150 mM), potassium ferricyanide (50 mg, 150 μM), methylsulfonamide (4.8 mg, 50 mM), and the container was cooled to 0 ° C. with ice water, and then osmium tetroxide (0.1 M
Toluene solution (25 μl, 2.5 μM) was added and stirred for 5 minutes. Then, desmosterol benzoate (2
0 mg, 41 μM) was added, cooling was stopped and stirring was continued for 20 hours. Then sodium bisulfite (150mg)
Was added and the mixture was stirred for 30 minutes, then partitioned with ethyl acetate-water. The organic layer was washed successively with 2N hydrochloric acid, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the target compound (20 mg, 94%). The product was a single spot by TLC, ¹ H-N
No signal of impurities was observed in MR. NMR spectrum (CDCl ₃ , 270 MHz) δ
ppm: 0.696 (3H, s), 0.953 (3H, d, J = 6.4Hz), 1.070 (3H,
s), 1.164 (3H, s), 1.220 (3H, s), 3.29 (1H, br.d, J = 8Hz), 4.8
5 (1H, m), 5.42 (1H, br.d, J = 4.2Hz), 7.38-8.07 (5H, m). The stereochemical purity at the 24-position of this substance is partly due to pyridine-benzoyl chloride. Accordingly, 3,24- dibenzoate body guidance, where it is determined based on the integrated intensity of the signal of 18H ₃ in NMR, 24S body: 24R body 94: the 6 and found. NMR spectrum (CDCl ₃ , 500 MHz) δ
ppm: 0.630 (3H, s), 0.943 (3H, d, J = 6.4Hz), 1.054 (3H,
s), 1.281 (6H, s), 4.86 (1H, m), 5.02 (1H, br.d, J = 10Hz), 5.4
1 (1H, br.d, J = 4Hz), 7.40-8.09 (10H, m).

[0052]

Example 2 Cholest-5-ene-3β, 24,25-triol
3- Benzoate In Example 1, (DHQ) ₂ -PHAL was replaced by (DHQD) ₂ -PHAL (2.0 mg, 2.5 μm).
M) was used in the same manner, and the target compound 19 mg (89
%) Was obtained. The product is a single spot on TLC,
No signal of impurities was observed in NMR. NMR spectrum (CDCl ₃ , 270 MHz) δ
ppm: 0.704 (3H, s), 0.940 (3H, d, J = 6.4Hz), 1.073 (3H,
s), 1.169 (3H, s), 1.220 (3H, s), 3.32 (1H, br.t, J = 6.5Hz),
4.86 (1H, m), 5.42 (1H, br.d, J = 4.2Hz), 7.38-8.07 (5H, m). The stereochemical purity at the 24-position of this substance is the same as in Example 1, As the 3,24-dibenzoate form, the 24S form:
The 24R form was 5:95. NMR spectrum (CDCl ₃ , 500 MHz) δ
ppm: 0.673 (3H, s), 0.941 (3H, d, J = 6.4Hz), 1.060 (3H,
s), 1.279 (6H, s), 4.86 (1H, m), 5.06 (1H, br.d, J = 10Hz), 5.4
1 (1H, br.d, J = 4Hz), 7.40-8.09 (10H, m).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C07M 7:00

Claims (3)

[Claims] 1. A general formula: [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a hydroxyl group, a substituted hydroxyl group or a protected hydroxyl group. ]
A cholesterol derivative represented by the formula: is oxidized in the presence of a stereoselective catalyst to optionally remove a protecting group of a protected hydroxyl group. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the optically active 24,25-dihydroxy cholesterol derivative represented by these. 2. A dihydroquinine compound is used as a stereoselective catalyst according to claim 1, wherein (24S) -24,2
A method for producing a 5-dihydroxycholesterol derivative. 3. The method according to claim 1, wherein a dihydroquinidine compound is used as a stereoselective catalyst, and (24R) -24,
A method for producing a 25-dihydroxycholesterol derivative.