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WO2006049038A1 - Procédé de synthèse de dérivé de 3-(hydroxyméthyl)morpholine optiquement actif - Google Patents

Procédé de synthèse de dérivé de 3-(hydroxyméthyl)morpholine optiquement actif Download PDF

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WO2006049038A1
WO2006049038A1 PCT/JP2005/019565 JP2005019565W WO2006049038A1 WO 2006049038 A1 WO2006049038 A1 WO 2006049038A1 JP 2005019565 W JP2005019565 W JP 2005019565W WO 2006049038 A1 WO2006049038 A1 WO 2006049038A1
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group
optically active
carbon atoms
chemical
formula
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Kouhei Mori
Akira Nishiyama
Nobuo Nagashima
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Kaneka Corp
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Kaneka Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/13—Saturated ethers containing hydroxy or O-metal groups
    • C07C43/135—Saturated ethers containing hydroxy or O-metal groups having more than one ether bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1785—Unsaturated ethers containing hydroxy or O-metal groups having more than one ether bound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1786—Unsaturated ethers containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a method for producing an optically active 3- (hydroxymethyl) morpholine derivative useful as a pharmaceutical intermediate, and a background art relating to an intermediate useful for the production of the morpholine derivative.
  • the yield of the chloroacetyl ester process is remarkably low, and the yield of other processes is also moderate, so the total yield is low.
  • it is necessary to use a large amount of expensive bis (2-methoxyethoxy) aluminum hydride in the reduction process and it cannot be said that it is an efficient production method considering the problem of yield.
  • the process is long and it is necessary to use an expensive reagent such as iodomethyl-triethylsilane.
  • the yield of the esterification process and the reduction process is extremely low, the total yield is extremely low, which is not a practical production method.
  • Patent Document 1 WO98 / 50035
  • Non-Patent Document 1 CS, Perkin Trans 1. 1985, 12. 2577 Disclosure of the invention
  • the object of the present invention is to provide an optically active 3- (hydroxymethyl) morpholine derivative useful as a pharmaceutical intermediate, which can be easily produced at low cost and easily available raw materials, and is practical for industrial production. And an intermediate useful for the preparation of the morpholine derivative.
  • the present invention relates to the general formula (1);
  • R 1 may have an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted aryl group having 6 to 20 carbon atoms, or an optionally substituted group. Represents an aralkyl group having 7 to 20 carbon atoms. ) Or general formula (4);
  • R 2 may have an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted aryl group having 6 to 20 carbon atoms, or an optionally substituted group. It represents an aralkyl group having 7 to 20 carbon atoms, and R 1 and R 2 may be the same or different.
  • the present invention provides a general formula (5);
  • the present invention provides an optically active glycerin derivative represented by the formula (1) or the formula (2). And a method for producing an optically active glycerin derivative represented by the above formula (3) or the above formula (4), wherein
  • the present invention provides an optically active glycerin derivative represented by the above formula (3) or the above formula (4) having the general formula (7);
  • P 2 is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a substituent, a substituent, and a alkenyl group having 2 to 20 carbon atoms, It has a substituent! / May be an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, a hydroxyl group, a methoxy group, or a benzyloxy group.
  • optically active 3- (hydroxymethyl) morpholines can be produced simply and efficiently from inexpensive and readily available starting materials on a commercial scale. The best form to do
  • optically active glycidol derivative as a starting material of the present invention has the general formula (5);
  • P 1 represents a hydroxyl-protecting group
  • * represents an asymmetric carbon atom.
  • the hydroxyl-protecting group is not particularly limited as long as it is generally used as a hydroxyl-protecting group.
  • protecting groups such as methoxymethyl group, benzyloxymethyl group, methylthiomethyl group, ⁇ -methoxybenzyloxymethyl group, ⁇ -trobenzyloxymethyl group, tert-butoxymethyl group, 2-methoxy group.
  • Toximethyl group 2- (trimethylsilyl) ethoxymethyl group, tetrahydrovinyl group, tetrahydrofuranyl group, 1 ethoxyethyl group, 1-methyl-1 methoxy group
  • Ether-type protecting groups such as til, aryl, t- butyl, and cyclohexyl
  • benzyl-type protecting groups such as benzyl, p-methoxybenzyl, diphenylmethyl, phenethyl, and trimethylmethyl
  • trimethylsilyl Silyl-type protecting group such as acetyl group, triethylsilyl group, triisopropyl silyl group, t-butyldimethylsilyl group
  • An acyl- or aroyl-type protecting group a carbonate-type protecting group such as a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbon group, or a t
  • an ether-type protecting group from the viewpoint of the stability of the protecting group during the reaction or the ease of deprotection, an ether-type protecting group; a benzyl-type protecting group; or a silyl-type protecting group is preferable.
  • t-butyl group and benzyl group Particularly preferred are t-butyl group and benzyl group, and t-butyl group is most preferred from the viewpoint of the reactivity of the regioselective ring-opening reaction with 2-heptanol ethanol or ethylene glycol described later.
  • the stereochemistry of the asymmetric carbon may be either an absolute configuration force or S.
  • R-form may be optically pure R-form or S-form, or it may be a mixture of R-form with some amount of S-form or a mixture of S-form with some amount of R-form.
  • optically active glycidol derivative represented by the above general formula (5) can be obtained, for example, by the method described in Journal of the Chemical Society and hemical Communications (22), 1053-1054, 1980. It can be obtained by reacting phosphorus and alcohol to form an optically active chlorohydrin and then reacting with a base.
  • optically active glycerin derivative which is an important intermediate in the production method of the present invention is represented by the general formula (1);
  • X represents a halogen atom.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a chlorine atom or a bromine atom, and more preferably. Or a chlorine atom.
  • the optically active glycerin derivatives represented by the general formulas (1) and (2) are novel compounds not described in any literature that are useful as pharmaceutical intermediates.
  • R 1 and R 2 may have a substituent, and may be an alkyl group having 1 to 20 carbon atoms or a substituent. It may be! / May be an aryl group having 6 to 20 carbon atoms, or may have a substituent! / May be an aralkyl group having 7 to 20 carbon atoms. R 1 and R 2 may be the same or different. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; a nitrogen group; and 0 to 3 substituents.
  • Examples of the optionally substituted alkyl group having 1 to 20 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n butyl group, isobutyl group, s butyl group, t butyl group, n- Examples thereof include a pentyl group, an isopentyl group, an n-hexyl group, an n-octyl group, an n-dodecyl group, a tododecyl group, a chloromethyl group, a trichloromethyl group, and a trifluoromethyl group.
  • the aryl group having 6 to 20 carbon atoms which may have a substituent includes a phenyl group, a 1 naphthyl group, a 2 naphthyl group, a 2 methylphenol group, a 3 methylphenol group, and a pmethylphenol group.
  • the aralkyl group having 7 to 20 carbon atoms is a benzyl group, a 2-methylbenzyl group, a 3-methylbenzyl group, a 4-methylbenzyl group, a 2-methoxybenzyl group, a 3-ethoxybenzyl group, 1-phenyl group, 2-phenyl group, 1- (4-methylphenyl) ethyl group, 1- (4-methoxyphenyl) ethyl group, 3-phenylpropyl group, 2-phenylpropyl group, etc. can give.
  • R 1 or R 2 or both are a methyl group, an ethyl group, a phenyl group, a p-chlorophenyl group, or a p-methylphenyl group, more preferably R 1 or R 2 , Displacement force or both forces S methyl group, p-methylphenol group.
  • the direction force of R 1 and R 2 being the same is also preferred. Therefore, it is most preferable that R 1 and R 2 are the same and are a methyl group or a p-methylphenol group.
  • optically active glycerin derivatives represented by the general formulas (3) and (4) are novel compounds not described in any literature that are useful as pharmaceutical intermediates.
  • optically active 3 (hydroxymethyl) morpholine derivative which is the product of the present invention, is represented by the general formula (6);
  • P 2 has a hydrogen atom and a substituent, but may have an alkyl group having 1 to 20 carbon atoms and a substituent. ! / /, A carbon group having 2 to 20 carbon atoms, having a substituent! / May have an aryl group having 6 to 20 carbon atoms, or a carbon group having 7 to 20 carbon atoms which may have a substituent An aralkyl group, a hydroxyl group, a methoxy group, or a benzyloxy group.
  • substituents include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamido.
  • halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamido.
  • an alkylamino group having 1 to 12 carbon atoms a dialkylamino group having 1 to 12 carbon atoms, an aralkylamino group having 7 to 12 carbon atoms, a dialalkylamino group having 7 to 12 carbon atoms, and 1 to 1 carbon atoms 2 alkylsulfoamino groups, sulfonic acid groups, sulfonamido groups, azide groups, trifluoromethyl groups, carboxyl groups, acyl groups having 1 to 12 carbon atoms,
  • the alkenyl group having 2 to 20 carbon atoms may include a allyl group, a bur group, a 2-methyl probe group, and a butyr group.
  • P 2 is preferably a hydrogen atom, t-butyl group, aryl group, phenyl group, benzyl group, hydroxyl group, methoxy group, or benzyloxy group, more preferably a phenyl group or a benzyl group, and particularly preferably. Is a benzyl group.
  • the optically active 3- (hydroxymethyl) morpholine derivative represented by the general formula (6) may form a salt with an acid.
  • the acid include an optically active acid and a non-optically active acid.
  • the optically active acid include sulfonic acids such as camphorsulfonate; carboxylic acids such as malic acid, mandelic acid, and tartaric acid; N — (Benzenesulfol) An amino acid protected on nitrogen such as phenylalanine.
  • non-optically active acid which can be obtained at low cost, for example, mineral acids such as hydrogen chloride, hydrogen bromide, phosphoric acid and sulfuric acid; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; acetic acid and sulfur Examples thereof include carboxylic acids such as acids.
  • optically active 3- (hydroxymethyl) morpholine which is the final product of the present invention, is represented by the formula (8);
  • * represents an asymmetric carbon atom.
  • the optically active 3- (hydroxymethyl) morpholine represented by the general formula (8) may form a salt with an acid.
  • the acid include an optically active acid and a non-optically active acid.
  • the optically active acid include sulfonic acids such as camphor sulfonate; carboxylic acids such as malic acid, mandelic acid, and tartaric acid; N— Examples thereof include amino acids protected on nitrogen such as (benzenesulfol) furanalanine.
  • non-optically active acid which can be obtained at low cost, for example, mineral acids such as hydrogen chloride, hydrogen bromide, phosphoric acid and sulfuric acid; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; acetic acid and sulfur Examples thereof include carboxylic acids such as acids.
  • the optically active glycerin derivative represented by the above formula (1) is represented by the above formula (2) when ethylene glycol is used.
  • Each of the optically active glycerin derivatives represented is obtained.
  • Specific examples of 2-haloethanol used here include 2-fluoroethanol, 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, and the like. It is preferable to use black mouth ethanol.
  • the use amount of the 2-haloethanol or ethylene glycol is preferably 1 to: LOO-fold molar amount, more preferably 1 to 20 with respect to the optically active glycidol derivative (5). Double molar amount.
  • This step is preferably performed using a catalyst for the purpose of improving any one of shortening of the reaction time, improvement of the reaction yield, reduction of the reagent, suppression of by-products, and reduction of the reaction temperature.
  • the catalyst include boron trifluoride jetyl ether complex, lithium perchlorate, aluminum chloride, scandium chloride, zinc chloride, magnesium chloride, titanium tetrachloride, tin tetrachloride, hafnium chloride, zirconium chloride, yttrium Lewis acids such as triflate, scandium triflate, titanium propoxide, zirconium propoxide, or aluminum propoxide; Bronsted acids such as trifluoroacetic acid, trichlorodiacetic acid, acetic acid, propionic acid, pivalic acid, or benzoic acid; 4Quaternary ammonium salts such as tetraptyl ammonium, tetrabutyl ammonium bromide,
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc .
  • Alkaline earth metal hydroxides such as magnesium carbonate
  • alkali metal carbonates such as sodium carbonate, lithium carbonate or cesium carbonate
  • alkaline earth metal carbonates such as magnesium carbonate
  • boron trifluoride jetyl ether complex zinc chloride, titanium tetrachloride, tin tetrachloride, hafnium chloride, zirconium chloride, titanium propoxide, zirconium propoxide, aluminum propoxide, trichlorodiacetic acid, acetic acid, propion Acid, salt, tetraptyl ammonium, bromide tetraptyl ammonium, hydrogen sulfate tetrabutyl ammonium, cesium fluoride, potassium fluoride, sodium fluoride, calcium fluoride, sodium hydroxide , Potassium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate.
  • boron trifluoride jetyl ether complex zinc chloride, titanium tetrachloride, tin tetrachloride, hafnium chloride, zirconium chloride, titanium propoxide, zirconium propoxide, aluminum propoxide, trichlorodiacetic acid, acetic acid, propionic acid , Salt tetrabutyl ammonium, tetrabutyl ammonium bromide, tetrabutyl ammonium sulfate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate Especially preferred is cesium carbonate. These may be used alone or in combination of two or more.
  • the amount of the catalyst used may be the minimum amount at which the reaction proceeds smoothly.
  • the amount is preferably 0.001 to 10 times the molar amount, more preferably 0.01 to 3 times the molar amount relative to the optically active glycidol derivative (5).
  • the above-mentioned 2-haloethanol or ethylene glycol which is particularly necessary as a reaction solvent, can be used as the reaction solvent as it is.
  • a reaction solvent for example, water; ether solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether; ester solvents such as ethyl acetate and isopropyl acetate
  • Solvent Hydrocarbon solvent such as benzene, toluene, hexane, etc .; Ketone solvent such as acetone, methylethyl ketone, etc .; -Tolyl solvent such as acetonitrile, propio-tolyl; Halogen system such as methylene chloride, black mouth form, etc.
  • Solvents Amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxide solvents such as dimethylsulfoxide; Urea solvents such as dimethylpropylene urea; Phosphonic acids such as hexamethylphosphoric acid triamide
  • a triamide solvent may be used. Preferred are tetrahydrofuran, ethyl acetate, toluene and the like. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.
  • the amount of the reaction solvent used is preferably 50 times or less, more preferably 20 times or less, with respect to the optically active glycidol derivative (5).
  • the reaction temperature is preferably ⁇ 30 to 200 ° C., more preferably ⁇ 10 to 120 ° C. from the viewpoint of shortening the reaction time and improving the yield.
  • the reaction time is preferably 5 minutes to 24 hours, more preferably 30 minutes to 12 hours, from the viewpoint of yield improvement.
  • the method and order of addition of the optically active glycidol derivative represented by the above formula (5), 2-haloethanol or ethylene glycol, the additive, and the solvent during the reaction are not particularly limited.
  • a general process for obtaining a reaction fluid product may be performed.
  • excess raw materials and the reaction solvent are distilled off by the operation such as heating under reduced pressure as it is after the completion of the reaction, or water is added to the reaction solution after the completion of the reaction, and, if necessary, an aqueous sodium hydroxide solution, Add alkaline water solution such as sodium hydrogen carbonate aqueous solution or acid aqueous solution such as hydrochloric acid aqueous solution or sulfuric acid aqueous solution to neutralize the solution. Extraction is performed using a solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like.
  • the target product can be obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure.
  • the target product obtained in this way has sufficient purity that can be used in the subsequent step.
  • crystallization, fractionation The purity may be further increased by a general purification method such as distillation or column chromatography.
  • optical activity represented by the formula (3) or the formula (4) is obtained by sulfonating the hydroxyl group of the optically active glycerin derivative represented by the formula (1) or (2).
  • the process for producing an active glycerin derivative will be described.
  • the reaction solution obtained by the above-mentioned method may be used as it is, or an isolated and purified product may be used.
  • the optically active glycerin derivative represented by the formula (1) is sulphonylated
  • the optically active glycerin derivative represented by the formula (3) is converted into the formula (2).
  • the optically active glycerin derivative represented by the formula (4) can be obtained by sulfonylating the optically active glycerin derivative represented by formula (4).
  • This step can be performed by using a sulfonylating agent in the presence of a base.
  • a sulfonating agent include halogenated sulfol and sulfonic anhydride.
  • the halogenated sulfone include methane chloride chloride, ethane chloride chloride, chloromethane sulfol chloride, benzene sulfone chloride, p-methylbenzene sulfol chloride, and p-chlorobenzene sulphonate.
  • sulfonic acid anhydride examples include trifluoromethanesulfonic acid anhydride and the like.
  • Preferred is methanesulfuric chloride or p-methylbenzenesulfuric chloride. These may be used alone or in combination of two or more.
  • the amount of the sulfonylating agent to be used is preferably 1 to 10-fold mol amount, more preferably 1 to 4-fold mol amount based on the optically active glycerin derivative (1).
  • the amount of the optically active glycerin derivative (2) is preferably 2 to 20 times by mole, more preferably 2 to 8 times by mole.
  • the base is not particularly limited, but a tertiary amino acid. Examples include triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylbiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4 diazabicyclooctane, etc. . More preferred is triethylamine.
  • the amount of the base to be used is preferably 1 to 10-fold mol amount, more preferably 1 to 4-fold mol amount based on the optically active glycerin derivative (1).
  • the amount of the optically active glycerin derivative (2) is preferably 2 to 20 times the molar amount, more preferably 2 to 8 times the molar amount.
  • a base may be used as it is as a reaction solvent, or an ether solvent such as tetrahydrofuran, 1, 4 dioxane, ethylene glycol dimethyl ether; ethyl acetate, isopropyl acetate, etc.
  • ether solvent such as tetrahydrofuran, 1, 4 dioxane, ethylene glycol dimethyl ether; ethyl acetate, isopropyl acetate, etc.
  • Ester solvents hydrocarbon solvents such as benzene, toluene and hexane
  • ketone solvents such as acetone and methyl ethyl ketone
  • -tolyl solvents such as acetonitrile and propio-tolyl
  • Halogen solvents such as N, N dimethylformamide, N, N dimethylacetamide and other amide solvents; dimethyl sulfoxide and other sulfoxide solvents; dimethylpropylene urea and other urea solvents; hexamethylphosphonic acid triamide and the like
  • a phosphonic acid triamide solvent may be used.
  • tetrahydrofuran, ethyl acetate, toluene, etc. are mentioned. These may be used alone or in combination of two or more. When two or more types are used in combination, the mixing ratio is not particularly limited.
  • the amount of the reaction solvent used is preferably 50 times or less, more preferably 20 times or less, with respect to the optically active glycerin derivative (1) or (2).
  • the reaction temperature is preferably ⁇ 30 to 80 ° C., more preferably ⁇ 10 to 50 ° C. from the viewpoint of shortening the reaction time and improving the yield.
  • the reaction time is preferably 5 minutes to 20 hours, more preferably 30 minutes to 5 hours, from the viewpoint of improving the yield.
  • optically active glycerin derivative represented by the general formula (1) or (2), the sulfonylating agent, the base, and the solvent during the reaction are not particularly limited.
  • a general process for obtaining a reaction fluid product can be performed. That's fine.
  • the reaction solution after completion of the reaction is neutralized by adding water, and if necessary, an aqueous solution of sodium hydroxide aqueous solution, an aqueous alkali solution such as aqueous sodium hydrogen carbonate solution, or an aqueous acid solution such as aqueous hydrochloric acid solution or sulfuric acid aqueous solution.
  • the extraction operation is performed using a general extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like.
  • the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step. Purity may be further increased by general purification techniques such as analysis, fractional distillation, column chromatography and the like.
  • optically active glycerin derivative represented by the formula (3) or (4) and the general formula (7);
  • the reaction solution obtained by the above-mentioned method may be used as it is, or an isolated and purified product may be used.
  • optically active glycerin derivative (3) can be reacted with the amine (7), or the optically active glycerol derivative (4) can be reacted with the amine (7).
  • E) A morpholine derivative (6) can be obtained.
  • amine (7) include ammonia, hydroxyamines, and primary amines.
  • hydroxyamines include hydroxyamine, methoxyamine, ethoxyamine, and benzyloxyamine
  • primary amines include, for example, arylamine, methylamine, ethylamine, butylamine, t-butylamine, A-line, p-methoxy-aline, p-chloroa-line, p-aminophenol, p-methylaline, benzylamine, methoxybenzylamine, 1-phenethylamine and the like.
  • the amount of the amine (7) used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the optically active glycerin derivative (3) or (4). It is.
  • this reaction may be performed in the presence of a base different from ammine (7)!
  • the base is not particularly limited, but triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylbiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo Tertiary amines such as [2, 2, 2] octane; inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate Can be used.
  • triethylamine potassium carbonate and sodium carbonate, and more preferred is triethylamine.
  • the amount of the base used is preferably 1 to 20 times the molar amount, more preferably 1 to 5 times the molar amount relative to the optically active glycerin derivative (3) or (4).
  • the above-mentioned amine (7) which requires a reaction solvent in particular, can be used as the reaction solvent as it is.
  • the base is a tertiary amine, it can be used as a reaction solvent.
  • reaction solvent for example, water; alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,4 dioxane and ethylene glycol dimethyl ether; Ester solvents such as ethyl acetate and isopropyl acetate; hydrocarbon solvents such as benzene, toluene and hexane; ketone solvents such as acetone and methyl ethyl ketone; -tolyl solvents such as acetonitrile and propio-tolyl; Halogen solvents such as methylene chloride and chloroform; N, N dimethylformamide, amide solvents such as N, N dimethylacetamide; Sulfoxide solvents such as dimethyl sulfoxide; Urea solvents such as dimethylpropylene urea ; Phosphonic acid triamide such as hexamethylphosphonic acid
  • tetrahydrofuran, toluene, etc. are mentioned. These may be used alone or in combination of two or more. When two or more types are used in combination, the mixing ratio is not particularly limited.
  • the amount of the reaction solvent used is preferably 50 times weight or less, more preferably 20 times weight or less, relative to the compound (3) or (4).
  • the reaction temperature is preferably 0 to 200 ° C, more preferably 40 to 120 ° C, from the viewpoint of shortening the reaction time and improving the yield.
  • the reaction time is preferably 5 minutes to 30 hours, more preferably 30 minutes to 15 hours, from the viewpoint of improving the yield.
  • optically active glycerin derivative (3) or (4), amine (7), base, and reaction solvent during the reaction are not particularly limited.
  • a general treatment for obtaining a reaction fluid product may be performed.
  • the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution as necessary, and is extracted by a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene. Extraction is performed using hexane, etc. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by heating under reduced pressure or the like, the desired product is obtained.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization,
  • the purity may be further increased by a general purification method such as fractional distillation or column chromatography.
  • the stereochemistry of the asymmetric carbon of the optically active glycerin derivative (3) or (4) proceeds with inversion. That is, when the absolute configuration of the optically active glycerin derivative (3) or (4) is S, the absolute configuration of the 3- (hydroxymethyl) morpholine derivative (6) is R, and its optical purity is almost maintained. . Similarly, in the case of the absolute configuration of the optically active glycerin derivative (3) or (4), the absolute configuration of the 3- (hydroxymethyl) morpholine derivative (6) is S, and its optical purity is also high. Almost maintained.
  • the optical purity of the optically active glycidol derivative (5) as a raw material is such that the desired 3- (hydroxymethyl) morpholine derivative (6) and the final product 3- (hydroxy It is almost reflected in the optical purity of (methyl) morpholine (8). Therefore, 3- (hydroxymethyl) morpholine derivative (6) or 3- (hydroxymethyl) morpholine (8) with high optical purity was obtained.
  • glycidol derivative (5) with high optical purity was used as a raw material. It may be used as.
  • the optically active 3- (hydroxymethyl) morpholine derivative or the salt thereof represented by the formula (8) is produced by deprotecting the optically active 3- (hydroxymethyl) morpholine derivative (6).
  • the process to perform is demonstrated.
  • the type of protecting group It may be suitably selected according to the above.
  • Protective Groups in Organic Synthesis, 3nd Ed. Theodora W. Green, John 'Willi' and 'Sands. According to the method described in (JOHN WILEY & SONS) Publishing, 1999, pp. 17-200, it may be deprotected according to the protecting group.
  • P 2 is a protecting group of ammine
  • the above-mentioned Protective Groups in Organic Synthesis, 3nd Ed. Deprotection may be performed according to the methods described. Specifically, for example, when P 2 is an aryl group in the optically active 3- (hydroxymethyl) morpholine derivative (6), a base such as potassium t-butoxide is allowed to act in a solvent such as dimethyl sulfoxide. This can be deprotected. Further, when P 2 is a benzyl group, it can be deprotected by allowing hydrogen to act in a solvent such as methanol in the presence of a transition metal catalyst such as palladium carbon.
  • P 2 when P 2 is a hydroxyl group, a methoxy group, or a benzyloxy group, it can be deprotected by allowing hydrogen to act in a solvent such as ethanol in the presence of a transition metal catalyst such as a Raney nickel catalyst.
  • P 1 and P 2 may be deprotected simultaneously if they can be deprotected at the same time. It is preferable to perform deprotection at the same time because the process is simplified.
  • the condensed product was purified by silica gel column chromatography to obtain the title compound (2.10 g, yield: 78%, purity: 85% by weight).
  • a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added for hydrolysis, and the aqueous layer was separated.
  • the obtained organic layer was concentrated under reduced pressure and then purified by column chromatography to obtain a monotosyl compound (1.6 g, yield: 55%, purity: 90% by weight).
  • This was mixed with p-methylbenzenesulfonyl chloride (0.96 g, 5 mmol) and ethyl acetate (20 ml), and then cooled to 5 ° C.
  • 1,4 diazabicyclo [2, 2, 2] -year-old kutan (0.71 g, 6 mmol) for 15 minutes, add calorie, and after the addition, raise the temperature to 25 ° C and stir for another 2 hours.
  • optically active 3- (hydroxymethyl) morpholines can be produced from inexpensive and readily available starting materials in a simple and efficient manner on a commercial scale.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention décrit un procédé de synthèse simple d’un dérivé de 3-(hydroxyméthyl)morpholine optiquement actif, employé en tant qu'intermédiaire de synthèse de médicaments. Ledit dérivé est obtenu à partir d'un produit de départ commercial. Ledit procédé est adapté à une production à l’échelle industrielle. La présente invention décrit également ledit dérivé de 3-(hydroxyméthyl)morpholine. La réaction entre un 2-halogénoéthanol ou l’éthylène glycol et un dérivé de glycidol optiquement commercial actif permet d’obtenir un dérivé de glycérol optiquement actif. Ensuite, l’un des groupements hydroxy dudit dérivé de glycérol est sulfonylé, avant de réagir avec une amine. Il est ainsi possible de synthétiser un dérivé de 3-(hydroxyméthyl)morpholine ou un sel de ce composé.
PCT/JP2005/019565 2004-11-04 2005-10-25 Procédé de synthèse de dérivé de 3-(hydroxyméthyl)morpholine optiquement actif Ceased WO2006049038A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0977762A (ja) * 1995-09-08 1997-03-25 Shin Etsu Chem Co Ltd ２−アリロキシメチル−１，４−ジオキサンの製造方法
JPH10265473A (ja) * 1997-01-24 1998-10-06 Kyorin Pharmaceut Co Ltd ピロロインドール誘導体及びその製造中間体
WO2004011451A1 (fr) * 2002-07-29 2004-02-05 Kaneka Corporation Procede de production industrielle de derives de 1,4-benzodioxane optiquement actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0977762A (ja) * 1995-09-08 1997-03-25 Shin Etsu Chem Co Ltd ２−アリロキシメチル−１，４−ジオキサンの製造方法
JPH10265473A (ja) * 1997-01-24 1998-10-06 Kyorin Pharmaceut Co Ltd ピロロインドール誘導体及びその製造中間体
WO2004011451A1 (fr) * 2002-07-29 2004-02-05 Kaneka Corporation Procede de production industrielle de derives de 1,4-benzodioxane optiquement actifs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GREENE TW, WUTS DGM.: "Protective Groups in Organic Synthesis.", 16 August 1999, pages: 65 - 79, XP002995079 *
YOUNES ME AND CHAABOUNI M M.: "Synthesis of substituted dithia-9-crown-3-ethers.", SYNTHETIC COMMUNICATIONS., vol. 29, no. 22, 1999, pages 3939 - 3948, XP002995078 *

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