WO2003051904A1 - Procede de production d'un derive de pregnane - Google Patents

Procede de production d'un derive de pregnane Download PDF

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WO2003051904A1
WO2003051904A1 PCT/JP2002/011547 JP0211547W WO03051904A1 WO 2003051904 A1 WO2003051904 A1 WO 2003051904A1 JP 0211547 W JP0211547 W JP 0211547W WO 03051904 A1 WO03051904 A1 WO 03051904A1
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group
derivative
substituent
formula
chloride
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PCT/JP2002/011547
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Japanese (ja)
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Makoto Nakazawa
Shigeo Ohzono
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Kuraray Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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 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.).
  • 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.
  • 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.
  • stigmasterol used as a starting material can be obtained at low cost, but it requires 20 steps to synthesize squalamine.
  • 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.
  • 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.
  • the present inventors have proposed a method for forming the 21-position hydroxyl group of (5 ⁇ , 7a, 20S) -17,21-dihydroxy-1 20-methylpredana_3_one.
  • Protected derivatives such as (5 ⁇ , 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.
  • 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.
  • 21-silyloxypredanane derivative (I) or compound (I) wherein a hydroxyl group is protected in the presence of a base.
  • 21-hydroxypredanane derivative (III) represented by the following formula:
  • 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
  • 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.
  • 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.
  • 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.
  • substituents 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.
  • These alkyl group and alkynyl group may have a substituent.
  • substituents examples 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.
  • 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.
  • substituents examples 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.
  • 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.
  • substituent examples 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
  • 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.
  • 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.
  • 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.
  • 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,
  • 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
  • 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.
  • alkyl group or aralkyl group is used as a hydroxyl-protecting group.
  • aldehyde alkynole / peroxide such as tert-butynochloride and tert-amyl chloride; benzinolek mouth, benzinoleb mid, o-methinolebenzyslek mouth, m-methinolebenzinorecro Lido, ⁇ -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
  • 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.
  • acetyl chloride 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, be
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the reaction is carried out using 1-methoxymethyl chloride, 1-methoxymethyl bromide, benzyloxymethyl chloride, and p-methoxybenzyloxy.
  • 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,
  • 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.
  • 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.
  • 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
  • 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.
  • two or more bases may 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, (5 ⁇ , 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.
  • a salt or an acid coexist in the reaction system.
  • 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.
  • 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.
  • 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.
  • 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.
  • a solvent 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.
  • 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).
  • 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.
  • the reaction mixture is poured into saline or water and extracted with an organic solvent such as getyl ether, ethyl acetate, methylene chloride.
  • an organic solvent such as getyl ether, ethyl acetate, methylene chloride.
  • 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.
  • This compound reacts with getylphosphono-1-methyl-2-butanone to give (5 ⁇ , 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
  • 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].
  • the fact that (5 ⁇ , 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, (5 ⁇ , 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.
  • 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.
  • 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
  • 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.
  • Solvents that have low solubility at low temperatures and high solubility at high temperatures 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a flask with a capacity of 50 Om1 was obtained by the method of Reference Example 2 (5, 7 ⁇ , '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.
  • 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.
  • 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 (5 ⁇ , 7 ⁇ , 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))
  • the precipitate has the following properties by drying under reduced pressure: (5 ⁇ , 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).
  • 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.
  • 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.
  • the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with dichloromethane (3 ⁇ m 1 X 2).
  • 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.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un procédé de production d'un dérivé de 21-hydroxypregnane de formule (III), caractérisé par la protection du groupe hydroxy en position 7 d'un composé de formule (I), et ultérieurement par l'élimination du groupe silyle de protection en position 21. (Dans les formules, R1, R2 et R3 représentent chacun indépendamment un alkyle, un alcényle, un alkynyle, un aryle ou un arylkyle éventuellement substitué ; et R4 représente un groupe de protection hydroxy.) Par ce procédé, un dérivé de pregnane utile en tant que, par exemple, intermédiaire pour la squalamine, peut être produit de manière efficace, par le biais d'un petit nombre d'étapes, à partir de matières facilement disponibles.
PCT/JP2002/011547 2001-12-19 2002-11-06 Procede de production d'un derive de pregnane WO2003051904A1 (fr)

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JP2001386808 2001-12-19
JP2001-386808 2001-12-19

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020552A1 (fr) * 2000-09-08 2002-03-14 Kuraray Co., Ltd. Procédé de préparation de dérivés de prégnane

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020552A1 (fr) * 2000-09-08 2002-03-14 Kuraray Co., Ltd. Procédé de préparation de dérivés de prégnane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HONG-SEOK KIM ET AL., BIOORG. MED. CHEM., vol. 8, no. 8, 2000, pages 2059 - 2065, XP002949909 *

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