WO2003051904A1

WO2003051904A1 - Process for producing pregnane derivative

Info

Publication number: WO2003051904A1
Application number: PCT/JP2002/011547
Authority: WO
Inventors: Makoto Nakazawa; Shigeo Ohzono
Original assignee: Kuraray Co., Ltd.
Priority date: 2001-12-19
Filing date: 2002-11-06
Publication date: 2003-06-26

Abstract

A process for producing a 21-hydroxypregnane derivative represented by the general formula (III), (III) characterized by protecting the 7-position hydroxy group of a compound represented by the formula (I) (I) and subsequently eliminating the 21-position protective silyl group. (In the formulae, R1, R2, and R3 each independently represents optionally substituted alkyl, alkenyl, alkynyl, aryl, or aralkyl; and R4 represents a hydroxy-protecting group.) By the process, a pregnane derivative useful as, e.g., an intermediate for squalamine can be efficiently produced through a small number of steps from easily available materials.

Description

Specification

Method for producing predanane derivative

Technical field

The present invention relates to a method for producing a predanane derivative. The pregnane derivative produced according to the present invention is useful, for example, as a synthetic intermediate of squalamine (squa1amine) represented by the following formula.

squalamine

Squalamine is a compound that has been reported to have potent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, fungi, etc. and also has anticancer activity, and is attracting attention as a new antibiotic [Journal J. Org. Chem., Vol. 63, pp. 378 (1998); Journal of Organic Chemistry (J. O.) RG. Chem.), 63, 859 (1998); see WO 98 Z 24800, etc.).

Background art

Conventionally, squalamine has been extracted from shark liver ffil, but its extraction efficiency is extremely low, 0.001 to 0.002 wt%, and chemical synthesis methods have been studied. As a chemical synthesis method of squalamine, 1) a method using 3 / 3-acetoxy-5-cholenic acid as a starting material [Tetrahedron Letters, Vol. 35, p. (1994)), 2) 3 -Hydroxy-5-Colenic acid as a starting material [Journal 'Ob' Organic 'Chemistry (J. Org. Chem.), 60 vol. 5 121 pages (1995); see WO 94/1 19 366], 3) 21-hydroxy-20-methyl Method using Regna-4-en-3-one as a starting material (see WO 98Z24 800), 4) Method using stigmasterol as a starting material [Journal of Organic Organic Chemistry (J. Org. Chem.), Vol. 63, pp. 378 (1998); Journal Off, Organic 'Chemistry (J. Org. Cem.), Vol. 63, Vol. 9 (1998); see WO98 / 24800].

Used as a starting material in the above methods 1), 2) and 3) 3] 3-Acetoxy ■ 5-colenic acid, 3-hydroxy-5-cholenic acid, 21-hydroxy-1- 20-methylpredaner 4-one-3 _On is expensive. In addition, the method 1) requires 17 steps to obtain squalamine, the method 2) requires 19 steps, and the method 3) requires 15 steps, all of which are complicated. . Therefore, these methods cannot be said to be industrially advantageous methods for producing squalamine.

On the other hand, in the above method 4), stigmasterol used as a starting material can be obtained at low cost, but it requires 20 steps to synthesize squalamine. In addition, silver carbonate used in the process of selectively oxidizing the hydroxyl group at the 3-position is expensive, and special reaction equipment is required because it passes through the ozone oxidation process at a low temperature. Therefore, this method is not necessarily an industrially advantageous method.

Therefore, an object of the present invention is to provide a method capable of efficiently producing a predanane derivative useful as a squalamine synthesis intermediate or the like from a readily available raw material in a short step.

DISCLOSURE OF THE INVENTION 'To achieve the above-mentioned object, the present inventors have proposed a method for forming the 21-position hydroxyl group of (5α, 7a, 20S) -17,21-dihydroxy-1 20-methylpredana_3_one. Protected derivatives, such as (5α, 7a, 20S) —7-hydroxy-20-methylpredaner 3 _one-1 21-ol (1,1-dimethylethyl) dimethylsilyl ether [Bioorganic & Medicinal Chemistry (Biol g. Med. Chem.), Vol. 8, pp. 259 (2000)] Synthetic intermediate in method 4), synthesized from stigmasterol in 7 steps (5, 7a, 2 OS) —20-formyl-13- (spiro-1,2,-(1,, 3 'dioxolane)) It has been found that 1-prednan-17-benzoyl benzoate can be produced in a high yield in three steps without using an expensive reactant.

Also, (5,7a, 2 OS) —7-hydroxy-20-methylpredana-1 3-one—21-ol (1,1-dimethylethyl) dimethylsilyl ether and (5,7a, 20S)- 21-(((1,1-dimethylethyl) dimethylsilyl) oxy) -20-methylpredana-3-one-17-ol benzoate has crystallinity and is obtained from the process of manufacturing these. A recrystallization operation in which the crude product can be industrially easily carried out, for example, a recrystallization method or a solvent in which the crude product is heated in the presence of a solvent, dissolved in the solvent, and then cooled to precipitate the desired product from the solvent. The present inventors have found that the crude product can be purified by a suspension washing method in which the crude product is suspended and washed, and impurities are dissolved in a solvent and purified.

That is, the present invention

① Formula (I)

(Wherein, I ¹ , R ² and R ³ each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a group which may have a substituent. A alkynyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.) 21-silyloxypredanane derivative represented by the following formula:

(Hereinafter abbreviated as 21-silyloxypredanane derivative (I) or compound (I)), wherein a hydroxyl group is protected in the presence of a base.

(Wherein R: R ² and R ³ have the same meanings as described above, and R ⁴ represents a hydroxyl-protecting group.) (Hereinafter abbreviated as predanane derivative (II)) Method,

(2) A general formula (I I I) characterized in that the silyl group of the 21-silyloxy group of the predanane derivative (II) is deprotected.

(Wherein, R ⁴ has the same meaning as described above.) A method for producing a 21-hydroxypredanane derivative (hereinafter abbreviated as 21-hydroxypredanane derivative (III)) represented by the following formula:

③ Formula (IV)

(Wherein, R ⁴¹ represents a hydrogen atom or a benzoyl group.) (((1,1-dimethylethyl) dimethylsilyl) methyl) 20-methylpredanane derivative (hereinafter abbreviated as 21-silyl20-methylpredanane derivative (IV)), comprising: 1-silyl mono 20-methylpredanane derivative

Crystallizing (IV), and

④ formula (II-1)

(Hereinafter abbreviated as compound (II-11)), that is, (5,7a, 20S) -21-(((1,1,1-dimethylethyl) dimethylsilyl) oxy) Achieved by providing 20-methylpredana-3-one-17-ol benzoate.

Detailed description of the invention

The alkyl group represented by RR ² and R ³ is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. Group, 1-methylpropyl group, 2-methylpropyl group, 1,1-dimethylethyl group (tert-butyl group), n-pentyl group, 1-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethyl Propyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group and the like. Of these, an alkyl group having 1 to 4 carbon atoms, particularly a methyl group and a 1,1-dimethylethyl group are preferred. These alkyl groups may have a substituent. Examples of such a substituent include a hydroxyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group, and a propoxy group. Alkoxyl groups such as butoxy group; aryloxy groups such as phenoxy group; benzyloxy group etc. Aralkyloxy group and the like.

The alkenyl group represented by RR ² and R ³ is preferably a straight-chain or branched alkenyl group having 3 to 6 carbon atoms, such as ² -propyl group and 2-ptiel group. , 3-buteninole, 1-methyl-2-propyl, 2-methyl-2-propyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-12- Butul group, 1-methyl-3-butenyl group, 2-methyl-12-butenyl group, 2-methyl-3-butul group, 2-methylidenebutyl group, 3-methyl-2-butene 2-norethyl group, 3-methynole _3- Buteninole, 1-ethynole 2-propenyl, 11-hexyl and the like. The alkynyl group represented by I ¹ , R ² and R ³ is preferably a straight-chain or branched-chain alkynyl group having 3 to 6 carbon atoms, for example, a 2-propyl group or a 2-propyl group. PETINYL, 3-PETYL, 2-PENTULLE, 3-PENTINOLE, 4-PENTINOLE, 3-METHINOLE-2-PROPINYL, 2-ETHENYLPROPYL, 2-HEXHELL Is mentioned. These alkyl group and alkynyl group may have a substituent. Examples of the substituent include a hydroxyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group and an ethoxy group. And alkoxyl groups such as propoxy and butoxy groups; aryloxy groups such as phenoxy groups; and aralkyloxy groups such as benzyloxy groups.

The aryl group represented by R \ R ² and R ³ is preferably an aryl group having 6 to 12 carbon atoms, for example, phenyl, 2-methynolephenyl, 3-methylphenyl, 4-methylphenyl, 2,3 —Dimethylphenyl group, 2,4-Dimethylphenol group, 2,5-Dimethylphenyl group, 2,6-Dimethylphenyl group, 4-Propylphenyl group, 4-Butylphenyl group, Naphthinole group, 2, Examples include a 3-dimethinolenaphthynole group and a 2,4-dimethylnaphthyl group. These aryl groups may have a substituent. Examples of the substituent include a hydroxyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group and a propyl group. , Isopropyl, butyl, isobutyl, sec_butyl, ter alkyl groups such as t-butyl group; alkoxyl groups such as methoxy group, ethoxy group, propoxy group and butoxy group; aryl groups such as phenyl group; and aralkyloxy groups such as benzyloxy group.

The aralkyl group represented by RR ² and R ³ is preferably an aralkyl group having 7 to 13 carbon atoms, and examples thereof include a benzyl group, an 11-phenylethyl group, and a naphthylmethyl group. These aralkyl groups may have a substituent. Examples of the substituent include a hydroxyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group, a propyl group and an isopropyl group. Alkyl groups such as methoxy, ethoxy, propoxy and butoxy groups; aryl groups such as phenyl groups; benzyloxy groups, etc. Aralkyloxy group and the like.

As the group R \ R ² and R ³ represents preferably a linear or branched alkyl group having a carbon number 1 to 6, among them an alkyl group having 1 to 4 carbon atoms, in particular methyl, 1, A 1-dimethylethyl group is preferred.

In the above general formula, the protecting group for the hydroxyl group represented by R ⁴ may be any protecting group as long as it acts as a protecting group for a hydroxyl group, for example, an alkyl group such as a tert-butyl group or a tert-amyl group; , O-methylbenzyl, m-methylbenzyl, p-methylbenzyl, p-nitrobenzyl, p-methoxybenzyl, p-phenylbenzyl, diphenylmethyl, triphenylmethyl, etc. Aralkyl groups; acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, methoxyacetyl group, triphenylmethoxyacetyl group, phenoxyacetyl group, p-chlorophenoxyacetyl group, Phenylacetyl group, diphenylacetyl group, propionyl group, butyryl group, valeryl group, 4 _ Pentenoyl group, pivaloyl group, crotonoyl group, benzoyl group, o-methenolbenzoyl group, m-methylbenzoyl group, p-methynolbenzoyl group, 2,3-dimethylbenzoyl group, 2,4-dimethylbenzoyl group , twenty five - Acinole groups such as dimethylbenzoyl group, 2,6-dimethylbenzoyl group, 2,4,6-trimethylbenzoyl group, p-phenylbenzoinole group, etc .; methoxycarbonyl group, 9-fluorenyl methoxycarbonyl Alkoxy groups such as ethoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloromouth ethoxycarbonyl group, 1,1-dimethyl-2,2,2,2-trichloroethoxycarbonyl group, 2- (trimethinoresilinole) ethoxycarbonyl group Carbonyl group; vinyloxycarbonyl group, aryloxycarbinole group, etc./requenyloxycarbinole group; phenoxy group, carbonyl group, ρ-2, phenyloxycarbonyl group, etc. Xycarbonyl group; benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, 3,4-dimethoxybenzene Di / reoxycanoleboninole group, o-nitrobenzene group, p-nitrobenzene group, 2- (4-nitrophenyl) ethoxycarbonyl group, 2- ( 2,4-dinitrophenyl) aralkyloxycarbonyl groups such as ethoxycarbol group; methoxymethyl group, benzyloxymethyl group, -methoxybenzyloxymethyl group, p-nitrobenzylmethoxymethinole group, o-Alkoxyalkyl groups such as nitrobenzylmethoxymethyl group, (4-methoxyphenoxy) methyl group, tert-butoxymethyl group, 2-methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group; trimethylsilyl group , Ethyldimethylsilyl group, isopropynoledimethylsilinole group, tert-butinoresimetylsilyl group Group, Toryechirushiriru group, tert- Buchirujifue two Rushirinore groups, such as trisubstituted silyl groups, such as preparative Rifuenirushiriru group. Of these, an acyl group, particularly a benzoyl group, is preferred.

Hereinafter, each step will be described.

Step 1: Step of protecting the 7-hydroxyl group of compound (I) to obtain predanane derivative (II)

The protection of the hydroxyl group at the 7-position of the compound (I) can be carried out by a method similar to a method generally used for protecting a hydroxyl group.

For example, the above-mentioned alkyl group or aralkyl group is used as a hydroxyl-protecting group. In the case of aldehyde, alkynole / peroxide such as tert-butynochloride and tert-amyl chloride; benzinolek mouth, benzinoleb mid, o-methinolebenzyslek mouth, m-methinolebenzinorecro Lido, ρ-methinobenzoyl chloride, p-nitrobenzylinochloride, p-methoxybenzylinochloride, p-phenylbenzyl chloride, diphenylmethyl chloride, triphenylmethyl chloride, etc. Metal hydrides such as lithium hydride, sodium hydride, potassium hydride, and hydrogen hydride; alkaline metals such as lithium, sodium, and potassium; alkaline earth metals such as magnesium and calcium; sodium carbonate , Carbonates such as carbon dioxide lime; sodium hydrogen carbonate, carbonated water In the presence of a base such as carbonated water Motoshio such force Riumu, as possible out be carried out by reacting the compound (I). The amount of the alkyl halide or aralkyl halide to be used is preferably 1 mol or more, more preferably 1 to 10 mol, per 1 mol of compound (I). The amount of the base to be used is preferably 1 mol or more, more preferably 1 to 10 mol, per 1 mol of the alkyl halide or aralkyl halide.

When the above-mentioned acetyl group is used as a hydroxyl-protecting group, acetyl chloride, acetyl chloride, chloroacetyl chloride, dichloroacetyl ^ / chloride, trichloroacetyl chloride, trifluoroacetyl chloride , Methoxyacetyl chloride, trifenylmethoxyacetyl chloride, triphenyl methoxyacetinochloride, phenoxyacetinol chloride, p-chlorophenoxyacetyl chloride, phenylenoacetyl chloride, phenylacetinolebromide , Diphenylethyl chloride, propioyl chloride, butyryl chloride, valeryl chloride, 41-pentenoinolek, Viva iruku, crotonoinorek, benzoyl chloride, benzoyl bromide, o_methyl Benzoyl chloride, m-methinobenzoyl chloride, p-methylbenzoyl chloride, 2,3-dimethinobenzoyl chloride, 2,4-dimethylbenzoyl chloride, 2,5-dimethinobenzoyl chloride Acid halides such as 2,2,6-dimethylbenzoinolechloride, 2,4,6-trimethylbenzoinolechloride and p-phenylbenzoyl chloride Acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, methoxyacetic anhydride, triphenylmethoxyacetic anhydride, phenoxyacetic anhydride, p-chlorophenyloxyacetic anhydride, phenylacetic anhydride, diphenylacetic anhydride

Acid anhydrides such as acetic acid, 4-pentenoic anhydride, vivalic anhydride, crotonic anhydride, benzoic anhydride, and p-phenylbenzoic anhydride; lithium hydride, sodium hydride, potassium hydride, Metal hydrides such as calcium hydride; lithium metals such as lithium, sodium, and potassium; alkaline earth metals such as magnesium and canoleum; carbonates such as sodium carbonate and carbonated lime; sodium hydrogen carbonate Hydrogen carbonate such as potassium bicarbonate; trimethylamine, triethylamine, diisopropinoleethylamine, pyridine, N, N-dimethylaminopyridine, N, N-dimethylamine, N, N-ethylinorea The reaction can be carried out by reacting with compound (I) in the presence of a base such as an amine such as phosphorus or imidazole. . The amount of the acid halide or the acid anhydride to be used is preferably 1 mol or more, more preferably 1 to 10 mol, per 1 mol of compound (I). The amount of the base used is preferably 0.1 mol or more, more preferably 1 to 10 mol, per 1 mol of the acid halide or acid anhydride. Further, two or more types of bases may coexist, and when two or more types of bases coexist, the amount of the base used is such that at least one base is 0.1 with respect to 1 mol of acid halide or acid anhydride. More preferably, it is at least 0.1 mole and more preferably at least 0.1 to 10 moles of one base.

When the above-mentioned alkoxycarbonyl group, alkenyloxycarbonyl group, aryloxycarbonyl group, or aralkyloxycarbonyl group is used as the hydroxyl-protecting group, the reaction is carried out using methyl chloroformate, Ethyl chloroformate, 2,2,2_trichloroethinochloroformate, 9-phnoolereninolemethinole chloroformate, 1,1-dimethyl-1,2,2,2-trichloroethyl chloroformate, 2 chloroformate -(Trimethylsilinole) Anorecoxycarbohalide such as etinole; vinole chloroformate, alkenyloxycarbonyl halide such as aryl chloroformate; Mouth formic acid! ) 1-norethoxycanolepoenole halides such as phenolic monophenols; benzyl chloroformate, p-methoxybenzyl chloroformate, chloroformate 3,4 dimethoxybenzene, chloroformate o_ Aralkyloxycarbonyl halides such as nitrobenzinole, chlorobenzyl chloroformate, chloroformate 2- (4-trophenyl) ethyl, and chloroformate 2- (2,4-dinitropheninole) ethyl carbonate; sodium carbonate Carbonates such as sodium bicarbonate; sodium bicarbonate; bicarbonates such as bicarbonate; trimethylamine, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, N, N-dimethylanily Compounds in the presence of bases such as amines, N, N-acetylamine, amides such as imidazole, etc. It can be carried out by reacting with I). The amount of alkoxycarboenole halide, anorequeenoleoxycanolepoenole halide, arinoreoxycanolebonyl halide or aralkyloxycarbol halide used is 1 mole per mole of the compound (I). 1 mol or more is preferable, and the range of 1 to 10 mol is more preferable. The amount of the base used is preferably at least 0.1 mol, and more preferably from 1 to 10 mol, per mol of the alkoxycarbonyl halide, alkoxycarbonyl halide, aryloxycarbonyl halide or aralkyloxycarbonyl halide. Is more preferable. Furthermore, two or more bases may coexist, and when two or more bases coexist, the amount of the base used is alkoxycarbonyl halide, alkenyloxycarbonyl halide, aryloxycarbonyl halide. Alternatively, at least one base is preferably at least 0.1 mole per mole of aralkyloxycarbonyl halide, and at least one base is in a range of at least 0.1 to 10 moles. Is more preferred.

When the above-mentioned alkoxyalkyl group is used as a protecting group for a hydroxyl group, the reaction is carried out using 1-methoxymethyl chloride, 1-methoxymethyl bromide, benzyloxymethyl chloride, and p-methoxybenzyloxy. Methyl chloride, p-Nitrobenzyl methoxymethyl chloride, o-Etrobenzyl methoxymethyl chloride, (4-Methoxyphenoxy) methinochloride, tert-Butoxymethinochloride, 2-Methyl chloride Metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkoxyalkyl halides such as toxhetoxymethyl chloride and 2_ (trimethinoresilyl) ethoxymethyl chloride; Alkali metals such as lithium, sodium and potassium; alkaline earth metals such as magnesium and calcium; carbonates such as sodium carbonate and potassium carbonate; hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; trimethyla In the presence of bases such as amines such as amines, triethylamine, diisopropyl pyrethylamine, pyridine, N, N-dimethylaminopyridine, N, N-dimethylamine, N, N_ethylethylamine, etc., the compound ( The reaction can be carried out by reacting with I). The amount of the alkoxyalkyl halide to be used is preferably 1 mol or more, more preferably 1 to 10 mol, per 1 mol of compound (I). The amount of the base to be used is preferably at least 0.1 mol, more preferably from 1 to 10 mol, per mol of the alkoxyalkyl halide. Further, two or more bases may coexist, and when two or more bases coexist, the amount of the base used is at least 0.1 mol per one mol of the alkoxyalkyl halide. More preferably, the content of one base is at least 0.1 to 10 mol.

When the above-mentioned trisubstituted silyl group is used as a hydroxyl-protecting group, the reaction is carried out using trimethylsilyl chloride, trimethylsilyl bromide, ethyldimethylsilyl chloride, isopropyldimethylsilyl chloride, tert-butyl. Tri-substituted silylno, such as dimethylsilyl chloride, triethynolesilyl chloride, tert-butyldiphenylsilyl chloride, and triphenylsilyl chloride; ride; trimethylsilyl trifrenolelomethanesnolehonate, etino Resin methinoresilinole triflenole mouth Methanesulfonate, isopropyldimethinoresilinere trifluoromethanesulfonate, tert-butyldimethylsilinole trifluoromethanesulfonate, triethylsilyl trifleolenomethanes; / lephonate, tert-butinoresi Et Ninoreshirinore triflate Honoré Oro methane Sno Reho sulfonate, triflate et el silyl Torifunore O b trisubstituted silyl triflate Ruo b methanesulfonate such as methanesulfonate Metal hydrides such as sodium hydride and potassium hydride; carbonates such as sodium carbonate and potassium carbonate; hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; triethylamine, getylaminopyridine, imidazole, 2 , 6-reaction with compound (I) ′ in the presence of a base such as an amine such as lutidine. The amount of the trisubstituted silyl halide or trisubstituted silyl trifluoromethanesulfonate to be used is preferably 1 mol or more, more preferably 1 to 10 mol, per 1 mol of compound (I). The amount of the base to be used is preferably 0.1 mol or more, more preferably 0.1 to 10 mol, per 1 mol of trisubstituted silyl halide or trisubstituted silyl trifluoromethanesulfonate. Further, two or more bases may coexist.When two or more bases coexist, the amount of the base used is at least one base per mole of trisubstituted silyl halide or trisubstituted silyl trifluoromethanesulfonate. The base is preferably at least 0.1 mol, more preferably at least 0.1 to 10 mol of one base.

The reaction for protecting the hydroxyl group of compound (I) can be carried out in the presence or absence of a solvent. The solvent that can be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane, benzene, and dichlorobenzene; and solvents such as tetrahydrofuran, getyl ether, and dimethoxetane. I-Tenole; hydrocarbons such as pentane, hexane, heptane, octane, petroleum ether, ^^, benzene, and tonolene; Can be When a solvent is used, its use amount is not particularly limited, but is usually preferably in the range of 1 to L00 by weight based on the compound (I).

The reaction temperature is between 180 ° C and 200 ° C. (The range is preferably from 120 to 180 ° C. The reaction time is usually from 0.1 to 100 hours, preferably from 1 to 24 hours.

The predanane derivative (II) thus obtained is a simple organic compound. Isolation and purification can be performed by the method used for purification. For example, pour the reaction mixture into saline or water and extract with an organic solvent such as getyl ether, ethyl acetate, methylene chloride. If necessary, wash the extract with saturated aqueous sodium bicarbonate to remove acidic substances, wash with diluted hydrochloric acid, water, saline, etc. to remove basic and water-soluble substances, and then add sulfuric anhydride. The crude product obtained by drying over magnesium, anhydrous sodium sulfate, etc. and concentrating is purified by distillation, chromatography, recrystallization, etc., if necessary.

A benzoyl group is particularly preferable as a protecting group for the hydroxyl group at the 7-position. Compound (II-11) in which the 7-position hydroxyl group of compound (I) is protected with a benzoyl group, that is, (5α, 7a, 20S) — 21 — (((1,1-dimethylethyl) dimethylsilyl) oxy) 120-Methylpredaner 3-one-17-ol benzoate is a novel compound and can be purified by recrystallization which is easily carried out industrially. '

Step 2: Step of deprotecting the silyl group of the 21-position silyloxy group of the predanane derivative (II) to obtain a 21-hydroxypredanane derivative (III)

The reaction of deprotecting the silyl group of the silyloxy group at the 21-position of the predanane derivative (II) to obtain the 21-hydroxypredanane derivative (III) is performed by a generally known method for deprotecting the silyl group of the silyloxy group. Available: Protective-Groups 'In' Organic Synthesis (Third Edition, 1114 (1999)), John Wiley & Sons Publishing (John W iley & Sons, Inc.).

In the reaction, it is particularly preferable that at least a salt or an acid coexist in the reaction system. Examples of such salts include fluorine-containing ammonium salts such as tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride; Fluorine containing lithium, sodium fluoride, potassium fluoride, cesium fluoride, etc. Alkali metal salts; and fluorinated alkaline earth metal salts such as calcium fluoride. Examples of the acid include sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesnolephonic acid, benzenesnolephonic acid, and p-tonorenesnolefonic acid; and mineral acids such as hydrofluoric acid, hydrochloric acid, and sulfuric acid. Lewis acids such as trifluoroboron and trifluoroboron getyl ether complex; acetic acid; and halogen-containing acetic acids such as trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid.

When salts are allowed to coexist, the use amount thereof is not particularly limited, but usually 1 mol or more is preferable per 1 mol of predanane derivative (II), and the range of 1 to 10 mol is more preferable. In the case of coexisting an acid, the amount of the acid used is not particularly limited, but is usually preferably at least 0.01 mol per mol of the predanane derivative (II), and is preferably in the range of 0.01 to 1 mol. More preferred. Further, two or more of the above-mentioned acids and salts may be used as a mixture.

The reaction can be performed in the presence or absence of a solvent. The solvent that can be used is not particularly limited as long as it does not adversely affect the reaction, but is preferably an organic solvent, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and benzyl alcohol. Alcohols such as tetrahydrofuran, getyl ether and dimethoxetane; hydrocarbons such as tonolen, pentane, hexane, heptane, octane and petroleum ether; dichloromethane, chlorophonolem, carbon tetrachloride, dichloroethane, tetrachloroethane, Halogenated hydrocarbons such as black benzene, o-dichlorobenzene and the like, and mixtures thereof. When a solvent is used, its use amount is not particularly limited, but is usually preferably in the range of 1 to 200 times the weight of the predanane derivative (II).

The reaction can be carried out in the presence or absence of water as long as the reaction is not adversely affected. When water is present, the amount thereof is not particularly limited, but is usually preferably in the range of 0.001 to 200 times the weight of the predanane derivative (II). In addition, water contained in the above-mentioned solvent, and also contained in the above-mentioned acids, salts or mixtures thereof The reaction may be carried out in the presence or absence of water. The weight of the water contained is usually preferably in the range of 0.001 to 200 times the weight of the predanane derivative (II). The reaction temperature is preferably in the range of 100 ° C to 200 ° C, and more preferably in the range of 130 ° C to 180 ° C. The reaction time is generally 0.1 to 100 hours, preferably 1 to 24 hours.

The reaction is preferably carried out by mixing the predanane derivative (11), if necessary, a salt or acid, and a solvent, and stirring the mixture at a predetermined temperature.

The 21-hydroxypredanane derivative (III) thus obtained can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, the reaction mixture is poured into saline or water and extracted with an organic solvent such as getyl ether, ethyl acetate, methylene chloride. If necessary, wash the extract with a saturated aqueous solution of sodium bicarbonate to remove acidic substances, wash with diluted hydrochloric acid, water, saline, etc. to remove water-soluble substances, and then add anhydrous magnesium sulfate and sulfuric anhydride. The crude product obtained by drying with sodium and concentrating is purified as necessary by distillation, chromatography, recrystallization, etc.

21 1-Hydroxypredanane derivative (III), for example (5α, 7α, 20S) -21-hydroxy-20-methinolepredanane-13-one-1-7-onolebenzoate is in the third position By protecting the ketone, (5,7a, 20S) 1-21-hydroxy-3_ (spiro_2) '((1', 3, dioxolan)) 20_methylpredanane-1-7 All benzoate and then oxidation of the hydroxyl group at the 1-position (5α, 7,20S) -20-honoremil-13- (spiro-1 2 '-(1,1,3, dioxolan)) 1-predanane_7-ol Induced by benzoate (see Reference Examples 4 to 6). This compound reacts with getylphosphono-1-methyl-2-butanone to give (5α, 7a, 20R, 22E) —24-oxo-13- (spiro-1,2- (1,, 3 , Gioxoran)) -Cholester-1 7-Ornole Benzoate, and furthermore, the journal 'Ob' Ogayuk 'Chemistry (J. Org. Chem.), Vol. 63, pp. 378-86 (1 9 9 8); journal Squaramine by the method (see the scheme below) described in Norezo Organic 'Chemistry (J. Org. Chem.), Vol. 63, p. 589 (1989). Is converted to

By the way, the 21-silyloxypredanane derivative (I) which is a starting material of the above step 1, for example, (5,7a, 2OS) —7-hydroxy-1-20-methylpredaner 3-one-1 A method for synthesizing 1-onore (1,1-dimethylethyl) dimethinolesilinolate is known [Bioorg. Med. Chem., 8 vol. Page 259 (2000); see WO 01/79255]. However, the fact that (5α, 7a, 2OS) -17-hydroxy-20_methylpredana-13-one-12-ol (1,1-dimethylethyl) dimethylsilyl ether can be purified by the recrystallization method unknown.

Compound (II) in which the 7-hydroxyl group of compound (I) is protected with a benzoyl group, that is, (5α, 7a, 20S) — 21 — (((1,1-dimethylethylenole) dimethylsilyl ) (Oxy) '20 -methylpredana_3-one-17-oneole benzoate can be purified by a recrystallization method which can be easily carried out industrially. That is, (5α, 7a, 2OS) _7-hydroxy-12-methylpredana-13-one-21-ol (1,1'-dimethinoleethyl) dimethylsilyl ether and (5α, 7a) , 20 S) — 21 _ (((1,1-dimethylethyl) dimethylsilyl) 1 20 — methylpredaner 3-one 1 7-all benzoate (ie, 21-silyl _ 20 — Since the methylpredanane derivative (IV)) has crystallinity, the crude product obtained from the process for producing them is subjected to a recrystallization operation that can be easily carried out industrially, for example, by heating the crude product in the presence of a solvent. Purification by the recrystallization method in which the desired product is precipitated from the solvent by cooling after dissolution in the solvent, or the suspension washing method in which the crude product is suspended and washed in the solvent and the contaminants are dissolved in the solvent and purified can do.

Hereinafter, an example of a purification method (crystallization purification method) of the 21-silyl_20-methylpredanane derivative (IV) by crystallization will be described.

Step 3: Crystal purification method of 21-silyl-20-methylpredanane derivative (IV)

The crystal purification of the 21-silyl mono20-methylpredanane derivative (IV) can be usually performed in a solvent.

As the solvent, a solvent in which the solubility of the 21-silyl- 20-methylpredanane derivative (IV) in a solvent (hereinafter, simply referred to as “solubility”) is large at a high temperature and small at a low temperature is preferable. The case of high temperature includes, for example, heating under reflux of the solvent, and the case of low temperature includes, for example, near the freezing point of the solvent when the freezing point of the solvent is below room temperature or above room temperature. The room temperature referred to in the present specification is 15 to 30 ° C. The difference between the solubility at a high temperature and the solubility at a low temperature is preferably as large as possible, but it is preferable that the solubility at a high temperature is at least 10% larger than the solubility at a low temperature.

Further, a solvent in which the solubility of the 21-silyl-20-methylpredanane derivative (IV) is 50% or less, preferably 10% or less based on the weight of the solvent at a low temperature, for example, room temperature, is preferable.

Solvents that have low solubility at low temperatures and high solubility at high temperatures Such solvents may be used, but preferred are organic solvents, for example, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, methinolecyclohexane, octane, and isootatan; benzene, toluene, o-- Aromatic hydrocarbons such as xylene, m-xylene, and xylene; ethers such as getyl ether, diisopropyl ether, di (n-propyl) ether, di (n_butyl) ether, tetrahydrofuran, and tetrahydropyran; Examples include esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate, and mixtures thereof.

The amount of the solvent to be used is not particularly limited, but is usually in the range of 0.001 to 100% by weight, preferably 0.00, relative to the 21-silyl_20_methylpredanane derivative (IV). 1 to: The range is L00 weight times.

1- silyl - The 2 0- suitable solvent, especially in the crystal purification of methylprednisolone Turan derivative (IV), when R "represents a hydrogen atom, an ether (particularly diisopropyl ether); the R ⁴¹ is Benzoiru group When represented, aliphatic hydrocarbons (especially hexanes) are mentioned.

The temperature for crystal refining is 14 hours. The temperature is preferably from C to 200 ° C., particularly preferably from 120 ° C. to 180 ° C., or the range of the boiling point of the solvent at atmospheric pressure. The pressure is preferably from atmospheric pressure to reduced pressure. When the pressure is reduced, the pressure range is preferably such that the temperature range is from 140 ° C. to 200 ° C.

The method for crystal purification is as follows: The power of adding the above solvent to the crude crystal of 21-silyl20-methylpredanane derivative (IV) \ The 21-silyl- 20-methylpregnane derivative (IV) Add the crude crystals and stir. Heat as necessary to confirm that the crude crystals have dissolved, then allow to cool to precipitate crystals. At the time of cooling, a seed crystal may be added as an aid for crystal precipitation, if necessary.

When the reaction extract containing the crude crystals of the 21-silyl-1 20-methylpredanane derivative (IV) is heated and concentrated under atmospheric pressure or reduced pressure to obtain crude crystals, the above solvent is added to the above solvent. And then purify the crystals without obtaining crude crystals. A seed crystal may be added as an aid for crystal precipitation at the time of cooling after replacement by solvent concentration.

In these crystal purifications, the time for crystal precipitation or the time to remove impurities is such that the target compound dissolved in the solvent is precipitated at the temperature at the time of crystal purification, and the target compound is saturated in the solvent. Alternatively, it is desirable that the time be such that the impurities contained in the target compound are sufficiently dissolved in the solvent and the impurities are saturated in the solvent, for example, in the range of 0.01 to 100 hours. Preferably, the range is from 0.1 to 24 hours.

Separation of crystals from the obtained solution containing crystals is performed by developing the solution containing crystals on filter paper or filter cloth and filtering. If necessary, the crystals may be washed with the above solvent, or may be dried with a dryer or the like to remove the solvent.

Hereinafter, the present invention will be described more specifically with reference to Examples. 'The present invention is not limited to these Examples.

Reference Example 1 Synthesis of (7α, 20S) -7,2 1-dihydroxy-20-methylpredana — 1,4-1-gen-3-one

(7 α, 20 S) — 7—Hydroxy 3 _Oxopredana-1, 4-Gen-1

To 200.0 g (54.8 mm o 1) ′ of 20—canolenorehdehide was added 20 nmol of ethanol, and the mixture was cooled with ice while stirring. To this solution, 0.61 g (16.lmmo1) of sodium borohydride was added in several portions, and after the addition was completed, the mixture was stirred for 1 hour under ice-cooling. The reaction solution was neutralized by adding 3% hydrochloric acid, and after adding 20 O.m1 of water, ethanol was distilled off under reduced pressure. The crude crystals precipitated in the residue were collected by filtration and washed with water. Toluene is added to the obtained crude crystals, which is heated. After water in the crude crystals is removed by azeotropic distillation with toluene, the toluene is distilled off under reduced pressure to obtain the following physical properties (7α, 2 OS) -7,21-Dihydroxy-20-methylpredaner 1,4-Gen-1-one 18.8 g (93% yield) was obtained.

IH- NMR spectrum (27 OMH z, CD C 1 3, TMS, ppm) δ: 0. 7 6 5 (s, 3 H), 1. 048 (d, 3 H, J = 6. 6 H z), 1.238 (s, 3H), 2.490 (dd, 1H, J = 3.3, 13.9Hz), 2.7 3 7 (ddd, 1 H, J = 1.8, 3.3, 13.9 Hz), 3.36 6 (dd, 1 H, J = 6.9, 10.2 Hz) , 3.635 (dd, 1H, J = 3.3, 10.2Hz), 4.041 (brs, 1H), 6.143 (m, 1H), 6. 2 5 3 (dd, 1 H, J = 1.8, 10.1 Hz), 7.02 (d, 1 H, J = 10.1 Hz).

Reference Example 2 Synthesis of (5α, 7a, 2OS) — 7,21-dihydroxy-l-20-methylpregna-3-one.

Under a nitrogen atmosphere, liquid ammonia (70 ml) was stored in a three-necked flask with a capacity of 20 Om1 at 178 ° C, and then 0.43 g (58 lmmol) of lithium metal was removed at 178 ° C. While keeping it. After complete dissolution of lithium metal, the mixture was obtained by the method of Reference Example 1 (7α, 2OS) —7,21-dihydroxy_20—methinolepredaner 1,4_gen-1 A solution of 2.0 g (5.81 mmo 1) of 3-one suspended in 50 ml of tetrahydrofuran was slowly added dropwise, and after completion of the addition, the mixture was stirred at 178 ° C for 2 hours. After adding 3.73 g (69.7 mmo 1) of ammonium chloride to the reaction solution, the reaction solution was stirred for 12 hours while gradually warming to room temperature to remove ammonia. To the obtained white residue, toluene 5 Om 1 and 3% hydrochloric acid 10 Om 1 were added and dissolved, and an organic layer and an aqueous layer were separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, and 2.09 g of the obtained crude product was subjected to silica gel column chromatography (developing solution: ethyl ethyl acetate = 2/1 (volume (5 ratio, 7 a, 2 OS) — 7, 21-dihydroxy — 20-methylpredana-3-one having the following properties (1.32 g): (Yield 65%).

(5 α, 7 a, 2 O S) — 7,21-dihydroxy-20-methylpredana-1-one

- NMR spectra (2 7 OMH z, CDC 1 3, TMS, ppm) δ: 0.

7 10 (s, 3H), 1.00 7 (s, 3H), 1.044 (d, 3H, J = 6.9Hz), 1.0-2.5 (m, 22H ), 3.339 (dd, 1H, J = 6. 9, 10.9 Hz) 3.6 1 4 (dd 1 HJ = 3.0, 10.9 Hz), 3.84-3.85 (brs, 1H).

Reference Example 3 (5 a, 7 a, 2 OS) — 7-Hydroxy-1 20 -methylpredana-1 3 -one 2 1 honole (1,1,1-dimethylethyl) Synthesis of dimethylsilinoleyl ether (21-silyl) Of oxypredanane derivative (I))

In a nitrogen atmosphere, a flask with a capacity of 50 Om1 was obtained by the method of Reference Example 2 (5, 7α, '2 OS) -7,21-dihydroxy-20-methylpredana-3-one 56 35 g (0.162 mol), 14.8 g (0.217 mo1) of imidazonole and 25 Om1 of tetrahydrofuran were added, dissolved with stirring, and cooled with ice. To this solution was added 26.2 g (0.174mO1) of tert-butyldimethylchlorosilane, and after the addition was completed, the mixture was stirred for 15 minutes under ice-cooling, and then heated to room temperature. Warmed and stirred for 1 hour. The reaction solution was poured into 500 ml of water, and extracted twice with 250 ml of ethyl acetate. The organic layer from which the aqueous layer was separated was washed successively with 250 ml of water and 250 ml of a saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and then crude (5H, 7A, 20S) There was obtained 6.9.8 g of 1-hydroxy-1-20-methynolepredaner 3-one-one-one-nor '' (1,1-dimethylethynole) dimethylsilinole ether.

3-on--2 1 -all (1,1,1-di <chinoreechinore) Dimethinoreshi! ; Purification of the residue (crystal purification method of 21--silinole 20-methylpredanane derivative (IV))

Crude (5 strains, 7a, 20S) obtained in Reference Example 3 — 7-Hydroxy-1 20-methylonepredaner 3-one-1 1-onole (1,1-dimethynoleethyl) dimethylsilyl ether 6 9.98 g of diisopropyl ether (140 ml) was added, and the mixture was stirred at room temperature for 1 hour. After stirring, filtration was performed, and the obtained crystals were washed with diisopropyl ether (169 m1) and dried under reduced pressure to have the following physical properties (5a, 7a, 2 OS) — 7-hydroxy-1 2 0-Methylpredana-3-one-one 2-one- (1,1-dimethinoleethynole) dimethylsilyl ether 3 7.39 g (A total yield of 50% through Reference Example 3 and Example 1).

Lfi—NMR spectrum (27 OMHz CD C 1 a, TMS, ppm) 8: 029 (s, 6H), 0.699 (s, 3H), 0.8 9 0 (s, 9H), 0.992 (d, 3H, J = 7.9Hz), 1.007 (s, 3H), 1.1—2

4 (m, 22H), 3.26 4 (dd, 1H, J = 7.9, 9.9Hz), 3.

57 0 (dd, 1 H, J = 3.0, 9.9 Hz), 38 7 4 (b d, 1 H, J =, 1.7 Hz).

Melting point: 2 1 1 to 2 17 ° C

Example 2 — (5 α, — 7, _ 20 S) — 21 — (((1-Dimethylethizole) dimethinolesilinole) oxy) _ 20 —Methylpredana-3-one- 7-ol Synthesis of benzoate (Step to obtain predanane derivative (II))

(5 (x, 7a, 2 OS) —7—Hydroxy-1 20—Methinole Predana 3-One—1 in a flask having a capacity of 500 ml under a nitrogen atmosphere. 1-Wall (1, 1-Dimethinoleethinole) Dimethinolesilinole ethenole 37.39 g (80: 8 mmo1), 4-dimethylaminopyridine 9.7 g (79. 4 mmo1), pyridine 32.6 ml (403 mmo1), potassium carbonate 11.2 g (81.0 mmo1) and toluene 370 ml Benzoinolechloride 23.46 ml (202 mmo 1) was slowly added dropwise to this solution, and after the addition was completed, the mixture was stirred for 15 minutes under ice cooling, and then heated to reflux. The reaction solution was developed in 300 ml of water, the organic layer and the aqueous layer were separated, and the aqueous layer was re-extracted with 300 ml of toluene. Aqueous saturated sodium bicarbonate solution 300 m 1 The mixture was washed successively with water (300 ml), diluted hydrochloric acid (198 ml) (prepared from 33 ml of 35% hydrochloric acid and water (149 ml)) and water (300 ml). After drying over sodium sulfate and concentrating by filtration, the crude (5,7a, .20S) -210 ((((1,1-dimethylethyl) dimethylsilyl) methoxy) -20-methinolev regna-1 3-on-7-onole benzoate 55.1 g was obtained.

Example 3 (5α, 7α, 20S) 1 2 1 — (((1) 1-dimethylethyl) G Purification of methylsilyl) oxy) -20-methinolepredaner 3-one-one 7-ol benzoate (Method for crystal purification of 21-silyl-one 20-methylpredanane derivative (IV))

Crude (5α, 7a, 20S) —21 _ (((1,1,1-dimethylethyl) dimethylsilyl) obtained in Example 2) -20_methylpredaner 3-one-one Hexane 20 Om1 was added to 55.1 g of 7-all benzoate, and the mixture was heated to 65 ° C and dissolved. After confirming dissolution, the mixture was stirred for 15 minutes and cooled. After stirring for 15 minutes under ice-cooling, the mixture was filtered and the precipitate was washed twice with hexane 5 Om1 cooled under ice-cooling. The precipitate has the following properties by drying under reduced pressure: (5α, 7a, 20S) —21 — (((1,1-dimethylethyl) dimethylsilyl) oxy) 1 20—Methylpredna 13 26.2 g of 1-one-7-all benzoate was obtained (total yield of 57% through Examples 2 and 3).

ifi one NMR spectra (2 7 OMH z, CD C 1 3, chloroform reference (7. 2 6 ppm) ppm) δ - 0. 0 0 5 (s, 6 H), 0. 7 2 1 (s , 3H), 0.886 (s, 9H), 0.985 (d, 3H, J = 5.9Hz), 1.79 (s, 3H), 1 0—1.8 (m, 15 H), 1.9-2.5 (m, 7 H), 3.17 1 (dd, 1 H, J = 8.9, 9.9 Hz ), 3.543 (dd, 1H, J = 3.0, 9.9Hz), 5.184 (bd, lH, J = 2.OHz), 7.464 (dd, 2H, J = 6.9, 7.9Hz), 7.576 (dd, 1H, J = 6.9, 6.9Hz), 8.Oil (d, 2 H, J = 7.9 Hz).

Melting point: 16 6 ~ 16 9 ° C '

Example 4 Synthesis of (5a, 7a, 2OS) —21-hydroxy-3-oxo-20-methinolepredanan-17-ol benzoate (Step of Obtaining 21-Hydroxypregnane Derivative (III))

(5,7a, 20S) 1-2 1 — (((1,1,1-dimethylethyl) dimethylsilyl) oxy) obtained by the method of Example 3 in a 5 Om1 three-necked flask One 3-On _ 7-Ornole Benzoate 1.0 g (1.76 mmo 1) was dissolved in 1 Om 1 of tetrahydrofuran, 0.6 ml of 9% hydrochloric acid was added, and the mixture was stirred at 40 ° C for 7 hours. After the completion of the reaction, the reaction solution was concentrated, and extracted by adding 20 ml of water and 3 Om1 of ethyl acetate. The aqueous layer was separated, and the separated aqueous layer was further extracted with 20 ml of ethyl acetate. The organic layers were combined, washed twice with 10 lii 1 of saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 0.80 g of crude (5-hydroxy, 7a, 20S) —21-hydroxy-3-oxo-1 20-methylpredanane_7-ol benzoate having the following physical properties. . Acetone (2 ml) was added to the obtained crude product, and the mixture was dissolved by heating and cooled with ice. The crystals were filtered, and the precipitate was washed with 0.5 ml of water-cooled acetone. The precipitate was dried under reduced pressure to give (5 ο ;, 7a, 2 OS) — 21 1-hydroxy-1-3-oxo-1 2-methylinolepredanan — 7-all benzoate 0.30 g. Was obtained (38% yield).

IH- NMR spectra (2 7 0MH z, CD C 1 3, TMS, ppm) δ: 0. 7 2 9 (3 H, s), 1. 0 4 4 (3 H, d, J = 5. 9 Hz), 1.080 (3H, s), 0.9-2.5 (22H, m), 3.341 (1H, dd, J = 5.9, 9. 9Hz), 3.587 (1H, dd, J = 2.0, 9.9Hz), 5.192 (1H, bs), 7.475 (2H, d, J = 7.9 Hz), 7.57 (1 H, dd, J = 6.9, 7.9 Hz), 8.06 (2H, d, J = 6. 9 Hz).

Melting point: 156-16-1 ° C

Example 5 (5a, 7a, 2OS) —Synthesis of 21-hydroxy-13-oxo —20-methylpredanane-17-ol benzoate (Step of obtaining 21-hydroxypregnane derivative (III)) )

Obtained by the method of Example 3 in a 5 Om1 three-necked flask (5α, 7a, 20

S) 1 2 1— (((1,1-dimethylethyl) dimethylsilyl) oxy) 1 2 0 1-methylpredaner 3-one-1 7-ol benzoate 5.00 g (8.82 mm o 1) of tetrahydrofuran Dissolve in 5 Om 1, then 18% hydrochloric acid 1.7

4 ml was added and the mixture was stirred at 40 ° C for 7 hours. After the reaction is completed, the reaction mixture is concentrated and acetic acid Ethyl 5 Om1 was added for extraction. The aqueous layer was separated, washed with saturated aqueous sodium hydrogen carbonate (3 Om1), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 3.99 g of crude (5,7a, 20S) -21-hydroxy-3-oxo-1-20-methylprednan-17-ol benzoate in the same manner as in Example 4. Was. 14 ml of acetone was added to the obtained crude product, which was dissolved by heating and cooled with ice. The crystals were filtered and ice-cooled acetone 0.

The precipitate was washed with 5 ml. The precipitate was dried under reduced pressure to obtain 2.60 g of (5 o !, 7a, 2 OS) -21-hydroxy-3-oxo-20-methylpredanane-17-all benzoate ( Yield 65%).

Reference Example 4 (5,7,2 OS) — 21—Hydroxy-1-3- (spiro-1,2- (1,, 3′-dioxolane)) —20—Methinolepredanane-1—7—Ornole benzoate Synthesis of

(5a, 7a, 20S) obtained by the method of Example 4—21-hydroxy_3—oxo-1 20-methinolepredanane-1 7-onole benzoate 16.59 g (3

6.65 mm o 1) is dissolved in 166 ml of tonolene, ethylene glycolone 6.0 g (258 mm o 1), p_toluenesulfonic acid monohydrate 0.4 9 g (2.

6mmo 1) was added, and the mixture was stirred under heating and reflux for 40 hours. After the reaction was completed, the reaction solution was added to a saturated aqueous solution of sodium bicarbonate (10 Om1) and washed. After separating the aqueous layer, the organic layer was washed with 100 ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, and the resulting crude product (16.2 g) was purified by silica gel column chromatography (developing solution: ethyl acetate hexane = 1/6). Has the following physical properties (5α,

7 a, 20 S) —— 21—Hydroxy 3 -— (spiro-1,2,1,1- (1,, 3,1-dioxolane)) — 20-Methylpredanane-1-7-ol benzoate 5.16 g Was obtained (yield 28%).

IH- NMR spectra (2 7 0MH z, CDC 1 3, TMS, ppm) S: 0. 6 9 9 (s, 3 H), 0. 8 8 2 (s, 3 H), 1. 0 3 9 (d, 3 H, J = 6.9 Hz), 1.00-2.10 (m, 22 H), 3.32 8 (dd, 1 H, J = 5.9, 9.9 H z), 3.57 7 (dd, 1 H, J = 3.0, 9.9 H z), 3.83-3.93 (m, 4H), 5.159 (brd, 1H, J = 2.OHz), 7.48 (dd, 2H, J = 6.9 , 6.9 Hz), 7.59 (d, 1 H, J = 6.9 Hz), 8.056 (d, 2 H, J = 6.9 Hz).

Reference Example 5 (5α, 7a, 2 OS) — 2 1—Hydroxy 3 -— (Spiro-1,2,-(1 ′, 3, dioxolane)) One 20-Methinolepredanane — 7—Onoré benzoate Synthesis of

(5α, 7a, 2 OS) obtained by the method of Example 4 — 21—hydroxy-13-oxo-20—methinolepredanane-17-ozle benzoate 3.97 g (8. 7.7 mm o 1) was dissolved in 49 m 1 of toluene, and ethylene glycol 2.75 g (44.3 mm o 1), -tonoreensnorephonic acid monohydrate 0.05 g (0. 3 mmo 1) was added, and the mixture was stirred for 4 hours while heating under reflux. After completion of the reaction, the reaction solution was added to 10 ml of a saturated aqueous solution of sodium bicarbonate and washed. After separating the aqueous layer, the organic layer was washed with saturated saline 1 Om 1. The organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, and 4.71 g of the obtained crude product was purified by silica gel column chromatography (developing solution: ethyl acetate Z hexane = 1Z6) to give a crude product. As in Reference Example 4, (5h, 7a, 2OS) — 21—Hydroxy 3 -— (spiro-1 ′) — (1,1,3, dioxolan)) — 20—methinolepredanane There were obtained 3.44 g of 7-onolle benzoate (yield: 79%).

Reference Example 6 (5α, 7a, 2OS) 1 20 _ forminoleate 3-(spiro_2, 1 (1,, 3 'dioxolane))-Predanane 1 7-All benzoate

(5α, 7a, 20S) —21-Hydroxy-13- (spiro-1,2- (1,1,3′-dioxolan)) obtained by the method of Reference Example 4—20-Methylpre 1-Nanone 7-Ornole Benzoate 2 1 · 4 g (43 mm o 1), 2, 2, 6, 6-Tetramethinole 1-Piperidienoleoxy, Freeradicanole 0.13 g (0.8 mm o 1) in dichloromethane (2,4 ml) and ice-cooled, and dissolve 0.51 g (4.3 mm o 1) of lithium bromide in 21 ml of water. Ice-cooled solution It was added below and stirred vigorously. Next, an aqueous solution obtained by adding sodium bicarbonate (1.0 g) to an aqueous solution of sodium hypochlorite (2.64 wt%, 108 ml, 40 mmo 1) was added to this mixture. The mixture was allowed to react under ice-cooling for 2 hours. After completion of the reaction, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with dichloromethane (3 ◦m 1 X 2). The extract was combined with the organic layer, washed successively with water (50 ml × 2) and saturated brine (20 ml), dried over anhydrous magnesium sulfate, and concentrated. Purification by gel force ram chromatography (developing solution: ethyl acetate hexane = 1/4 (volume ratio)) gives the following physical properties (5α,

7a, 2OS) -20-formyl-3- (spiro-1 '-(1,, 3'-dioxolane))-prednan-1-7-ol benzoate 16.9 g was obtained (yield 7).

9%).

Ifi- NMR spectra (2 7 OMH z, CD C 1 3, TMS, ppm) δ: 0. 7 2 5 (s, 3 H), 0. 8 8 6 (s, 3 H), 1. 10 8 (d, 3H, J = 6.9Hz), 1.13-1.97 (m, 21H), 2.30-2.38 (m, 1H) , 3.830-3.929 (m, 4H), 5.166 (m, 1H), 7.483 (dd, 2H, J = 6.9, 6. 9Hz), 7.580 (ddd, 1H, J = 2.0, 6.9, 6.9Hz), 8.0050 (dd, 2H, J = 2.0, 6.9 Hz), 9.5 18 (d, 1 H, J = 3.0 Hz).

Industrial applicability

According to the present invention, a predanane derivative useful as a squalamine synthesis intermediate or the like can be efficiently produced in a short step from easily available raw materials. This application is based on a patent application No. 201-3868608 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. Formula (I)

(Wherein, I ¹ , R ² and R ³ each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a group which may have a substituent. A good alkyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.

Formula (II) characterized in that a hydroxyl group is protected in the presence of a base by a 21-silyloxypredanane derivative represented by

(In the formula, RR ² and R ³ have the same meanings as described above, and R ⁴ represents a hydroxyl-protecting group.)

A method for producing a predanane derivative represented by the formula:

2. General formula (II)

(Wherein, I ¹ , R ² and R ³ each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a group which may have a substituent. A good alkynyl group, a substituted or unsubstituted aryl group or an optionally substituted aralkyl group, and R ⁴ represents a hydroxyl-protecting group.)

Wherein the silyl group of the silyloxy group at the 21-position of the predanane derivative represented by the formula is deprotected:

(Wherein, R ⁴ has the same meaning as described above.) A method for producing a 2-hydroxypredanane conductor represented by the formula:

3. Equation (IV)

(In the formula, R "represents a hydrogen atom or a benzoyl group.) A method for purifying (((1,1,1>)-methyl) -20-methinolepredanane derivative, wherein the 21 (((1,1,1-dimethylethyl) dimethylsilyl) -age 20) -methylbut derivative A method characterized by crystallization.

4. Equation (II-1)

(5α, 7a, 20S) — 21 — (((1,1-dimethylethyl) dimethylsilyl)) 20-methylpredaner 3-one-one 7-all benzoate.