WO2006049038A1

WO2006049038A1 - Process for producing optically active 3-(hydroxymethyl)morpholine derivative

Info

Publication number: WO2006049038A1
Application number: PCT/JP2005/019565
Authority: WO
Inventors: Kouhei Mori; Akira Nishiyama; Nobuo Nagashima
Original assignee: Kaneka Corporation
Priority date: 2004-11-04
Filing date: 2005-10-25
Publication date: 2006-05-11
Also published as: JPWO2006049038A1

Abstract

A process by which an optically active 3-(hydroxymethyl)morpholine derivative useful as an intermediate for medicines can be easily produced from an inexpensive, easily available raw material and which is practical for industrial production; and the useful intermediate. A 2-haloethanol or ethylene glycol is caused to act on an easily available, optically active glycidol derivative to yield an optically active glycerol derivative. Thereafter, a hydroxy group of the derivative is sulfonylated and an amine is caused to act thereon. Thus, an optically active 3-(hydroxymethyl)morpholine derivative or a salt thereof is produced.

Description

Specification

Process for producing optically active 3- (hydroxymethyl) morpholine derivative

Technical field

TECHNICAL FIELD [0001] 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.

[0002] As a method for producing an optically active 3- (hydroxymethyl) morpholine derivative, the following methods are known.

[0003] 1) N-Benzylation of L-serine, followed by N-chloroacetylation followed by cyclization, and reduction of the resulting amide carboxylic acid with sodium bis (2-methoxyethoxy) aluminum hydride A method for producing N-benzylthio 3- (hydroxymethyl) morpholine (Non-patent Document 1).

[0004] 2) After L-N-Boc-serine was O-arylated, methyl esterified, followed by ozone oxidation, the resulting hemiacetal was reduced with triethylsilane, and finally the ester site was hydrogenated. Reduction with sodium borohydride (Patent Document 1).

[0005] In the method 1), 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. In addition, 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. In the method 2), the process is long and it is necessary to use an expensive reagent such as iodomethyl-triethylsilane. In addition, since 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.

[0006] As described above, the production method of the optically active 3- (hydroxymethyl) morpholine derivative known at present has not been able to be put into practical use industrially.

Patent Document 1: WO98 / 50035

Non-Patent Document 1: CS, Perkin Trans 1. 1985, 12. 2577 Disclosure of the invention

Problems to be solved by the invention

[0007] In view of the above, 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.

Means for solving the problem

[0008] In view of the above, the present inventors have conducted extensive studies. As a result, 2-haloethanol or ethylene glycol was allowed to act on an optically active glycidol derivative to form an optically active glycerin derivative, and then the hydroxyl group was converted to a sulfo group. A method for obtaining an optically active 3- (hydroxymethyl) morpholine derivative was found by reacting with Louis and further reacting with an amine, and the present invention was completed.

That is, the present invention relates to the general formula (1);

[0010] [Chemical 16]

[Wherein P ¹ represents a protecting group for a hydroxyl group, X represents a halogen atom, and * represents an asymmetric carbon atom) or the general formula (2);

[0012] [Chemical 17]

[0013] (where

* Is the same as above. It is related with the optically active glycerol derivative represented by this.

[0014] Further, the present invention provides a general formula (3); [0015] [Chemical 18]

[0016] (where

X and * are the same as above. 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);

[0017] [Chemical 19]

[0018] (where

* Is the same as above. 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.

[0019] Further, the present invention provides a general formula (5);

[0020] [Chemical 20]

[0021] (wherein

* Is the same as above. The method for producing an optically active glycerin derivative represented by the above formula (1) or the above formula (2), wherein 2-haloethanol or ethylene glycol is allowed to act on the optically active glycidol derivative represented by About.

[0022] Further, 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

[0023] Further, 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 NH (7)

2

(Wherein 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. And an amine represented by the general formula (6);

[0024] [Chemical 21]

[0025] (where

P ² and * are the same as above. ) The optically active 3- (hydroxymethyl) morpholine derivative represented by formula (I) or a salt thereof.

The invention's effect

[0026] According to the present invention, 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

[0027] Hereinafter, the present invention will be described in detail.

[0028] First, raw materials, intermediates, and products used in the present invention will be described.

[0029] The optically active glycidol derivative as a starting material of the present invention has the general formula (5);

[0030] [Chemical 22]

It is represented by Here, P ¹ represents a hydroxyl-protecting group, and * 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. For example, a protective 'groups' in 'organic' synthic dliRA Protective Groups m Organic Synthesis , 3nd Εα. No, written by Theodora W. Green, published by John WILEY & SONS, 1999, pages 17-200 Specific examples include protecting groups such as methoxymethyl group, benzyloxymethyl group, methylthiomethyl group, ρ-methoxybenzyloxymethyl group, ρ-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-butoxycarbol group; a phosphinate-type protecting group such as a dimethylphosphier group Can be mentioned. Among the protecting groups for the hydroxyl 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. More preferably, a methoxymethyl group, benzyloxymethyl group, methylthiomethyl group, p-methoxybenzyloxymethyl group, p-trobenzyloxymethyl group, t-butoxymethyl group, 2-methoxyethoxymethyl group, 2- (trimethylsilyl) ) Ethoxymethyl group, tetrahydrobiral group, tetrahydrofuranyl group, 1 ethoxyethyl group, 1-methyl-1-methoxyethyl group T-butyl group, benzyl group, p-methoxybenzyl group, triphenylmethyl group, trimethylsilyl group, triethylsilyl group, triisopropylpropylsilyl group, or t-butyldimethylsilyl 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.

[0032] The stereochemistry of the asymmetric carbon may be either an absolute configuration force or S.

Further, it 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. .

[0033] The 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.

[0034] Next, the optically active glycerin derivative which is an important intermediate in the production method of the present invention is represented by the general formula (1);

[0035] [Chemical 23]

[0036] or general formula (2);

[0037] [Chemical 24]

It is represented by here,

* Is the same as described in the general formula (5), and X represents a halogen atom. Examples of 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.

[0039] Next, an optically active glycerin derivative which is another important intermediate in the production method of the present invention is represented by the general formula (3);

[0040] [Chemical 25]

[0041] or general formula (4);

[0042] [Chemical 26]

[0043] here,

X and * are the same as described in the general formulas (1) and (2), and 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. , 2 Tylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-trifluorophenyl group, m--trifluorophenyl -Four group, 4-Ferule group, p-Chrome port group, p-Bromophenol group, etc. Even if it has a substituent, 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. Preferably, either 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. In addition, 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.

[0044] The 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.

[0045] Next, the optically active 3 (hydroxymethyl) morpholine derivative, which is the product of the present invention, is represented by the general formula (6);

[0046] [Chemical 27]

[0047] here,

* Is the same as in the general formulas (1) to (4), and 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. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamido. Group, 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, aroyl groups having 7 to 12 carbon atoms, hydroxyl groups, 1 carbon atom -12 alkyloxy group, C7-12 aralkyloxy group, C6-C12 aryloxy group, C1-C12 acyloxy group, C7-C12 arooxy group, C3-C12 silyloxy group Group, an alkylsulfonyloxy group having 1 to 12 carbon atoms, or an alkylthio group having 1 to 12 carbon atoms, and the number of substituents is 0 to 3. It may have a substituent, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, and an aralkyl having 7 to 20 carbon atoms which may have a substituent. The group is the same as described above. 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.

[0048] In the present invention, the optically active 3- (hydroxymethyl) morpholine derivative represented by the general formula (6) may form a salt with an acid. Examples of the acid include an optically active acid and a non-optically active acid. Examples of 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. Preferably, it is a 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.

[0049] Next, the optically active 3- (hydroxymethyl) morpholine, which is the final product of the present invention, is represented by the formula (8);

[0050] [Chemical 28]

[0051] Here, * represents an asymmetric carbon atom.

[0052] In the present invention, the optically active 3- (hydroxymethyl) morpholine represented by the general formula (8) may form a salt with an acid. Examples of the acid include an optically active acid and a non-optically active acid. Examples of 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. Preferably, it is a 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.

[0053] Next, the production method of the present invention will be described.

[0054] First, 2-haloethanol or ethylene glycol is allowed to act on the optically active glucosyl derivative represented by the formula (5), thereby being represented by the formula (1) or the formula (2). The process for producing the optically active glycerin derivative will be described.

[0055] When 2-haloethanol is used as the alcohol to be reacted, 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.

[0056] Here, 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.

[0057] 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. Said Examples of 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, tetrabutyl ammonium hydrogen sulfate; triphenyl methyl phosphorous or triphenyl methylphosphoric chloride Quaternary phospho-um salt such as hum; iron chloride (111), or Radical generators such as 2, 3-dichloro-5, 6-disyanobenzoquinone; alkali metal fluorides or alkaline earth metal fluorides such as cesium fluoride, potassium fluoride, sodium fluoride, calcium fluoride, etc. Etc. In addition, only when ethylene glycol is reacted, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc .; calcium hydroxide, barium hydroxide, or water 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 can be used. Preferably, 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. More preferably, 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. [0058] 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).

[0059] In the present reaction, 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. When a reaction solvent is used to ensure the fluidity of the reaction solution, 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).

[0060] 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.

[0061] The reaction time is preferably 5 minutes to 24 hours, more preferably 30 minutes to 12 hours, from the viewpoint of yield improvement.

[0062] 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. As a process after the reaction, a general process for obtaining a reaction fluid product may be performed. For example, 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.For the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization, fractionation The purity may be further increased by a general purification method such as distillation or column chromatography.

[0063] Next, the 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.

[0064] As the optically active glycerin derivative represented by the formula (1) or (2), the reaction solution obtained by the above-mentioned method may be used as it is, or an isolated and purified product may be used.

[0065] In this step, if 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).

[0066] This step can be performed by using a sulfonylating agent in the presence of a base. Here, examples of the sulfonating agent include halogenated sulfol and sulfonic anhydride. Examples of the halogenated sulfone include methane chloride chloride, ethane chloride chloride, chloromethane sulfol chloride, benzene sulfone chloride, p-methylbenzene sulfol chloride, and p-chlorobenzene sulphonate. And m-trobenzene sulphonyl chloride and the like, and examples of the sulfonic acid anhydride 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.

[0067] 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.

[0068] 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.

[0069] As the reaction solvent in this step, 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. 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; methylene chloride, chloroform, etc. 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. Preferably, 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).

[0070] 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.

[0071] The reaction time is preferably 5 minutes to 20 hours, more preferably 30 minutes to 5 hours, from the viewpoint of improving the yield.

[0072] The addition method and the order of addition of the 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.

[0073] As a process after the reaction, a general process for obtaining a reaction fluid product can be performed. That's fine. For example, 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. Then, the extraction operation is performed using a general extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like. When 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.

[0074] Next, the optically active glycerin derivative represented by the formula (3) or (4) and the general formula (7);

P ² NH (7)

2

(Wherein P ² is the same as above), by reacting an amine represented by the formula (6), to produce an optically active 3- (hydroxymethyl) morpholine derivative represented by the formula (6) or a salt thereof. explain.

[0075] As the optically active glycerin derivative represented by the above formula (3) or (4), the reaction solution obtained by the above-mentioned method may be used as it is, or an isolated and purified product may be used.

In this step, the 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.

Here, specific examples of the amine (7) include ammonia, hydroxyamines, and primary amines. Specific examples of hydroxyamines include hydroxyamine, methoxyamine, ethoxyamine, and benzyloxyamine, and examples of 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. Ammonia, hydroxyamine, methoxyamine, benzyloxyamine, arylamine, t-butylamine, benzylamine, and the like are preferable, and benzylamine is more preferable. [0078] 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.

[0079] In addition, this reaction may be performed in the presence of a base different from ammine (7)! Here, 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. Preferred are 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).

[0080] In the present reaction, the above-mentioned amine (7), which requires a reaction solvent in particular, can be used as the reaction solvent as it is. Also, when the base is a tertiary amine, it can be used as a reaction solvent. When a reaction solvent is further used to ensure the fluidity of the reaction solution, 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 triamide Bromide based solvent may be used. Preferably, 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).

[0081] 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. [0082] The reaction time is preferably 5 minutes to 30 hours, more preferably 30 minutes to 15 hours, from the viewpoint of improving the yield.

[0083] The method and order of addition of the optically active glycerin derivative (3) or (4), amine (7), base, and reaction solvent during the reaction are not particularly limited.

[0084] As the treatment after the reaction, a general treatment for obtaining a reaction fluid product may be performed. For example, 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.

In the reaction of this step, 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. That is, in the production method of the present invention, 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. In this case, glycidol derivative (5) with high optical purity was used as a raw material. It may be used as.

Next, 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. Here, for P ¹ deprotection, the type of protecting group It may be suitably selected according to the above. For example, 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. Specifically, for example, in the case of the P ¹ -butyl group in the optically active 3- (hydroxymethyl) morpholine derivative (6), this can be achieved by acting an acid aqueous solution such as hydrochloric acid or hydrobromic acid. Can be deprotected. When P ^{1 is a} benzyl group, deprotection can be achieved by allowing hydrogen to act in the presence of a transition metal catalyst such as palladium carbon in a solvent such as methanol or ethanol.

[0087] In addition, when 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. Further, 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.

[0088] In this step, 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.

Example

[0089] The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

Example 1 Production of (R) —1— (Benzyloxy) —3— (2-Ethoxy) -2-propanol [0090] [Chemical 29]

[0091] Boron trifluoride-ether complex (0.28 g, 2 mmol) was dissolved in 2-chloro ethanol (24.2 g, 300 mmol) and cooled to an internal temperature of -15 ° C. (R) benzyl glycidyl ether (3.28 g, 20 mmol, optical purity: 98% ee.) Was added dropwise thereto over 30 minutes. After stirring at the same temperature for 5 hours, 20 ml of saturated aqueous sodium hydrogen carbonate solution and 20 ml of toluene were added to hydrolyze. The aqueous layer was separated and concentrated under reduced pressure to give the title compound (5.27 g, yield: 68%, purity: 62% by weight).

[0092] ^J H NMR (400MHZ, CDC13): δ 7. 36— 7. 25 (m, 5H), 4. 56 (s, 2H), 4.0 0 0- 3.98 (m, 1H), 3 76— 3. 72 (m, 2H), 3. 67— 3. 50 (m, 6H), 4. 56 (s, 2H) 2. 62 (brs, 1H)

Example 2 Production of (R) -2- (benzyloxy) mono 1- [(2-cycloethoxy) methyl] ethyl methanesulfonate

[0093] [Chemical 30]

[0094] (R) -1- (Benzyloxy) -3- (2-chloroethoxy) 2 propanol (4.0 g, lOmmol) prepared by the method described in Example 1 was added to toluene (40 ml), methanesulfo dichloride. 4. Mix with Nore (2. 79 g, 24 mmol) C was chilled. To this was added dropwise triethinoleamine (2.73 g, 27 mmol) over 30 minutes. After completion of the dropwise addition, the temperature was raised to 25 ° C and the reaction was carried out for 14 hours. Water (15 ml) was added for hydrolysis, and the organic layer was further washed with water (15 ml). The solvent was distilled off under reduced pressure to obtain the title compound (5.43 g, yield: 100%, purity: 76% by weight). [0095] Ή NMR (400MHz, CDC13): δ 7. 37— 7. 33 (m, 5H), 4. 89—4. 86 (m, 1 H), 4.40-4. 38 (dd, 2H), 3. 67— 3. 50 (m, 8H), 3. 08 (s, 3H)

Example 3 Production of (R) —1— (Benzyloxy) 3 — (2 Hydroxyethoxy) 2 Propanol

[0096] [Chemical 31]

[0097] (R) - benzyl glycidyl ether (3. 28 g, 20 mmol, optical purity:. 98% ee), E Ji glycol (12.40g, 198mmol), 20 weight ^_0/0 Mizusani匕aqueous solution (8. 00 g, 40 mmol) and tetrabutyl ammonium hydrogen sulfate (1.69 g, 5 mmol) were mixed, and the mixture was stirred at 50 ° C. for 4 hours. Ethyl acetate (40 ml) and water (20 ml) were added thereto and extracted, and the aqueous layer was extracted three times with ethyl acetate (20 ml). The organic layers were combined and concentrated under reduced pressure to give the title compound (6.80 g, yield: 64%, purity: 42% by weight).

[0098] ^J H NMR (400MHZ, CDC13) δ: 7.36— 7.25 (m, 5Η), 4. 55 (s, 2H), 4.

08-3. 98 (m, 1H), 3.72—3.53 (m, 8H), 3.01 (brs, 1H), 2.68 (brs, 1H)

Example 4 (R) — Preparation of 2 (benzyloxy) 1 {[2 (methylsulfo-ruoxy) ethoxy] methyl} ethyl methanesulfonate

[0099] [Chemical 32]

[0100] (R) -1- (Benzyloxy) -3- (2-hydroxyethoxy) -2-propanol (3.19 g, 6 mmol), ethyl acetate (20 ml), triethyl produced by the method described in Example 3 Amamine (3.03 g, 30 mmol) was mixed and then cooled to 5 ° C. To this, methanesulfuric chloride Honyl (2.29 g, 20 mmol) was added and stirred for 1 hour. Ethyl acetate (20 ml) and water (20 ml) were added thereto for extraction, and the organic layer was washed with water (20 ml) and concentrated under reduced pressure. Obtained thick

T

S

The condensed product was purified by silica gel column chromatography to obtain the title compound (2.10 g, yield: 78%, purity: 85% by weight).

[0101] ^J H NMR (400MHZ, CDC13) δ: 7. 36— 7. 25 (m, 5H), 4. 93— 4. 85 (m, 1H), 4. 55 (t, 2H), S 4. 34 (dd, 2H), 3. 78— 3.68 (m, 6H), 3. 07 (s, 3H), 3. 02 (s, 3H) B

Example 5 Preparation of (R) -2-({2 — [(4 Methylphenol) sulfooxy] 3 [(Phenylmethyl) oxy] propyl} oxy) ethyl 4 Methylbenzenesulfonate [0102] ]

[0103] (R) -1- (Benzyloxy) -3- (2-hydroxychetoxy) -2 prono V-l (2.53 g, 5 mmol), triethylamine (2. 49g, 25m m _o l), after mixing the acetic acid Echiru (25 ml), cooled to 5 ° C. P-Methylbenzen chloride (4.69 g, 25 mmol) was dissolved in ethyl acetate (10 ml) and added to the previous mixture over 30 minutes. After completion of the addition, the temperature was raised to 25 ° C, and the mixture was further stirred for 2 hours. 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. Add 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. did. Saturated aqueous sodium hydrogen carbonate solution (1 Oml) was added for hydrolysis, the aqueous layer was separated, and the organic layer was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography to obtain the title compound (1.68 g, yield: 76%, purity: 91% by weight). [0104] Ή NMR (400MHz, CDC13) δ: 7. 77— 7. 72 (m, 4H), 7. 35— 7. 19 (m, 9H), 4. 64—4.61 (m, 1H) , 4.40 (dd, 2H) 4.09 (t, 2H), 3.60—3.45 (m, 6H), 2.45 (s, 3H), 2.43 (s, 3H)

Example 6 Production of (S) 3- (benzyloxymethyl) N benzylmorpholine

[0105] [Chemical 34]

[0106] was prepared by the method described in Example 2 (R)-2-(benzyloxy) - 1- [(2 Kuroroe butoxy) methyl] Echiru methanesulfonate (2. 0g, 6mmol, 97 weight ^_0/0) , Benzylamine (3.2 g, 30 mmol) were mixed and then stirred at 90 ° C. for 12 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) were added for extraction, and the aqueous layer was separated. The organic layer was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (1.25 g, yield: 68%, purity: 97% by weight, optical purity: 96% ee.). .

[0107] ^J H NMR (400MHZ, CDC13) δ: 7.35—7, 22 (m, 10Η) 4. 50 (s, 2Η), 4.

05 (d, 1H), 3. 86-3. 83 (m, 1H), 3. 72— 3. 50 (m, 5H), 3. 33 (s, 1H), 2. 70-2. 62 ( m, 2H), 2.30— 2.25 (m, 1H)

The optical purity was measured under the following HPLC analysis conditions. Column: CHIRAL PAK AD-H (250mm X Φ4.6mm, Daicel Chemical), Solvent: Hexane ZlPA = 20Zl (volZvol), Flow rate: 1. Oml / min, Column temperature: 30 ° C, Detection wavelength: 210nm

Example 7 (S) — 1— [1,1, (Dimethyloleethinole) oxy] 3 — [(2 Hydroxyethyl) oxy] 2-Propanol Production

[0108] [Chemical 35]

[0109] (S) After mixing t-butyldaricidyl ether (1.3 g, 10 mmol, optical purity: 97% ee.), Ethylene glycol (6.2 g, lOOmmol), cesium fluoride (0.3 g, 2 mmol) The mixture was stirred at 120 ° C for 4 hours. The mixture was allowed to cool to room temperature, acetyl acetate (100 ml) was added, and the mixture was washed with water (50 ml). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (1.68 g, yield: 86%).

[0110] ^J H NMR (400MHZ, CDC13) δ: 4.17 (d, 2Η), 3.98—3.47 (m, 9H), 1.

24 (s, 9H)

Example 8 Preparation of (S) -2-{[3-[(l, 1-dimethyl) oxy] 2 (methylsulfo-butoxy) propyl] ethyl methanesulfonate

[0111] [Chemical 36]

[0112] (S) -1 [1, 1 (Dimethylethyl) oxy] -3-[(2 hydroxyethyl) oxy] -2 propanol (1.65 g, 9 mmol), triethyl produced by the method described in Example 7 Tyramine (3.93 g, 39 mmol) was mixed and cooled to 5 ° C. Methanesulfuryl chloride (3.47 g, 30 mmol) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. After washing twice with water (20 ml) and concentrating the organic layer under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (2. llg, yield: 70%).

[0113] ^J H NMR (400MHZ, CDC13) δ: 4. 77—4. 74 (m, 1Η), 4. 35 (d, 2H), 3.

79-3.70 (m, 4H), 3.65 (ddd, 2H), 3.10 (s, 3H), 3.08 (s, 3H), 1.21 (9 H)

Example 9 Production of (R) -3- (t-butoxymethyl) -N benzylmorpholine

[0114] [Chemical 37] ', Me Bu

[0115] (S) -2- 2- [[3 -— [(1,1-Dimethyl) oxy] -2- (methylsulfo-dioxy) propyl] ethyl methanesulfonate (1) produced by the method described in Example 8 80 g, 5 mmol) and benzylamine (3.46 g, 20 mmol) were mixed and stirred at 80 ° C. for 8 hours. Ethyl acetate (30 ml) was added, followed by washing with water (15 ml), and the organic layer was concentrated under reduced pressure. This was purified by silica gel column chromatography to obtain the title compound (787.8 mg, yield: 57%, optical purity: 97% ee.).

[0116] ^J H NMR (400MHZ, CDC13) δ: 7.40— 7.25 (m, 5Η), 3.95 (dd, 2H), 3.75-3.55 (m, 4H), 3.51 ( dd, 2H), 2.60— 2.55 (m, 2H), 2.20 (ddd, 1 H), 1.20 (s, 9H)

The optical purity was measured under the following HPLC analysis conditions. Column: CHIRAL PAK AD-H (250 mm X Φ4.6 mm, Daicel Chemical), solvent: hexane ZlPA = 99Zl (volZvol), flow rate: 1. Oml / min, column temperature: 30 ° C, detection wavelength: 254 nm

Example 10 Production of (S) -3- (hydroxymethyl) -N-benzylmorpholine

[0117] [Chemical 38]

[0118] (R) -3-tert-butoxymethyl-N-benzylmorpholine (149. 8 mg, 0.6 mmol) and 6N aqueous hydrochloric acid (3 ml) prepared by the method described in Example 9 were mixed, 100. Stir at C for 30 min. The mixture was adjusted to ρΗΙΟ.0 with a 30 wt% aqueous sodium hydroxide solution and extracted with ethyl acetate (30 ml). The extract was washed with water (20 ml), dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the solvent was evaporated under reduced pressure to give the title compound (116.8 mg, yield: 9 9%, optical purity: 97% ee.).

[0119] ^J H NMR (400MHZ, CDC13) δ: 7.38— 7. 28 (m, 5H), 4. 17 (d, 1H), 3.

97 (dd, 1H), 3.85 (dd, 1H), 3.78— 3.64 (m, 2H), 3.60— 3.45 (m, 2H) 3.25 (d, 1H), 2.70 (ddd, 1H), 2.60— 2.57 (m , 1H), 2.37 (ddd, 1H) The optical purity was measured under the following HPLC analysis conditions. Column: CHIRAL PAK AD-H (250mm X Φ4.6mm, Daicel Chemical), solvent: hexane ZlPA = 95Z5 (volZvol), flow rate: 1. Oml / min, column temperature: 30 ° C, detection wavelength: 254nm

Example 11 Production of (S) -3- (hydroxymethyl) morpholine acetate

[0120] [Chemical 39]

[0121] (S) -3- (hydroxymethyl) -N benzyl morpholine (103 mg （0.5 mmol), acetic acid (30 mg, 0.5 mmol), methanol (4 ml) prepared by the method described in Example 10 Then, 10% noradium carbon (10 mg) was mixed and replaced with hydrogen under reduced pressure (1 atm). The mixture was stirred at 23 ° C. for 15 hours, and the catalyst was filtered off. The solvent was evaporated to obtain the title compound (90.8 mg, yield: 100%).

[0122] ^J H NMR (400MHZ, D20) δ: 4.25 (d, 2Η), 3. 85 (dd, 2H), 3. 78 (dd, 2 H), 3.52 (ddd, 1H), 3.45 ( d, 1H), 3.32 (ddd, 1H), 1.92 (s, 3H) Experimental Example 12 (R) 3 (t-Butoxymethyl) N Production of phenol morpholine

[0123] [Chemical 40]

(S) — 2— {[3— [(1, 1-dimethyl) oxy] produced by the method described in Example 8 2 (Methylsulphonyloxy) propyl] ethyl methanesulfonate (2.0 g, 6 mmol), a-line (2.41 g, 26 mmol), triethylamine (1.57 g, 16 mmol) are mixed and mixed at 80 ° C.

C

For 8 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (741.7 mg, yield: 24%).

¾ NMR (400MHZ, CDC13) δ: 7. 25 (t, 2Η), 6. 86 (d, 2H), 6. 79 (t, 1 H), 4. 14 (d, 1H), \ H 3. 98 (dd, 1H), 3.70—3.62 (m, 4H), 3.30—3.05 (m, 3H), 1.2 (s, 9H) B

Example 13 Production of (R) —1— (Benzyloxy) 3— (2-Chloroethoxy) 2 Propanol

[0125] [Chemical 41]

[0126] Mixture of 2-clonal ethanol (1.21 g, 15 mmol), pinoclinic acid (306.4 mg, 3 mmol), (R) benzylglycidyl ether (164.2 mg, lmmol, optical purity: 98% ee. And stirred at 90-100 ° C for 48 hours. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution (20 ml) and toluene (20 ml) were added and hydrolyzed. The aqueous layer was separated and concentrated under reduced pressure to give the title compound (154. 8 mg, yield: 64%).

Example 14 Production of (R) —1— (Benzyloxy) 3— (2-Chloroethoxy) 2 Propanol

[0127] [Chemical 42]

[0128] 2 Black mouth ethanol (1.21 g, 15 mmol), titanium propoxide (568 mg, 2 mmol),

(R) -benzyl glycidyl ether (164.2 mg, 1 mmol, optical purity: 98% ee.) Was mixed and stirred at 25 ° C. for 92 hours. Saturated aqueous sodium hydrogen carbonate solution (20 ml), Toru (20 ml) was added to hydrolyze. The aqueous layer was separated and concentrated under reduced pressure to give the title compound (73.8 mg, yield: 31%).

Example 15 Production of (R) — 3— (t-butoxymethyl) -N benzylmorpholine

[0129] [Chemical 43]

[0130] (S) t-Butyldaricidyl ether (1.3 g, 10 mmol, optical purity: 97% ee.), Ethylene glycol (6.2 g, lOOmmol), potassium fluoride (0.2 g, 3 mmol) After mixing, the mixture was stirred at 100 ° C for 13 hours. The mixture was allowed to cool to room temperature, ethyl acetate (100 ml) was added, and the mixture was washed with water (5 Oml). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (S) -1- 1, 1- (dimethylethyl) oxy] -3-3- [(2-hydroxychetyl) oxy] 2 propanol. Obtained. This was mixed with triethylamine (2.53 g, 25 mmol) and cooled to 5 ° C. Methanesulfuryl chloride (2.86 g, 25 mmol) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. After washing twice with water (20 ml), the organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (S) — 2— {[3— [(1, 1 dimethyl) oxy] 2 ( Methylsulfo-methyloxy) propyl] ethyl methanesulfonate was obtained. To this, benzylamine (5.35 g, 50 mmol) was mixed and stirred at 80 ° C. for 5 hours. Ethyl acetate (50 ml) was added, followed by washing with water (20 ml), and the organic layer was concentrated under reduced pressure. This was purified by silica gel column chromatography to obtain the title compound (1.22 g, yield: 47%).

Example 16 Production of (R) — 3— (t-butoxymethyl) -N benzylmorpholine

[0131] [Chemical 44]

[0132] (S) t-Butyl daricidyl ether (1.3 g, 10 mmol, optical purity: 97% ee.), Ethylene glycol (6.2 g, lOOmmol), cesium carbonate (0.98 g, 3 mmol) mixed After that, the mixture was stirred at 100 ° C for 13 hours. The mixture was allowed to cool to room temperature, acetyl acetate (100 ml) was added, and the mixture was washed with water (50 ml). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain (S) — 1- [1, 1- (dimethylethyl) oxy] -3— [(2-hydroxyxetyl) oxy] -2 propanol Got. This was mixed with triethylamine (2.53 g, 25 mmol) and cooled to 5 ° C. Methanesulfuryl chloride (2.86 g, 25 mmol) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. After washing twice with water (20 ml), the organic layer was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (S)-2 — {[3— [(1, 1 dimethyl) oxy] 2 (Methylsulfo-dioxy) propyl] ethyl methanesulfonate was obtained. To this, benzylamine (5.35 g, 50 mmol) was mixed and stirred at 80 ° C. for 5 hours. Ethyl acetate (50 ml) was added, followed by washing with water (20 ml), and the organic layer was concentrated under reduced pressure. This was purified by silica gel column chromatography to obtain the title compound (1.47 g, yield: 56%).

Example 17 Preparation of (S) -l- [l, 1- (dimethylenoleethinole) oxy] 3 — [(2 hydroxyethyl) oxy] 2-propanol

[0133] [Chemical 45]

[0134] (S) —tert-butyldaricidyl ether (2.6 g, 20 mmol), ethylene glycol (24.

8 g, 400 mmol) and iron (III) chloride (1.2 g, 7 mmol) were mixed and then stirred at 120 ° C. for 3 hours. The mixture was allowed to cool to room temperature, and ethyl acetate (100 ml) was added and washed with water (50 ml). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (1.35 g, yield: 35%).

Example 18 Production of (S) -l- [l, 1 (dimethylethyl) oxy] 3-[(2 hydroxyethyl) oxy] 2-propanol

[0135] [Chem 46]

[0136] (S) —tert-butyldaricidyl ether (1.3 g, lOmmol), ethylene glycol (22.

3 g, 358 mmol) and tetraptylammonium hydrogen sulfate (0.7 g) were mixed and then stirred at 120 ° C. for 12 hours. The mixture was allowed to cool to room temperature, and ethyl acetate (100 ml) was added and washed with water (200 ml). The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (1.03 g, yield: 53%).

Industrial applicability

[0137] According to the present invention, 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.

Claims

The scope of the claims

Formula (1);

(Wherein P ¹ represents a hydroxyl-protecting group, X represents a halogen atom, * represents an asymmetric carbon atom) or general formula (2);

[Chemical 2]

(Where

* Is the same as above. An optically active glycerin derivative represented by:

[2] P ¹ is methoxymethyl, benzyloxymethyl, methylthiomethyl, p methoxybenzyloxymethyl, p-trobenzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) Ethoxymethyl, tetrahydrovinyl, tetrahydrofuryl, 1 ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, 2. The optically active glycerin derivative according to claim 1, which is a triethylsilyl group, a triisopropylpropyl group, or a t-butyldimethylsilyl group.

[3] The optically active glycerin derivative according to claim 1 or 2, wherein X is a chlorine atom.

[4] P ¹ is a t- butyl group or a base Njiru group, an optically active glycerol derivative according to claim 1.

[5] General formula (3);

[Chemical 3]

(In the formula, P ¹ represents a hydroxyl-protecting group, X represents a halogen atom, * represents an asymmetric carbon atom, R ¹ is an alkyl group having 1 to 20 carbon atoms which may have a substituent. Or having a substituent, V, an aryl group having 6 to 20 carbon atoms, or! / Having a substituent, and an aralkyl group having 7 to 20 carbon atoms.) Or Formula (4);

[Chemical 4]

(Where

* Is the same as above. 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. An optically active glycerin derivative, which represents an aralkyl group having 7 to 20 carbon atoms, and R ¹ and R ² may be the same or different.

[6] P ¹ is methoxymethyl group, benzyloxymethyl group, methylthiomethyl group, p methoxybenzyloxymethyl group, p-trobenzyloxymethyl group, t-butoxymethyl group, 2-methoxyethoxymethyl group, 2- (trimethylsilyl) Ethoxymethyl, tetrahydrovinyl, tetrahydrofuryl, 1 ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, 6. The optically active glycerin derivative according to claim 5, which is a triethylsilyl group, a triisopropylpropyl group, or a t-butyldimethylsilyl group.

7. The optically active glycerin derivative according to claim 5 or 6, wherein X is a chlorine atom.

[8] P ¹ is a t- butyl group or a base Njiru group, an optically active glycerol derivative according to any one of claims 5-7.

[9] R ¹ and R ² are identical, a methyl group or p Mechirufue - a le group claim 5-8ヽ The optically active glycerin derivative according to any one of the above,

Formula (5);

[Chemical 5]

¾ ^ ΟΡ ¹ (5)

(Wherein Ρ ¹ represents a protecting group for a hydroxyl group, and * represents an asymmetric carbon atom), 2-haloethanol or ethylene glycol is allowed to act on the optically active glycidol derivative represented by General formula (1);

[Chemical 6]

(In the formula, Ρ * is the same as above. X represents a halogen atom) or the general formula (2);

[Chemical 7]

(Where

* Is the same as above. The manufacturing method of the optically active glycerol derivative represented by this.

[11] Boron trifluoride jetyl ether complex, zinc chloride, titanium tetrachloride, tin tetrachloride, salt hafnium chloride, zirconium chloride, titanium propoxide, zirconium propoxide, aluminum-um propoxide, trichloroacetic acid, acetic acid, propion Acid, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, cesium fluoride, potassium fluoride, sodium fluoride, calcium fluoride, sodium hydroxide, water At least one of the group consisting of potassium oxide, sodium carbonate, potassium carbonate, or cesium carbonate. The production method according to claim 10, wherein the production is carried out using two catalysts.

Formula (1);

[Chemical 8]

[Chemical 9]

(Where

* Is the same as above. ), Wherein the hydroxyl group of the optically active glycerin derivative is sulfonated (3);

[Chemical 10]

(Where

[Chemical 11]

(Where

* Is the same as above. 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. A method for producing an optically active glycerin derivative, which represents an aralkyl group having 7 to 20 carbon atoms, and R ¹ and R ² may be the same or different.

13. The production method according to claim 12, wherein sulfo-louis is carried out using a sulfonyl halide.

[14] The production method according to claim 12 or 13, wherein the production method is R ¹ and Z or R ² acetyl group, or p-methylphenyl group.

[15] The optically active glycerin derivative represented by the formula (1) or (2) obtained by the method according to claim 10 or 11 is used. A method for producing a photoactive glycerin derivative.

[16] General formula (3);

[Chemical 12]

[Chemical 13]

(Where

* Is the same as above. 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. An aralkyl group having 7 to 20 carbon atoms, and R ¹ and R ² may be the same or different and the optically active glycerin derivative represented by the general formula (7);

P ² NH (7)

2

[Chemical 14]

(Wherein P ¹ P ² , * are the same as above), a method for producing an optically active 3- (hydroxymethyl) morpholine derivative or a salt thereof.

The optically active 3- (hydroxymethyl) morpholine derivative represented by the general formula (6) produced by the method according to claim 16 or a salt thereof is further deprotected, the formula (8);

[Chemical 15]

A process for producing optically active 3- (hydroxymethyl) morpholine or a salt thereof represented by the formula:

[18] P ² Gabe Njiru process according to claim 16 or 17 wherein the group.

[19] The optically active glycerin derivative represented by the formula (3) or (4) produced by the method according to any one of claims 12 to 15 is used. The manufacturing method as described in.

[20] The production method according to any one of claims 10 to 19, wherein X is a chlorine atom.

[21] The production method according to any one of [10] to [20], wherein P ¹ is a t-butyl group.