JP2001247584A - Sphingomyelin analog and method of producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound having an inhibitory activity against sphingomyelinases. SOLUTION: This new sphingomyelin analog is represented by the formula (wherein R1 and R2 mean each a long-chain alkyl group or the like which may have an unsaturated bond). Also, the effective method of producing the sphingomyelin analog is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel sphingomyelin analog which acts on a catalytic site of sphingomyelinase which is a phospholipid hydrolase and is expected to be a substance which competitively inhibits a substrate, and production thereof. About the law.

[0002]

2. Description of the Related Art Sphingomyelinase is an enzyme that hydrolyzes a phosphate ester portion of sphingomyelin, and sphingomyelin is decomposed into ceramide and phosphocholine by this action. It has also been clarified that ceramide, a metabolite, functions as a signaling factor for cell differentiation and apoptotic derivatives and inhibits the enzyme activity of protein kinase C.
In addition, since sphingomyelin and other sphingolipids are thought to play an important role in cell functions such as proliferation, differentiation and apoptosis as second messengers, the importance of sphingomyelinase has attracted attention, and its mechanism of action has been noted. Clarification is desired. Although the primary structure of sphingomyelinase has been elucidated in only a very small number of species, its sphingomyelinase inhibitor has not been elucidated in detail, including its higher-order structure and hydrolysis mechanism. It is desired to develop a potential material, and it is also desired that it be inexpensive and mass-synthesized.

[0003]

Means for Solving the Problems The present inventors have succeeded in synthesizing a novel sphingomyelin analog represented by the following formula (1). Further, they have found that the sphingomyelin analog of the present invention can be efficiently synthesized using γ-butyrolactone as a raw material. When synthesizing an optically active compound, it is important that the operation is simple, the yield is good, and the optical purity is kept high. As a production method that meets such a demand, there is a method of synthesizing a chiral intermediate that is easily converted into a chemical, and producing an objective substance through this compound. The important point in this method is that the chiral intermediate is easy to handle in terms of operation, and is inexpensive and available in large quantities. The compound according to the present invention often exists as an optical isomer, and the method of the present invention also satisfies these needs. That is, the present invention specifically acts on the catalytic site of sphingomyelinase, which is a phospholipid hydrolase, and sphingomyelin analogs expected as substances that competitively inhibit substrates, and methods for producing the same.
In particular, it is to provide an efficient manufacturing method.

The present invention provides the following general formula (1)

Embedded image (Wherein R ¹ and R ² are the same or different and each represent an alkyl group having 1 to 20 carbon atoms, an aryl group, or an aryl group substituted with 1 to 6 carbon atoms, which may have an unsaturated bond. )). Among the groups represented by R ¹ , C ¹ to C 2
Specific examples of the alkyl group of 0 include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a heptyl group,
Examples thereof include an octyl group, a decyl group, an undecyl group, a heptadecyl group, an allyl group, and a 1-pentadecenyl group. Preferred groups are a heptyl group and a 1-pentadecenyl group.

Among the groups represented by R ¹ , specific examples of the aryl group include a phenyl group, a 4-methoxyphenyl group and a 4-ethoxyphenyl group, and a preferred group is a phenyl group. Among the groups represented by R ¹ , specific examples of the aryl group-substituted alkyl group having 1 to 6 carbon atoms include a benzyl group and a 1-phenethyl group, and a preferred group is a benzyl group. Among the groups represented by the R ^2, specific examples of the alkyl group having 1 to 20 carbon atoms, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, heptyl group, octyl group, decyl group, undecyl group , Heptadecyl group, allyl group, 1-pentadecenyl group and the like,
Preferred groups are a heptyl group and a heptadecyl group. Specific examples of the aryl group among the groups represented by the R ² is a phenyl group, a 4-methoxyphenyl group, 4-ethoxyphenyl group and the like, preferred groups are a phenyl group.

Among the groups represented by R ² , specific examples of the aryl group-substituted alkyl group having 1 to 6 carbon atoms include a benzyl group and a 1-phenethyl group, and a preferred group is a benzyl group. Among the compounds of the present invention represented by the general formula (1), R ¹ is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a heptyl group, an octyl group, a decyl group, an undecyl group, a heptadecyl group, Allyl group, 1-pentadecenyl group, phenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, benzyl group, 1
A phenethyl group, wherein R ² is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a heptyl group, an octyl group, a decyl group, an undecyl group, a heptadecyl group, an allyl group, a 1-pentadecenyl group, a heptadecyl group, a phenyl group; Or a 4-methoxyphenyl group or a 4-ethoxyphenyl group. Particularly preferred compounds are those in which R ¹ is heptyl, 1-pentadecenyl, phenyl or benzyl, and R ² is pentyl, heptyl or heptadecyl.

[0007] The present invention also relates to a process for producing the compound of the above general formula (1). The production method of the compound (1) of the present invention will be described in detail below. The manufacturing process is shown in Scheme 1 below.

Scheme 1

Embedded image (In the above formula, R ³ represents an alkyl group having 1 to 6 carbon atoms, R ⁴ represents an amino protecting group, and R ⁵ represents a cyclic or acyclic alkyl group having 1 to 10 carbon atoms, an aryl group, or an aralkyl group. And R ¹ and R ² are the same as above.)

Step from (2) to (3) When ammonia is reacted with the compound represented by the general formula (2), a diol form represented by the general formula (3) is obtained. Examples of the ammonia reagent to be used include ammonia gas, aqueous ammonia, liquid ammonia and the like, and preferably aqueous ammonia. As the solvent used, N, N
Aprotic polar solvents such as dimethylformamide (DMF) and dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1,4-dioxane, 1,2-
Dimethoxyethane, diglyme, triglyme, ether solvents such as diethylene glycol monomethyl ether, nitrile solvents such as acetonitrile, dichloromethane, halogen solvents such as 1,2-dichloroethane, liquid ammonia, aqueous media, and mixed solvents thereof. Can be The reaction temperature is from −100 ° C. to the reflux temperature of the solvent, preferably from −78 ° C. to room temperature. This reaction proceeds without additives, but trimethylaluminum,
Organic aluminum compounds such as triethylaluminum,
The reaction proceeds smoothly by adding an organic zinc compound such as dimethyl zinc and diethyl zinc. The addition amount is 1 to 3 equivalents, preferably 1 to 1.5 equivalents.

Steps from (3) to (4) The oxazolidinone compound represented by the general formula (4) is obtained by subjecting the compound represented by the general formula (3) to Hoffmann rearrangement. Examples of the rearrangement reagent include sodium hypochlorite, sodium hypobromite, iodosobenzene, hydroxytosyloxyiodobenzene, bistrifluoroacetoxyiodobenzene, lead tetraacetate, N-
Bromosuccinimide (NBS) and an alkali or alkaline earth metal salt of a carboxylic acid, N-chlorosuccinimide and an alkali or alkaline earth metal salt of a carboxylic acid, and the like, preferably N-bromosuccinimide It is an alkali or alkaline earth metal salt of a carboxylic acid. Further examples of alkali salts or alkaline earth metal salts of carboxylic acids include sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, silver acetate, mercury acetate, calcium benzoate, and barium benzoate, preferably sodium acetate, Potassium acetate and silver acetate. The amount of the reagent used is preferably 1 to 3 equivalents, more preferably 1 to 3 equivalents to the azide compound as a substrate.
1.5 equivalents.

Examples of the reaction solvent include hydrocarbon solvents such as hexane, benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, ester solvents such as ethyl acetate and butyl acetate, and tetrahydrofuran. , 1,4-dioxane, 1,2
-Dimethoxyethane, diglyme, triglyme, ether solvents such as diethylene glycol monomethyl ether, acetone, methyl ethyl ketone, ketone solvents such as methyl isobutyl ketone, nitrile solvents such as acetonitrile, dichloromethane, halogen solvents such as 1,2-dichloroethane, Although an aqueous medium and a mixed solvent thereof may be used, preferably, an aprotic polar solvent such as N, N-dimethylformide and dimethyl sulfoxide;
Nitrile solvents such as acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
Ether solvents such as diglyme, triglyme, and diethylene glycol monomethyl ether are exemplified. In this case, the reaction temperature may be from 0 ° C. to the reflux temperature of the solvent.

Step (4) to (5) The obtained compound represented by the general formula (4) is reacted with a sulfonylating agent or a halogenating agent to convert the hydroxyl group to a leaving group, By reacting with a triester and protecting the amino group, a compound represented by the general formula (5) is obtained.

The sulfonylation is carried out in an organic solvent in the presence of a base.
The reaction is carried out by reacting the compound represented by the general formula (4) with a sulfonylating agent. Examples of the sulfonylating agent include toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride and the like. The amount of sulfonylation used is 1 equivalent or more, preferably 1 to 5 equivalents, based on the substrate.

The solvent used is tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
Ether solvents such as diglyme, triglyme, diethyl ether, diisopropyl ether and t-butyl methyl ether; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and chlorobenzene; N, N-dimethyl Aprotic polar solvents such as formamide and dimethyl sulfoxide,
Examples thereof include aromatic hydrocarbon solvents such as benzene and toluene, and mixed solvents thereof.

The base to be used includes triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, picoline, lutidine, collidine, 4-N, N-dimethylaminopyridine and the like. Secondary amines. These may be used alone or as a mixture. The reaction temperature is from -100 ° C to the reflux temperature of the solvent, preferably -5 ° C.
C to room temperature.

The halogenation is carried out by reacting the compound represented by the general formula (4) with a halogenating agent in a solvent. As the halogenating agent, phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, diphosphorus tetraiodide, phosphorus oxychloride, phosphorus oxybromide, diphenyltrichlorophosphorane, diphenyl Phosphorous halide compounds such as tribromophosphorane, triphenylphosphine dichloronide, triphenylphosphine dibromonide, triphenyldichloronide phosphonate, triphenyldibromonide phosphonate, triphenyldiiodonide phosphonate, thionyl chloride, bromide Sulfur halide compounds such as thionyl and sulfuryl chloride, benzyl chloride-triphenyl phosphonate, methyl iodide-triphenyl phosphonate, carbon tetrachloride-trioctylphosphine, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenyl Organic halo such as phenylphosphine Mixture of emission product and the organic phosphorus compound, chloride N, N- dimethyl chloro holmium bromide N, Vilsmeier reagent such as N- dimethylchlorosilane holmium and the like.

The amount of the halogenating agent to be used is 1 equivalent or more, preferably 1-2 equivalents, based on the substrate. The solvent used is not particularly limited as long as the solvent is inert to the halogenating agent. For example, tetrahydrofuran, 1,4-
Dioxane, 1,2-dimethoxyethane, diglyme,
Ether solvents such as triglyme, diethyl ether, diisopropyl ether, t-butyl methyl ether,
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbon solvents such as dichloroethane and chlorobenzene, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, aromatic hydrocarbon solvents such as benzene and toluene, pentane, hexane,
Examples thereof include aliphatic hydrocarbon solvents such as heptane, decane and cyclohexane, and mixed solvents thereof. Further, the halogenating agent itself can be used as the solvent. The reaction temperature is from -100 ° C to the reflux temperature of the solvent, preferably from -5 ° C to room temperature.

In the reaction with the phosphite triester,
The reagent to be used is not particularly limited, but examples include trimethyl phosphite, triethyl phosphite, tributyl phosphite and the like. As the amino group-protecting group, any known amino group-protecting group can be used, but preferably, as an acyl-type protecting group, formyl, acetyl, trifluoroacetyl, pivaloyl, etc.
6-alkylcarbonyl, substituted or unsubstituted benzoyl and the like; urethane-type protecting group; substituted or unsubstituted benzyloxycarbonyl; C1-6 alkoxycarbonyl and cycloalkanooxycarbonyl; and other protecting groups such as p-toluene A substituted or unsubstituted arylsulfonyl such as sulfonyl, and a substituted or unsubstituted phenyl-substituted alkyl group having 1 to 6 carbon atoms such as trityl are exemplified. Examples of the substituent in these groups include groups such as a halogen atom, a nitro group, a hydroxy group, and a cyano group. Particularly preferred are urethane-type protecting groups such as a benzyloxycarbonyl group, a t-butoxycarbonyl group and an ethoxycarbonyl group.

Step from (5) to (6) Ring opening of the compound represented by the general formula (5) with a base in the presence of an alcohol represented by R ⁵ OH (where R ⁵ is the same as described above) Then, the compound represented by the general formula (6) is obtained. Examples of the alcohol include alcohols having 1 to 6 carbon atoms such as methanol, ethanol, allyl alcohol, and propanol; benzyl alcohol; chlorobenzyl alcohol;
Substituted and unsubstituted benzyl alcohols such as nitrobenzyl alcohol are exemplified. Examples of the substituent in these groups include groups such as a halogen atom, a nitro group, a hydroxy group, and a cyano group. Preferred is benzyl alcohol, which is easy to remove. As the solvent, for example, hexane, benzene, hydrocarbon solvents such as toluene,
Aprotic polar solvents such as N, N-dimethylformide and dimethylsulfoxide; ester solvents such as ethyl acetate and butyl acetate; tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethylene glycol monomethyl Ether solvents such as ethers, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitrile solvents such as acetonitrile, halogen solvents such as dichloromethane and 1,2-dichloroethane, aqueous media, and mixed solvents thereof. No. Further, the alcohol used can be used as a solvent. Examples of the base used include alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate, and alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. Alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate are preferred. The amount of the base to be used is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to the substrate.

Step from (6) to (7) Deprotection of the amino group of the compound represented by the general formula (6) obtained, and then conversion of the amino group to R ² CO (where R ² is Same as above.), Ie, by amidation, the compound represented by the general formula (7)
The compound represented by is obtained. Deprotection of the amino group can be performed by a conventional method. In the subsequent amidation,
The reagents used include acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride,
1 carbon atoms such as caproyl chloride and benzoyl chloride
-20 cyclic or acyclic acyl chlorides. Examples of the solvent include hydrocarbon solvents such as hexane, benzene, and toluene; aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide;
Ester solvents such as ethyl acetate and butyl acetate; ether solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, and diethylene glycol monomethyl ether; ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone Examples thereof include solvents, nitrile solvents such as acetonitrile, halogen solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aqueous media, and mixed solvents thereof. The amount of the base used is 1 to 3 with respect to the substrate.
Equivalent, preferably 1 to 1.5 equivalent. Examples of the base used include alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate, and alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. Alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide are preferred.

Steps from (7) to (8) The compound represented by the general formula (8) is obtained by hydrolyzing the phosphate portion of the compound represented by the general formula (7) and then cholinelating the compound. A compound is obtained. Examples of the reagent used for the hydrolysis include trialkylsilyl halides such as trimethylsilyl chloride, trimethylsilyl bromide, and trimethylsilyl iodide. Reagents used for subsequent cholinelation include choline chloride-trichloroacetonitrile. As the base to be used, triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, picoline, lutidine, collidine,
And tertiary amines such as -N, N-dimethylaminopyridine.

Steps from (8) to (1) The sphingomyelin analog represented by the general formula (1) is obtained by deprotecting the hydroxyl group of the compound represented by the general formula (8) obtained. . Although the method of deprotection varies depending on the alkoxy group, when R ^5, which is easily removed, is a benzyl group, it can be carried out by catalytic reduction in a solvent under a hydrogen atmosphere. As a solvent to be used, ester solvents such as ethyl acetate and butyl acetate, tetrahydrofuran, 1,4
Ether solvents such as -dioxane and 1,2-dimethoxyethane, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, alcohol solvents such as methanol, ethanol and 2-propanol, aqueous media,
And a mixed solvent thereof. The catalyst to be used is not particularly limited as long as it is a catalyst used in this kind of catalytic reduction reaction. In particular, a metal-based catalyst such as palladium and platinum is preferable, and palladium is preferable in terms of yield and economy. Further, palladium-carbon having a palladium content of about 5 to 10% by weight is excellent. The amount of the catalyst used is suitably in the range of 0.5 to 50% by weight based on the substrate. The reaction is usually performed at room temperature and normal pressure.

Production of Optically Active (1) The optically active sphingomyelin analog can be efficiently synthesized by producing an optically active intermediate (2-2) by using the following method and using this compound as a raw material.

Scheme 2

Embedded image (R1 in the formula is the same as described above.)

Step from (2) to (2-1) Oxidation of the hydroxyl group of the compound represented by the general formula (2) gives a compound represented by the general formula (2-1). Oxidation methods include oxidation using chromic acids, oxidation using manganese dioxide, oxidation using dimethyl sulfoxide,
Oxidation using a nitroxyl compound and the like can be mentioned. Preferred examples include the following. (A) An oxidation method using chromic acid includes a method using a complex of chromic acid such as pyridinium chlorochromate and pyridinium dichromate and pyridine, and (b) an oxidation method using dimethyl sulfoxide (hereinafter abbreviated as DMSO) includes acetic anhydride / DMSO, triethylamine / sulfur trioxide / pyridine / DMSO, dicyclohexylcarbodiimide / pyridinium trifluoroacetate /
DMSO, electrophilic reagent such as water-soluble carbodiimide hydrochloride / pyridinium trifluoroacetate / DMSO / DM
A method of oxidizing DMSO as an active sulfonium salt using SO or a hydrogen donor / electrophile / DMSO, and (c) an oxidation method using a nitroxyl compound include:
2,2,6,6-tetramethylpiperidine-1-oxyl (hereinafter abbreviated as TEMPO) or 2,2,6,6-tetramethylpiperidine (hereinafter abbreviated as TEMP) and an oxidizing agent such as hydrogen peroxide, organic Peracids (m-chloroperbenzoic acid, peracetic acid,
Perphthalic acid, etc.) metal oxidizer (second body chloride, second body nitrate,
Ferrocyanate) in the reaction system using TMPO
And the method of using the same. Among these methods, a method using a complex of chromic acids such as pyridinium chlorochromate and pyridinium dichromate and pyridine is preferable.

As the solvent to be used, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane,
Ether solvents such as 1,2-dimethoxyethane, diethyl ether, diglyme, triglyme, diethylene glycol monomethyl ether, dichloromethane, 1,2
Halogen solvents such as dichloroethane; ester solvents such as methyl acetate and ethyl acetate; water; and mixed solvents thereof.

Step from (2-1) to (2-2) The compound represented by the general formula (2-2) is obtained by asymmetric reduction of the compound represented by the general formula (2-1). Can be
Examples of the reducing agent include Binaphthylphosphane (abbreviated as BINAP) -ruthenium chloride, BINAP-ruthenium bromide, and BINAP-ruthenium acetate.
INAP-ruthenium-based reagents, binaphthol-aluminum-based reagents, oxazaborolidine-based reagents, and camphenylborane-based reagents such as chlorodiisopinocamphenylborane, and the like, preferably BINAP-ruthenium chloride, BINAP-ruthenium bromide, BINAP-
It is a BINAP-ruthenium-based reagent such as ruthenium acetate. As the solvent to be used, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane,
Ether solvents such as 1,2-dimethoxyethane, diethyl ether, diglyme, triglyme, diethylene glycol monomethyl ether, dichloromethane, 1,2
Halogen solvents such as dichloroethane; ester solvents such as methyl acetate and ethyl acetate; water; and mixed solvents thereof.

Thereafter, using this compound (2-2) as a raw material,
The optically active compound (1) can be synthesized by the procedure described in the above scheme 1. The compound represented by the general formula (2), which is a raw material, is known, and is a tetrahedron letter (Tetrahed
ron Lett.) 23, 4285 (1982).

EXAMPLES Examples will be shown below, but the present invention is not limited to these examples.

Example 1 Synthesis of aldol compound (11)

Embedded image Diisopropylamine (9.71 mL, 69.7 mmol) in THF (58.
N-butyllithium (39.8 mL, 63.9 mmol)
After dropwise addition, the mixture was cooled to -78 ° C, and γ-butyrolactone (5.
00g, 58.1 mmol) in THF (116.2 mL) was added dropwise. 30
After stirring for a minute, add this to caprylaldehyde (10.9 mL, 69.7 mmol)
At -78 ° C in THF (58.1 mL). Then 1
After stirring for 2 hours, 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography, and the aldol form (erythro: threo form = 2: 1) (11) (11.6 g,
92.9%).

Synthesis of β-ketoester (12)

Embedded image Aldol Form (11) (9.01 g, 42.0 mmol) in acetone (2
(10 mL) The Jones reagent was added dropwise to the solution at 0 ° C. until it turned yellow. After stirring for 15 minutes, saturated saline was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography, and the β-ketoester (12) (8.21
g, 92.0%).

¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.39 (ddd,
J = 6.35, 8.05, 9.02 Hz, 1H), 4.32 (ddd, J = 6.34,
8.05, 8.78 Hz, 1H), 3.69 (dd, J = 6.34, 9.27 Hz, 1
H), 2.96 (ddd, J = 7.32, 7.56, 18.05 Hz, 1H), 2.78
(tdd, J = 6.34, 8.05, 12.94 Hz, 1H), 2.61 (ddd, J
= 7.08, 7.56, 17.81 Hz, 1H), 2.32 (m, 1H), 1.55-
1.67 (m, 2H), 1.20-1.36 (m, 8H), 0.88 (t, J = 7.08
Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 202.6, 172.
8, 67.5, 52.2, 42.2, 31.6, 29.0, 28.9, 23.9, 23.2,
22.6, 14.0 IR (NaCl neat): 2930, 1771, 1725, 1410, 1377 cm ^-1

Synthesis of aldol compound (13)

Embedded image DMF degassed from (R) -BINAP (419 mg, 0.67 mmol) and benzene ruthenium chloride dimer (168 mg, 0.34 mmol)
(2.1 mL) and stirred at 100 ° C. for 10 minutes, and then DMF was concentrated under reduced pressure. To this, β-ketoester (12) (8.93 g, 42.1 mmol) dissolved in degassed methylene chloride (21.0 mL) was added, stirred, and then transferred to an autoclave using a bridge. After repeating the operation of pressurizing hydrogen at 100 atm and reducing the pressure to 10 atm three times, the mixture was stirred at a hydrogen pressure of 100 atm at 60 ° C for 10 days.
After cooling to room temperature, the pressure was returned to normal pressure, the reaction mixture was separated and purified by silica gel chromatography, and the aldol compound (1
3) (8.30 g, 92.1%, 98.0% de) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.40 (ddd,
J = 2.93, 8.78, 9.02 Hz, 1H), 4.23 (ddd, J = 7.32,
9.03, 9.52 Hz, 1H), 4.18 (m, 1H), 2.68 (ddd, J =
2.93,9.27, 10.24 Hz, 1H), 2.39 (ddd, J = 9.52, 12.
44, 19.27 Hz, 1H), 2.16-2.24 (m, 2H), 1.72 (br s,
1H), 1.29-1.57 (m, 11H), 0.88 (t, J = 6.83 Hz, 3
H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 178.8, 69.2, 67.1,
45.5, 34.7, 31.7, 29.3, 29.2, 25.8, 22.6, 21.8, 1
4.0 IR (NaCl neat): 3482, 2901, 1782 cm ^-1 [α] _D ^27.0 -6.87 (c = 1.06, CHCl ₃ )

Synthesis of oxazolidinone compound (14)

Embedded image Aldol (13) (8.3 g, 38.7 mmol) in dimethyl ether (77.5 mL) was added to a 30% aqueous ammonia solution (120.7 m
L, 929.5 mmol), and after stirring for 20 hours, the solvent was distilled off under reduced pressure to obtain an amide. Without purification, THF (271.1 mL) was added at room temperature under an argon atmosphere, and then NBS (8.96 g, 50.4 mmol) and silver acetate (8.40 g, 50.
4 mmol) and stirred for 90 minutes. After adding methanol, insolubles were removed by filtration, and the mixture was concentrated under reduced pressure.
The residue is purified by silica gel chromatography,
Oxazolidinone (14) (4.56 g, two-step yield 51.3)
%).

Mp 96.0-96.5 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 6.13 (br s, 1H), 4.60
(ddd, J = 3.41, 7.81, 10.00 Hz, 1H), 3.96 (ddd, J
= 3.42, 7.81, 10.00 Hz, 1H), 3.89 (ddd, J = 4.64,
5.61, 10.73 Hz, 1H), 3.76 (ddd, J = 4.64, 7.81, 1
0.73 Hz, 1H), 1.85 (br s, 1H), 1.66-1.79 (m, 3H),
1.47-1.62 (m, 2H), 1.24-1.41 (m, 9H), 0.88 (t, J =
7.32 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 159.9,
80.3, 60.2, 54.5, 31.7, 31.6, 29.4, 29.3, 29.1, 25.
8, 22.6, 14.0 IR (KBr disk): 3362, 3260, 2927, 1724 cm ^-1 [α] _D ^26.0 -0.84 (c = 0.84, CHCl ₃ )

Synthesis of N-Boc Phosphate (15)

Embedded image Oxazolidinone compound (14) (1.0
g, 4.36 mmol) in methylene chloride (21.8 mL) at 0 ° C with triphenylphosphine (4.58 g, 17.4 mmol) and carbon tetrabromide
(2.89 g, 8.72 mmol) were added sequentially, and the mixture was stirred for 30 minutes. After evaporating the solvent of the reaction mixture under reduced pressure, the residue was purified by silica gel chromatography to obtain a brominated product. Trimethyl phosphite (3.74 mL, 21.8
1 mmol) and refluxed for 3 hours. Unreacted triethyl phosphite was distilled off under reduced pressure to obtain a phosphoric ester. This was dissolved in DMF without purification, cooled to 0 ° C,
Di-t-butyl dicarbonate (1.43 g, 6.54 mmol), 4-dimethylaminopyridine (160 mg, 1.31 mmol), and TEA
(0.918 mL, 6.54 mmol) were added in that order, and the mixture was stirred for 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and N-Boc
A phosphoric ester (15) (1.96 g, 100% yield in three steps) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.48 (m, 1
H), 4.27 (m, 1H), 4.05-4.15 (m, 4H), 2.09 (m, 1
H), 1.70-1.92 (m, 4H), 1.49 1.63 (m, 2H), 1.55
(s, 9H), 1.33 (t, J = 7.1 Hz, 6H), 1.20 1.38 (m, 9
H), 0.89 (t, J = 7.1 Hz, 3H) ¹³ C NMR (CDCl ₃ , 100MH
z) δ: 151.8, 149.4, 84.0, 78.3, 61.8 (JC-P = 5.8H
z), 61.7 (JC-P = 5.8 Hz), 57.9 (JC-P = 19.9 Hz), 3
1.6, 29.2, 29.0, 28.5, 27.9, 25.8, 22.6, 22.5, 21.
9, 21.9, 21.5, 16.5, 16.4, 14.0 IR (NaCl neat): 2932, 1723, 1254, 1026 cm ^-1 [α] _D ^25.0 +25.80 (c = 1.11, CHCl ₃ )

Synthesis of N-Boc-OZ-phosphate ester compound (16)
Success

Embedded image T of N-Boc phosphate (15) (100 mg, 0.22 mmol)
Benzyl alcohol (0.046m2) was added to HF (2.22mL) solution at room temperature.
L, 0.44 mmol) and cesium carbonate (14 mg, 0.44 mmol) were sequentially added and stirred for 3 hours. After cooling the reaction mixture to 0 ° C., a 2N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
The solution was concentrated under reduced pressure. The residue is purified by silica gel chromatography, and N-Boc-OZ-phosphate ester (16)
(100 mg, 80.6%).

¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.31 7.40
(m, 5H), 5.17 (s, 2H), 4.75 (ddd, J = 4.1, 4.4, 8.3
Hz, 1H), 4.65 (d, J = 9.8 Hz, 1H), 4.02-4.15
(m, 4H), 3.80 (m, 1H), 1.47-1.93 (m, 10H), 1.43
(s, 9H), 1.31 (t, J = 7.1 Hz, 6H), 1.20 1.32 (m, 6
H), 0.87 (t, J = 6.8 Hz, 3H) ¹³ C NMR (CDCl ₃ , 100 M
Hz) δ: 155.6, 155.0, 135.2, 128.6, 128.5, 128.2,
80.4, 79.6, 69.7, 61.6 (JC-P = 6.6 Hz), 61.6 (JC-P
= 6.6 Hz), 52.9 (JC-P = 17.3 Hz), 31.7, 30.6, 29.
3, 29.0, 28.3, 25.3, 22.6, 22.4 (JC-P = 142.4 Hz),
16.4, 16.4, 14.0 IR (NaCl neat): 3277, 2930, 1746, 1713, 1256, 1030
cm ^-1 [α] _D ^25.0 -0.67 (c = 0.94, CHCl ₃ )

N-acyl IoZ-phosphate ester (17)
Synthesis of

Embedded image N-Boc-OZ-phosphate ester (16) (430mg, 0.77mmo
After cooling a solution of l) in methylene chloride (3.85 mL) to 0 ° C., trifluoroacetic acid (1.54 mL) was added. After stirring for 3 hours,
The reaction mixture was added to a 1N aqueous solution of sodium hydroxide (5 mL) and a mixed solvent of chloroform (5 mL) which had been cooled. After stirring at the same temperature for 5 minutes, caproyl chloride (0.22 mL,
1.54 mmol) and stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform.
The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain N-acyl-OZ-phosphate ester compound (17) (316 mg, yield in two steps 71.7%).

¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.32 7.39
(m, 5H), 5.97 (d, J = 8.8 Hz, 1H), 5.15 (s, 2H), 4.
74 (m, 1H), 4.05-4.20 (m, 5H), 2.14 (t, J = 7.6
Hz, 2H), 1.15 1.91 (m, 28H), 0.89 (t, J = 6.8 Hz,
3H), 0.87 (t, J = 7.1 Hz, 3H) ¹³ C NMR (CDCl ₃ , 100
MHz) δ: 173.3, 155.1, 135.2, 128.6, 128.5, 128.2,
80.5, 69.7, 61.7, 51.2 (JC-P = 14.8 Hz), 36.7, 3
1.7, 31.4, 31.1, 29.3, 29.0, 25.4, 25.3, 22.6, 22.
4, 22.3 (JC-P = 141.4 Hz), 16.4, 14.0, 13.9IR (NaC
l neat): 3281, 2930, 1746, 1651, 1256, 1030 cm ^-1 [α] _D ^25.0 -1.18 (c = 0.81, CHCl ₃ )

Synthesis of OZ-choline derivative (18)

Embedded image N-acyl-OZ-phosphate ester (17) (209 mg, 0.365
mmol) in methylene chloride (0.365 mL) at room temperature in trimethylsilyl bromide (0.482 mL, 3.650 mmol) in methylene chloride
(0.730 mL) solution was added dropwise. After stirring for 3 hours, the solvent was concentrated under reduced pressure, 10% aqueous THF (1 mL) was added, and the mixture was stirred at 100 ° C for 1 hour. After concentrating the solvent under reduced pressure, choline chloride
(234mg, 1.679mmol) and pyridine (9.86mL) were added, and after heating to 60 ° C, trichloroacetonitrile (1.574mL, 15.695mm
ol) and stirred at the same temperature for 8 hours. Chloroform was added to the reaction mixture, the solid was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography. Subsequently, purification was performed by high performance liquid chromatography to obtain an OZ-choline derivative (18) (37 mg, 16.1%).

¹ H NMR (CD ₃ OD, 400 MHz) δ: 7.31-7.39
(m, 5H), 5.17 (d, J = 12.20 Hz, 1H), 5.12 (d, J =
12.20 Hz, 1H), 4.76 (m, 1H), 4.23 (m, 2H), 4.07
(m, 1H), 3.59 (m, 2H), 3.20 (s, 9H), 2.18 (t, J =
7.07 Hz, 2H), 1.87 (m, 1H), 1.46-1.69 (m, 7H), 1.2
2-1.36 (m, 14H), 0.91 (t, J = 6.83 Hz, 3H), 0.89
(t, J = 6.83 Hz, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ: 1
75.0, 155.0, 135.0, 128.0, 127.9, 127.6, 79.4, 68.
9, 66.3, 57.1, 57.0, 53.1, 51.8, 51.6, 25.5, 31.3,
30.9, 29.7, 28.8, 28.7, 25.3, 24.9, 23.8, 22.6, 2
2.4, 22.1, 21.9, 12.9, 12.8 IR (NaCl neat): 3387, 2928, 1738, 1649 cm ^-1

Synthesis of sphingomyelin analog (19)

Embedded image To a solution of OZ-choline derivative (18) (37 mg, 0.058 mmol) in methanol (0.58 mL) was added palladium carbon (7 mg), and the mixture was stirred.
The argon in the vessel was replaced with hydrogen. After stirring for 1 hour, the catalyst was filtered off by celite filtration, and the solvent was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of acetonitrile and water (1: 9) and purified by high performance liquid chromatography to obtain a sphingomyelin analog (19) (20 mg, 76.9%).

¹ H NMR (CD ₃ OD, 400 MHz) δ: 4.25 (m, 2
H), 3.73 (ddd, J = 3.17, 6.34, 9.51Hz, 1H), 3.61
(m, 2H), 3.44 (m, 1H), 3.22 (s, 9H), 2.21 (t, J =
7.56 Hz, 2H), 1.97 (m, 1H), 1.30-1.66 (m, 21H), 0.
92 (t, J = 6.59 Hz, 3H), 0.90 (t, J = 7.07 Hz, 3H);
¹³ C NMR (CD ₃ OD, 100 MHz) δ: 171.7, 73.0, 66.3, 5
7.1 (JC-P = 4.9 Hz), 54.6, 54.5, 53.1, 35.7, 33.2,
31.5, 31.1, 29.2, 28.8, 25.4, 25.3, 23.8, 23.4, 2
2.4, 22.1, 21.9, 12.9, 12.8 IR (KBr disk): 3420, 2928, 1642, 1053 cm ^-1

Example 2 Synthesis of aldol compound (20)

Embedded image Diisopropylamine (9.71mL, 69.7mmol) in THF
(60 mL) solution at 0 ° C. with n-butyllithium (39.8 mL, 6 mL).
After 3.9 mmol) was added dropwise, the mixture was cooled to -78 ° C, and a solution of butyrolactone (5.00 g, 58.1 mmol) in THF (120 mL) was added dropwise. After stirring for 30 minutes, this was added to caprylaldehyde (6.98
g, 69.7 mmol) in THF (60 mL). Then, after stirring for 1 hour, 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is separated by silica gel chromatography.
Purified, 2: 1 mixture of erythro and threo forms (20)
(9.19, 85%).

Synthesis of β-ketoester (21)

Embedded image The Jones reagent was added dropwise to a solution of aldol compound (20) (8.0 g, 42.9 mmol) in acetone (210 mL) at 0 ° C. until the solution turned yellow. After stirring for 15 minutes, saturated saline was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is separated by silica gel chromatography.
Purification gave β-ketoester (21) (6.87 g, 87%).

Synthesis of aldol compound (22)

Embedded image (R) -BINAP (330 mg, 0.53 mmol) and benzeneruthenium chloride dimer (135 mg, 0.27 mmol) were dissolved in degassed DMF (2 mL), stirred at 100 ° C. for 10 minutes, and then concentrated under reduced pressure. Here, degassed methylene chloride (20
β-ketoester (21) (6.20 g, 3
After adding 3.6 mmol) and stirring, the mixture was transferred to an autoclave using a bridge. After repeating the operation of pressurizing hydrogen at 100 atm and depressurizing to 10 atm three times,
Stirred for 10 days. After cooling to room temperature, the pressure was returned to normal pressure, and the reaction mixture was separated and purified by silica gel chromatography to obtain an aldol compound (22) (5.76 g, 92%, 98.0% de).

Synthesis of oxazolidinone compound (23)

Embedded image Aldol form (22) (5.76 g, 30.1 mmol) in DME (7
0% solution, 30% ammonia aqueous solution (94mL, 722.4mmo)
After l) was added and the mixture was stirred for 20 hours, the solvent was distilled off under reduced pressure to obtain an amide. Without purification, THF (250 mL) was added at room temperature under an argon atmosphere, followed by NB
S (6.96 g, 39.1 mmol) and silver acetate (8.40 g, 50.4 mmol)
Was added and stirred for 90 minutes. After adding methanol, insolubles were removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the oxazolidinone compound (23) (3.33 g, two-step yield: 55%).

Synthesis of N-Boc Phosphate (24)

Embedded image The oxazolidinone compound (25) (1.0
g, 4.97 mmol) in methylene chloride (25 mL) at 0 ° C. were successively added with triphenylphosphine (5.19 g, 19.8 mmol) and carbon tetrabromide (3.29 g, 9.94 mmol) and stirred for 30 minutes.
After evaporating the solvent of the reaction mixture under reduced pressure, the residue was purified by silica gel chromatography to obtain a brominated product. Triethyl phosphite (4.3 mL, 2
4.85 mmol) was added and refluxed for 3 hours. Unreacted triethyl phosphite was distilled off under reduced pressure to obtain a phosphoric ester. This was dissolved in DMF (25 mL) without purification,
After cooling to 0 ° C, di-t-butyl dicarbonate (1.62 g, 7.4
5 mmol), DMAP (182 mg, 1.49 mmol), and triethylamine (1.1 mL, 7.89 mmol) were sequentially added, and the mixture was stirred for 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture,
Extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain N-Boc phosphoric ester (26) (1.76 g, yield in three steps of 84%).

Synthesis of N-Boc-OZ-phosphate ester (25)
Success

Embedded image To a solution of N-Boc phosphoric acid ester (24) (100 mg, 0.24 mmol) in THF (2 ml) was added benzyl alcohol (0.05 mM) at room temperature.
l, 0.48 mmol) and cesium carbonate (156 mg, 0.48 mmol) were added successively and stirred for 3 hours. After cooling the reaction mixture to 0 ° C., a 2N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain N-Boc-OZ-phosphate ester compound (25) (104 mg, 82%).

N-acyl-OZ-phosphate ester (26)
Synthesis of

Embedded image N-Boc-OZ-phosphate ester (25) (500mg, 0.94mmo
After cooling the l) methylene chloride solution (5 mL) to 0 ° C., trifluoroacetic acid (2 mL) was added. After stirring for 3 hours, the reaction mixture was added to a cooled 1N aqueous sodium hydroxide solution (7 mL) and a mixed solvent of chloroform (7 mL). After stirring at the same temperature for 5 minutes, capryloyl chloride (0.3
2mL, 1.88mmol) and stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain N-acyl-OZ-phosphate ester compound (26) (339 mg, 65% in two steps).

OZ-sphingomyelin analog (27)
Synthesis

Embedded image N-acyl-OZ-phosphate ester (26) (253mg, 0.45mm
ol) in methylene chloride (0.5 mL) at room temperature in TMSBr (0.6 m
L, 4.5 mmol) in methylene chloride (1 mL) was added dropwise. Three
After stirring for an hour, the solvent was concentrated under reduced pressure, followed by 10% aqueous T
HF (2 mL) was added and the mixture was stirred at 100 ° C. for 1 hour. After the solvent was concentrated under reduced pressure, choline chloride (251 mg, 1.8 mmol) and pyridine (10 mL) were added, the temperature was raised to 60 ° C., trichloroacetonitrile (1.9 mL, 19.35 mmol) was added, and the mixture was stirred at the same temperature for 8 hours. . Chloroform was added to the reaction mixture, the solid was filtered off, and then the solvent was concentrated under reduced pressure.
The residue was purified by silica gel chromatography.
Subsequently, the product was purified by high performance liquid chromatography to obtain OZ-choline compound (27) (63 mg, 24%).

Synthesis of sphingomyelin analog (28)

Embedded image OZ-sphingomyelin analog (27) (50mg, 0.085m
mol) in methanol (1 mL)
After adding g) and stirring, the argon in the vessel was replaced with hydrogen. After stirring for 1 hour, the catalyst was filtered off by celite filtration, and the solvent was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of acetonitrile and water (1: 9), purified by high performance liquid chromatography, and sphingomyelin analog (28)
(28 mg, 74%).

[0055]

Industrial Applicability The novel sphingomyelin analog (1) according to the present invention has sphingomyelinase inhibitory activity and is expected to be applied as a drug, particularly as a sphingomyelinase inhibitor. Further, according to the method of the present invention, a sphingomyelin analog (1) having high optical purity or high optical purity can be produced.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C037 EA10 EA11 4C056 AA01 AB01 AC02 AD01 AE02 AF01 BA03 BA07 BB04 BC01 4C086 AA03 AA04 DA42 GA16 NA14 ZC20 4H050 AA01 AA02 AB20 AB27 AB84 AC40 AC50 AC80 BD70 BE14 BE60 WA13

Claims (13)

[Claims] 1. A compound of the general formula (1) (Wherein R ¹ and R ² are the same or different and each represent an alkyl group having 1 to 20 carbon atoms, an aryl group, or an aryl group substituted with 1 to 6 carbon atoms, which may have an unsaturated bond. ) Represented by sphingomyelin analogs. 2. The compound according to claim 1, wherein in the formula (1), R ¹ and R ² are the same or different and are an alkyl group having 10 to 17 carbon atoms which may have an unsaturated bond. 3. In the formula (1), R ¹ is a heptyl group,
The compound according to claim 1, wherein R ² is a pentyl group. 4. The compound according to claim 1, wherein in the formula (1), R ¹ is a 1-pentadecenyl group and R ² is a heptadecyl group. 5. The compound according to claim 1, wherein the compound represented by the formula (1) is an optically active substance. 6. A compound of the general formula (2) (Wherein R ¹ has 1 carbon atom which may have an unsaturated bond)
To 20 alkyl groups, aryl groups, or aryl group-substituted alkyl groups having 1 to 6 carbon atoms. ) Is reacted with ammonia to give a compound of the general formula (3) (Wherein R ¹ is the same as above) to obtain a compound represented by the formula:
Then, the compound is subjected to Hoffman rearrangement to obtain a compound represented by the general formula (4). (Wherein R ¹ is the same as above) to obtain a compound represented by the formula:
The hydroxyl group of this compound is changed to a leaving group and reacted with a phosphite triester, and then the amino group is protected. (Wherein, R ³ denotes an alkyl group having 1 to 6 carbon atoms, R ⁴
Represents an amino protecting group, and R ¹ is the same as described above. The compound represented by the general formula (6) is obtained by ring-opening in the presence of an alcohol. (Wherein, R ⁵ represents a cyclic or acyclic alkyl group having 1 to 10 carbon atoms, an aryl group, or an aralkyl group;
R ¹ , R ³ and R ⁴ are the same as above. ), The amino group is deprotected and then amidated to give a compound of the general formula (7) (Wherein R ² has 1 carbon atom which may have an unsaturated bond)
20 alkyl group means an aryl group or an aryl-substituted alkyl group having 1 to 6 carbon ^{atoms,, R 1, R 3,} R 5 are as defined above. Is obtained by hydrolysis of a phosphoric acid ester, followed by choline, by the general formula (8) (Wherein R ¹ , R ² , and R ⁵ are the same as described above), and finally, the hydroxyl group is deprotected. (Wherein R ¹ , R ² , and R ⁵ are the same as above). 7. The method for producing a sphingomyelin analog according to claim 6, wherein the starting material compound is represented by the general formula (2): (R ¹ is the same as above.) The compound represented by the general formula (2-1) is oxidized. (R ¹ is the same as above) to obtain a compound represented by the general formula (2-2), which was produced by asymmetric reduction of this compound. (R ¹ is the same. Above) preparation of optically active sphingomyelin analogue according to claim 6, characterized by using an optically active compound represented by the. 8. The method for producing an optically active sphingomyelin analog according to claim 7, wherein the steric form of the compound represented by the formula (2-2) is a threo form. 9. The process for producing an optically active sphingomyelin analog according to claim 7, wherein (R) -binaphthylphosphane-ruthenium chloride is used as the asymmetric reducing agent. 10. A compound represented by the general formula (5). Embedded image (Wherein R ¹ has 1 carbon atom which may have an unsaturated bond)
20 alkyl group means an aryl group or an aryl group-substituted alkyl group having 1 to 6 carbon atoms,, R ³ is C 1 -C
Represents an alkyl group of Ｒ6, and R ⁴ represents an amino protecting group. ) 11. A compound represented by the general formula (6). Embedded image (Wherein R ¹ has 1 carbon atom which may have an unsaturated bond)
20 alkyl group means an aryl group or an aryl-substituted alkyl group having 1 to 6 carbon atoms,, R ³ is 1 to carbon atoms
6, R ⁴ represents an amino protecting group, and R ⁵ represents a cyclic or acyclic alkyl group having 1 to 10 carbon atoms, an aryl group, or an aralkyl group. ) 12. A compound represented by the general formula (7). Embedded image (Wherein, R ¹ and R ² are the same or different and may have an unsaturated bond, an alkyl group having 1 to 20 carbon atoms, an aryl group, or an alkyl group having 1 to 6 carbon atoms substituted with an aryl group.) , R ³ represents an alkyl group having 1 to 6 carbon atoms, and R ⁵ represents a cyclic or acyclic alkyl group having 1 to 10 carbon atoms, an aryl group, or an aralkyl group.) 13. A compound represented by the general formula (8). Embedded image (Wherein, R ¹ and R ² are the same or different and may have an unsaturated bond, an alkyl group having 1 to 20 carbon atoms, an aryl group, or an alkyl group having 1 to 6 carbon atoms substituted with an aryl group.) , R ⁵ represents a cyclic or non-cyclic alkyl group having 1 to 10 carbon atoms, an aryl group, or an aralkyl group.)