JPH0759574B2 - Cyclic ether derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object] The present invention relates to a novel cyclic ether derivative having an excellent antagonistic activity against platelet activating factor (hereinafter abbreviated as PAF), an inner salt thereof and a salt thereof.

<Industrial application fields> (In the above formula, p represents 15 or 17)
Is a compound that has been analyzed and identified as a factor of the anaphylactic state, and has a strong platelet activation / aggregation action, neutrophil activation action, blood pressure lowering action and vascular permeability enhancing action, asthma, inflammation, It is considered to act as a kind of mediator in various pathological conditions such as endotoxin shock. Therefore, PAF antagonists are useful as excellent therapeutic agents for the above diseases.

<Prior Art> Known glycerin derivatives having a PAF antagonistic action include, for example, the following two compounds (VI) and (VII).

<Problems to be Solved by the Invention> The inventors of the present invention have conducted extensive studies for many years on the synthesis of a derivative having a PAF antagonistic action and its pharmacological activity. As a result, the 1-position and 2-position hydroxyl groups of glycerin , A conventional PAF antagonist having a chain substituent (for example, the compound (V
It was found that a derivative having a novel cyclic ether structure having a completely different structure from I) and (VII)) has a strong PAF antagonism with excellent durability and bioavailability, and the present invention completed.

[Constitution] Novel cyclic ether derivative of the present invention and its inner salt
And salts thereof have the general formula[Wherein l represents an integer of 2 to 4, A and B are the same or
Differently represent an oxygen atom or a sulfur atom. R¹And R²of
One of them is a straight or branched chain alkyl group having 10 to 22 carbon atoms.
Group, straight-chain or branched-chain aliphatic acyl having 10 to 22 carbon atoms
Basis or(Where R is³Is a linear or branched chain having 10 to 22 carbon atoms
Represents a branched chain alkyl group, R^FourIs a hydrogen atom, lower alkyl
Group, aralkyl group, lower aliphatic acyl group, aromatic acyl
Group, an alkyloxycarbonyl group or an alkenyl group
Indicates a oxycarbonyl group. ) And the other is the formula(Wherein X is a single bond,A group having⁶Is R^FourThe same group as above is shown. )
, M is an integer of 0 to 3, and n is an integer of 0 to 10.
Indicates R^FiveIs a hydrogen atom or optionally protected cal
Represents a boxy group, Z Is an anion, Q isA group having⁷, R⁸And R⁹Are the same or different
A hydrogen atom or a lower alkyl group is shown. ) Or expression
A group having —G (wherein G represents a 5- to 10-membered heterocyclic group)
You ) Is shown. ) Is shown. ]].

In the above general formula (I), the “linear or branched alkyl group having 10 to 22 carbon atoms” represented by one of R ¹ and R ² and represented by R ³ is, for example, decyl, 3- Methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7
-Dimethyloctyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, 1-
Methyl pentadecyl, 14-methyl pentadecyl, 13,13
-Dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl,
Nonadecyl, aicosyl, henaicosyl and docosyl can be mentioned, but a linear or branched alkyl group having 13 to 18 carbon atoms is preferable.

Examples of the “linear or branched aliphatic acyl group having 10 to 22 carbon atoms” represented by one of R ¹ and R ² include, for example, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonyl. Carbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl,
Undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, Examples thereof include 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl, nonadecylcarbonyl, aicosylcarbonyl and heniicosylcarbonyl, preferably a linear or branched chain having 13 to 18 carbon atoms. It is a branched-chain aliphatic acyl group.

The "lower alkyl group" represented by R ⁴ , R ⁷ , R ⁸ and R ⁹ is, for example, methyl, ethyl, n-propyl, isopropyl, n.
-Butyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2
Carbon number such as -methylpentyl, 3,3-dimethylpentyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl It represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms.

The “aralkyl group” represented by R ⁴ is, for example, benzyl,
Phenethyl, p-nitrobenzyl, o-nitrobenzyl, triphenylmethyl, diphenylmethyl, bis (o
-Nitrophenyl) methyl, 9-anthrylmethyl, 2,
4,6-Trimethylbenzyl, p-bromobenzyl, p-
It represents an aralkyl group such as methoxybenzyl and piperonyl, and is preferably a benzyl group.

The "lower aliphatic alkyl group" represented by R ⁴ is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, palmitoyl, stearoyl, an alkylcarbonyl group, chloroacetyl, Halogenated alkylcarbonyl groups such as dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl, etc. 1 to 6 carbon atoms
Represents an aliphatic acyl group, and is preferably an alkylcarbonyl group having 1 to 6 carbon atoms.

The “aromatic acyl group” represented by R ⁴ is, for example, an arylcarbonyl group such as benzoyl, α-naphthoyl and β-naphthoyl, a halogenated arylcarbonyl group such as 2-bromobenzoyl and 4-chlorobenzoyl, 2, Four,
Lower alkylated arylcarbonyl groups such as 6-trimethylbenzoyl and 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, 2 -(Methoxycarbonyl)
An aromatic acyl group having 7 to 12 carbon atoms such as a lower alkoxycarbonylated arylcarbonyl group such as benzoyl and an arylated arylcarbonyl group such as 4-phenylbenzoyl is shown, and preferably an aromatic acyl group having 7 to 12 carbon atoms. It is an arylcarbonyl group.

The “alkyloxycarbonyl group” represented by R ⁴ is, for example, a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxy. It represents an alkyloxycarbonyl group having 2 to 7 carbon atoms, such as a lower alkoxycarbonyl group substituted with halogen such as carbonyl or a tri-lower alkylsilyl group, preferably a lower alkoxycarbonyl group having 2 to 7 carbon atoms. is there.

The "alkenyloxycarbonyl group" represented by R ⁴ is
Examples thereof include an alkenyloxycarbonyl group having 3 to 7 carbon atoms such as vinyloxycarbonyl and allyloxycarbonyl, and preferably an alkenyloxycarbonyl group having 3 to 5 carbon atoms.

“An optionally protected carboxy group” represented by R ⁵
Examples of the protecting group for the above include a lower alkyl group; an aralkyl group; an aliphatic acyloxymethyl group such as acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl and pivaloyloxymethyl, 1-lower alkyl such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl Oxycarbonyloxyethyl group,
Phthalidyl or (2-oxo-5-methyl-1,3-
In vivo hydrolyzable carboxyl group protecting groups such as dioxolen-4-yl) methyl; such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, methoxyethoxymethyl Alkyloxymethyl group or 2,2,2-
It represents a halogeno lower alkyl group such as trichloroethyl, 2-haloethyl and 2,2-dibromoethyl, and is preferably an aralkyl group or a protective group for a carboxyl group which is easily hydrolyzed in vivo.

The “5- to 10-membered heterocyclic group” represented by —G includes at least one nitrogen atom, may contain an oxygen atom or a sulfur atom, and may be a condensed 5 to 14-membered heterocyclic group. Are shown, for example, pyrrolyl, azepinyl, morpholinyl, thiomorpholinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1,2,3-Oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl and groups corresponding to these groups, partially or fully reduced groups can be mentioned, and preferably, It contains at least one nitrogen atom, and may contain an oxygen atom or a sulfur atom, and represents a 5 to 14-membered aromatic heterocyclic group which may be condensed and represents, for example, pyrrolyl, azepinyl, morpholinyl, thiomorpholinyl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-
Mention may be made of oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl and isoquinolyl, more preferably imidazolyl, oxazolyl, thiazolyl, quinolyl, isoquinolyl and pyridinyl.

These groups further include the above lower alkyl groups, hydroxy lower alkyl groups such as hydroxymethyl, hydroxyethyl and hydroxypropyl, lower alkoxy groups such as methoxy and ethoxy, carbamoyl groups, and halogens such as fluorine, chlorine and bromine. It may have a substituent such as an atom.

Z The "anion" represented by is not particularly limited, but HZ and
Preferably hydrofluoric acid, hydrochloric acid, hydrobromic acid, and iodide water.
Inorganic such as hydrohalic acid like sulfuric acid, sulfuric acid and phosphoric acid
Acid; methanesulfonic acid, trifluoromethanesulfone
Acids, lower alkyl sulfones such as ethanesulfonic acid
Acid, benzenesulfonic acid, p-toluenesulfonic acid
Organic acids such as arylsulfonic acid, oxalic acid, and maleic acid
And amino acids such as glutamic acid and aspartic acid
Can be mentioned.

Further, in the formula (III), when Q represents the formula (IV),
When at least one of R ⁷ , R ⁸ and R ⁹ is a hydrogen atom (for example, when R ⁷ is a hydrogen atom), the formula (II
I) is (In the formula, X, m, n, R ⁵ , R ⁸ and R ⁹ have the same meanings as described above.)
It may be expressed as.

Similarly, when the -G group is not quaternary, the formula (II
I) is (In the formula, X, m, n, R ⁵ and Q have the same meanings as described above).

Further, when R ⁵ represents a carboxy group and Q represents a quaternary amine, the formula (III) is (In the formula, X, m, n and Q have the same meanings as described above.) (In the formula, X, m, n and Q have the same meanings as described above, and M represents an alkali metal atom such as sodium and potassium.)
It may exist in the form of a salt represented by.

The compound (I) of the present invention has stereoisomers having an asymmetric carbon and each of which is R-coordinate and S-coordinate, and each of them or a mixture thereof is included in the present invention. Included.

In the compound (I), preferably, (1) a compound in which l is 2 or 3 (2) X is a single bond, (Wherein R ⁶ has the same meaning as described above) (3) R ¹ is a linear or branched alkyl group having 10 to 22 carbon atoms or (Wherein R ³ and R ⁴ are as defined above) (4) R ² is of formula (III) (wherein X, m, n, R ⁵ and Q are as defined above) (5) m is an integer of 1 to 3 (6) n is an integer of 0 to 6 (7) Q is of the formula -G (wherein -G is as defined above). (8) l is 2 or 3, and R ¹ is a linear or branched alkyl group having 10 to 22 carbon atoms or (In the formula, R ³ and R ⁴ have the same meanings as described above),
R ² is of formula (III) (wherein X is a single bond, (Wherein R ⁶ has the same meaning as described above), and m is 1
To 3 and n is an integer from 0 to 6, R ⁵
Has the same meaning as above, and Q is a compound of the formula -G (in the formula, -G has the same meaning as described above).

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1, but the present invention is not limited to these compounds.

Suitable compounds among the above exemplified compounds include 9,10,32,
34,35,44,45,46,47,52,53,54,55,56,57,58,59,60,63,6
4,65,72,73,74,75,76,80,84,86,93,94,110,111,112,16
Mention may be made of 7,168 and 193. Further preferred compounds include 34,44,45,46,52,53,54,55,56,57,58,59,6
0, 72, 73, 74, 75, 76, 80, 93 and 94.

The cyclic ether derivative of the present invention can be produced by the method described below.

In the above formula, A, B, R ⁶ , R ⁷ , R ⁸ , R ⁹ , l, m and n have the same meanings as described above.

R ¹ ′ is a linear or branched alkyl group having 10 to 22 carbon atoms, a linear or branched aliphatic acyl group having 10 to 22 carbon atoms, or (Wherein R ³ and R ⁴ have the same meanings as described above),
Y is a halogen atom such as chlorine, bromine or iodine; a lower alkylsulfonyloxy group such as methanesulfonyloxy, trifluoromethanesulfonyloxy or ethanesulfonyloxy, or an arylsulfonyloxy such as benzenesulfonyloxy or p-toluenesulfonyloxy. Indicates a group. Q ′ is a group having the formula —O—R ²² (wherein
R ²² is preferably tetrahydropyran-2-yl, 3-
Bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4
A tetrahydropyranyl group such as -yl; a lower alkyloxymethyl group such as methoxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl Or aralkyl such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl. A group can be mentioned. ) Or a group having the formula -G (in the formula, -G has the same meaning as described above) and Q "represents a group having the formula Y (wherein Y has the same meaning as described above). or a group (wherein, -G is. which as defined above) having the formula -G .R ⁵ showing a 'is, .Y represents a hydrogen atom or a protected carboxy group' represents a halogen atom, Y ″ Represents a leaving group such as a halogen atom, an aralkyloxy group such as benzyloxy, a trihalogenomethyloxy group such as trichloromethyloxy, W represents a residue of an active carboxylic acid, and preferably Y The same groups as defined in the definition, a lower aliphatic acyloxy group and an aromatic acyloxy group are shown, R ²⁰ is a protecting group for a hydroxy group or a mercapto group, and examples thereof include diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-me Di- or triarylmethyl groups such as xyphenyldiphenylmethyl, p- (p-bromophenacyloxy) phenyldiphenylmethyl; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydro Tetrahydropyranyl groups such as pyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropyl Silyl groups such as silyl, methyldi-t-butylsilyl, diphenyl-t-butylsilyl, triisopropylsilyl; benzyl, p-methoxybenzyl,
Mention may be made of an optionally substituted benzyl group such as o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, p-cyanobenzyl or a lower aliphatic acyl group. Preferably, a benzyl group or a tetrahydropyranyl group is used as the hydroxy-protecting group,
A lower aliphatic acyl group is used as a protective group for the mercapto group.

Methods A and F are methods for producing a compound in which X is a single bond in the general formula (I) of the present invention or a synthetic intermediate thereof.

In the general formula (I) of the present invention, X is B or G Or a synthetic intermediate thereof.

In the general formula (I) of the present invention, X is the C method and the H method. (In the formula, R ⁶ has the same meaning as described above.) Or a synthetic intermediate thereof.

In the general formula (I) of the present invention, X is D Or a synthetic intermediate thereof.

Method E and Method J are separate methods for producing the compound (I) of the present invention or a synthetic intermediate thereof.

Method K is the synthetic intermediate (XIII), (XV),
(XVII), (XXIV), (XXVIII), (XXXIII), (XXXI
V), (XXXV), (XXXIX) or (XLIII) to the compound (X
LIV) or (XLIV ′) to react with the compound (I) of the present invention
Is a method of manufacturing.

The reaction reagents and reaction conditions in each of the above steps are described below.

In the first step and the second step, a compound (VIII) or compound (XII) having a hydroxy group or a mercapto group at the terminal is reacted with an alkylating agent (IX) or (XI) in the presence of a base to give an ether or a thioether. It is a step of producing the compound (X).

The solvent used is not particularly limited as long as it does not participate in this reaction, for example, ethers such as ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; N, N-dimethyl. Amides such as formamide, N, N-dimethylacetamide;
Dimethyl sulfoxide or hexamethyl phosphorotriamide can be mentioned, preferably benzene, N, N-
It is dimethylformamide or hexamethylphosphorotriamide.

The base used is not particularly limited as long as it does not affect the other parts of the compound, but preferably triethylamine, 1,5-diazabicyclo [5.4.0] undec-, which is an acid binder. Organic bases such as 5-ene, pyridine, 2,6-lutidine, N, N-dimethylaniline, N, N-dimethylaminopyridine; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or hydrogenation Examples thereof include alkali metal hydrides such as sodium and potassium hydride, and alkali metal hydroxides are preferable. The reaction temperature is not particularly limited and is, for example, 0 ° C to 150 ° C, preferably 60 ° C to 90 ° C. The reaction time mainly depends on the reaction temperature and the type of raw material compound,
For example, it is 1 hour to 3 days, preferably 4 to 16 hours.

After completion of the reaction, the target compound (X) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.

In the third step, in the compound (X), when the terminal Q ′ group is a group having the formula —O—R ²² (in the formula, R ²² has the same meaning as described above), this —O—R ²² In this step, the group is converted into a Y group to produce compound (XIII).

First, the protective group R ^{22 for} the hydroxy group is removed. When the hydroxy-protecting group is a tetrahydropyranyl group or a lower alkyloxymethyl group, it can be removed by treating with an acid in a solvent. The acid used is preferably acetic acid, p-toluenesulfonic acid, hydrochloric acid, acetic acid-sulfuric acid or the like. The solvent is not particularly limited, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water is preferable. The reaction temperature is 0 ° C to 100 ° C, preferably 20 ° C to 6 ° C.
It is carried out at 0 ° C., and the reaction time varies depending on the raw material compound, the reaction temperature and the type of acid, but is usually 1 hour to 24 hours.

When the hydroxy-protecting group is an aralkyl group,
It can be removed by contacting with a reducing agent.
For example, catalytic reduction is carried out at room temperature using a catalyst such as palladium carbon or platinum, or an alkali metal sulfide such as sodium sulfide or potassium sulfide is used. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or acetic acid. And the like, and mixed solvents of these organic solvents and water are suitable. The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 5 minutes to 12 hours, depending on the kinds of the raw material compound and the reducing agent.

Further, when the reaction substrate has a sulfur atom, when the hydroxy-protecting group is a benzyl group, it is preferably carried out by reacting aluminum chloride and sodium iodide at room temperature, and the protecting group is Alternatively, when the group is a triarylmethyl group, an acid (eg, trifluoroacetic acid, hydrochloric acid, acetic acid) is preferably used.

After completion of the reaction, the desired compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

The deprotected hydroxy group is then acylated, for example methanesulfonyl, toluenesulfonyl, trifluoromethanesulfonyl or trifluoroacetyl, to synthesize the ester or the hydroxy group is replaced with a halogen atom.

The solvent used in the ester synthesis is not particularly limited as long as it does not participate in this reaction, and for example, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; ether, tetrahydrofuran,
Mention may be made of ethers such as dioxane or aromatic hydrocarbons such as benzene and toluene, preferably dichloromethane or benzene. The base used is not particularly limited, but is preferably an acid binder such as triethylamine, pyridine, 2,6-lutidine, N, N-
It is an organic base such as dimethylaniline. The reaction temperature is not particularly limited, but is preferably 0 ° C. to 25 ° C., and the reaction time is preferably 0.5 to 24 hours, varying mainly depending on the reaction temperature or the kind of the raw material compound.

The halogen substitution reaction is not particularly limited as long as it is a reaction that can substitute a hydroxyl group for a halogen atom, but is preferably carried out using carbon tetrahalide and triphenylphosphine or phosphorus trihalide. The solvent used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, or nitriles such as acetonitrile are preferable. The reaction temperature is not particularly limited, but it is preferably -25 ° C to room temperature, and the reaction time is usually 1 to 60 minutes, varying mainly depending on the reaction temperature or the kind of the raw material compound.

The halogen-substituted compound can also be synthesized by reacting the above-synthesized ester with an alkali metal halide such as sodium iodide, sodium bromide or potassium chloride. The solvent used is a polar solvent capable of dissolving an alkali metal halide and is not particularly limited as long as it does not participate in the reaction, for example, sulfoxides such as dimethyl sulfoxide, N, N- Mention may be made of amides such as dimethylformamide or phosphoric triamides such as hexamethylphosphorotriamide, with N, N-dimethylformamide being preferred. Although the reaction temperature is not particularly limited, it is preferably carried out at 20 ° C to 80 ° C, and the reaction time mainly depends on the reaction temperature or the kind of the raw material compound, but is usually 1 to
24 hours.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

In the fourth step, the compound (VIII) having a hydroxy group or a mercapto group at the terminal is treated with a reactive derivative of carboxylic acid (XI
V) is reacted with or without a base to produce an ester or thiol ester compound (XV).

When Y is a halogen atom, the reaction is carried out in a solvent in the presence of a base.

The reaction solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent,
Halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane, or aromatic hydrocarbons such as benzene and toluene are preferably used.

The base used is not particularly limited as long as it is an amine, but triethylamine, diethylamine or pyridine is preferably used.

The reaction temperature and the reaction time will differ depending on the conditions of the starting material, solvent and base used, but when carried out in the range of 0 ° C to 120 ° C, 2 to 24 hours are preferable.

When Y represents a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower aliphatic acyloxy group or an aromatic acyloxy group, a base is not always necessary in the reaction and immediately reacts, but when a base is used, Be accelerated.

The solvent used in this case is not particularly limited as long as it does not participate in this reaction, for example, chloroform,
Halogenated hydrocarbons such as dichloromethane and dichloroethane or ethers, ethers such as tetrahydrofuran and dioxane may be mentioned, and dichloromethane or tetrahydrofuran is preferable. Although the reaction temperature is not particularly limited, it is usually 0 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C., and the reaction time varies depending mainly on the reaction temperature or the kind of the starting compound, 0.
5 to 24 hours.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

In the fifth step, a compound (VIII) having a hydroxy group or a mercapto group at the terminal is reacted with an isocyanate compound (XVI) to produce a carbamate or thiol carbamate compound, and further, if desired, by substituting an imino group, This is a step of producing compound (XVII).

The compound (XVI) has, for example, the formula (In the formula, m, n, R ⁵ ′ and Q ″ have the same meanings as described above), and the compound represented by DPPA (diphenylphosphoryl azide)
In an inert solvent such as chloroform, toluene, benzene, dichloromethane or tetrahydrofuran, preferably in toluene or benzene in the presence of an organic base such as triethylamine or tributylamine, at 0 ° C to 150 ° C.
Compound (VIII) can be directly added to this solution for 2 to 24 hours,
By reacting at 60 ° C to 150 ° C, the target compound (X
VII) can be produced. Preferably, the compound (XV
When I) was synthesized, it was washed with saturated aqueous sodium hydrogen carbonate solution and water to remove phosphorus compounds, the solvent was distilled off, dried, and then dissolved in a solvent (preferably toluene) selected from the above exemplified solvents. Then, the compound (VIII) is added and reacted.

The imino group substitution reaction is carried out by a conventional method, for example, it is achieved by reacting a carboxylic acid halide or a carboxylic acid anhydride in the presence of an organic base. The solvent used is not particularly limited as long as it does not participate in this reaction, but it is preferably an aromatic hydrocarbon such as benzene or toluene, or pyridine. The base used is not particularly limited as long as it is an organic base, but is preferably triethylamine, diisopropylethylamine, N, N-dimethylaminopyridine or pyridine. The reaction temperature is not particularly limited, but it is preferably 20 ° C. to 120 ° C., and the reaction time is 1 to 24 hrs, varying mainly depending on the reaction temperature and the kind of the raw material compound.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

In the sixth step and the seventh step, compound (VIII) having a hydroxy group or mercapto group at the terminal is reacted with compound (XVIII) in the presence of an organic base to produce compound (XIX), which is isolated or isolated. Amine compound (XX) without
And the reaction in the presence of an organic base to produce a carbamate or thiol carbamate compound (XXI). The solvent used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, and tetrahydrofuran and dioxane. Ethers such as are preferred.
The base used is not particularly limited as long as it is an organic base, but preferably triethylamine, 1,5-diazabicyclo [5.4.0] -undec-5-ene, pyridine, 2,6-
It is lutidine, N, N-dimethylaniline or N, N-dimethylaminopyridine. The reaction temperature is not particularly limited and is, for example, 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
℃. The reaction time mainly depends on the reaction temperature and the kind of the raw material compound, but is 0 through the 6th and 7th steps.
5 to 24 hours.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

In the eighth step, in the compound (XXI), when the terminal Q ′ group is a group having the formula —O—R ²² (in the formula, R ²² has the same meaning as described above), this —O— By converting the R ²² group into a Y group and further substituting an imino group, if desired, a carbamate or thiol carbamate compound (XV
II) is a process for producing, the first step is performed in the same manner as the third step, and the second step is performed in the same manner as the protection reaction in the fifth step.

In the ninth step, compound (XIX) is converted to hydroxy compound (XXI
I) by reacting with a carbonate compound (XXII
This is a process of manufacturing I) and is performed in the same manner as the seventh process.

In the tenth step, in the compound (XXIII), when the terminal Q ′ group is a group having the formula —O—R ²² (in the formula, R ²² has the same meaning as described above), this —O— This is a step of converting the R ²² group into a Y group, and is carried out in the same manner as the third step.

In the eleventh step, the hydroxy group or mercapto group at the 2-position of the compound (XXV) in which the hydroxy group or mercapto group at the 3-position is protected is converted into the corresponding compound (XXVI) or (XXVI ′) according to the above-mentioned Steps 1 to 10. ) Is manufactured.

The twelfth step is a step for producing a compound (XXVII) or (XXVII ′) by removing the protecting group for the hydroxy group or mercapto group at the 3-position of the compound (XXVI) or (XXVI ′).

When the hydroxy-protecting group is a di- or triarylmethyl group, elimination of the entraining group is performed with an acid such as trifluoroacetic acid, hydrochloric acid or acetic acid. When the protecting group for the hydroxy group is a benzyl group, the elimination thereof is carried out by reduction, preferably catalytic reduction using palladium-carbon as a catalyst. Further, when the hydroxy-protecting group is a silyl group, a fluorine anion is used for the elimination reaction, but tetrabutylammonium fluoride is preferably used. Further, when the hydroxy-protecting group is a tetrahydropyranyl group, elimination is carried out by an acid (eg acetic acid, tosylic acid).

When the reaction substrate has a sulfur atom, when the hydroxy-protecting group is a benzyl group, it is preferably carried out by reacting aluminum chloride and sodium iodide at room temperature, and the protecting group is Alternatively, when the group is a triarylmethyl group, an acid (eg, trifluoroacetic acid, hydrochloric acid, acetic acid) is preferably used.

In addition, deprotection of a thiol group protected by an acetyl group or the like is performed using sodium methoxide-methanol, ammonia water,
It is carried out using a base such as aqueous sodium hydroxide or aqueous potassium hydroxide, and preferably a 10 to 30% sodium methoxide-methanol solution is used.

In the 13th step, the hydroxy group or mercapto group at the 3-position is
Alkylation, acylation or carbamation, optionally in the same manner as in the third step, when the Q ′ group is a group of the formula —O—R ²² (in the formula, R ²² has the same meaning as described above), In this step, this group is converted into a Y group to produce compound (XXVIII).

Examples of the alkylation method include compound (XXVII) or (XXV
It is carried out in the same manner as in the first step by reacting II ′) with a compound having the formula Y—R ¹ ′ (wherein Y and R ¹ ′ have the same meanings as described above).

In addition, the 3-position mesylate of the compound (XXVII) or (XXVII ′) is converted to a compound having the formula M—A—R ¹ ′ (wherein M, A and R).
¹ 'is as defined above. ) Is also achieved. However, in this case, the configuration at the 3-position is reversed.

The solvent used is not particularly limited as long as it does not participate in this reaction, for example, aromatic hydrocarbons such as benzene and toluene; N, N-dimethylformamide, N, N
Mention may be made of amides such as dimethylacetamide or dimethylsulfoxide, preferably benzene or N, N-dimethylformamide. The reaction temperature is not particularly limited, but is, for example, 0 ° C. to 120 ° C., preferably 70 ° C. to 120 ° C., and the reaction time mainly depends on the reaction temperature and the kind of the raw material compound, but is preferably Is 1 to 24 hours.

Examples of the acylation method include compound (XXVII) or (XXVI
I ′) is a compound having the formula YR ¹ ′, where Y and R
¹ 'is as defined above. ) Or the formula R ¹ ′ -OR ¹ ′
Can be achieved by reacting an acid anhydride having the formula (wherein R ¹ ′ has the same meaning as described above), and the reaction conditions are
It is carried out in the same manner as the fourth step.

As the carbamation method, the compound (XXVII) or (XXVII ′) is reacted with an isocyanate compound having the formula R ³ —N═C═O (wherein R ³ has the same meaning as described above). And can be achieved in the same manner as the fifth step.

The 14th step is a step of reacting compound (XXIX) with compound (IX) to obtain compound (XXX),
It is carried out in the same manner as the process.

The 15th step is a step of reacting the compound (XXXI) with the compound (XXXII) to obtain the compound (XXX), and is carried out in the same manner as the 2nd step. Unlike the 2nd process, 3
A compound in which the configuration of the position is inverted is produced.

The 16th step is a step of converting the compound (XXX) into the compound (XXXIII), and is carried out in the same manner as the 3rd step.

The seventeenth step is a step of reacting compound (XXIX) with compound (XIV) to obtain compound (XXXIV),
It is carried out in the same manner as the fourth step.

The 18th step is a step of reacting compound (XXIX) with compound (XVI) to obtain compound (XXXV), and is carried out in the same manner as in the 5th step.

The nineteenth step is a step of reacting compound (XXIX) with compound (XVIII) to obtain compound (XXXVI), and is performed in the same manner as sixth step.

The 20th step is a step of reacting the compound (XXXVI) with the compound (XX) to obtain a compound (XXXVII),
It is carried out in the same manner as the seventh step.

The 21st step is a step of converting the compound (XXXVII) into the compound (XXXV), and is carried out in the same manner as the 3rd step.

The 22nd step is a step of reacting compound (XXXVI) with compound (XXII) to obtain compound (XXXVIII), and is carried out in the same manner as 9th step.

The 23rd step is a step of converting the compound (XXXVIII) into the compound (XXXIX), and is carried out in the same manner as the 3rd step.

The twenty-fourth step is from compound (XL) to compound (XLI) or (X
LI ′), which is carried out in the same manner as the 11th step.

The 25th step is a step of obtaining compound (XLII) or (XLII ′) from compound (XLI) or (XLI ′), and is carried out in the same manner as 12th step.

The 26th step is a step of obtaining compound (XLIII) from compound (XLII) or (XLII ′), and is carried out in the same manner as 13th step.

The 27th step is the compound (XIII) produced as described above,
(XV), (XVII), (XXIV), (XXVIII), (XXXII
I), (XXXIV), (XXXV), (XXXIX) or (XLIII), when Q ″ represents a group having the formula Y (wherein Y has the same meaning as described above), and An amine compound (XLIV) or a compound having the formula HG (wherein -G has the same meaning as described above) is reacted, and further, if desired,
The compound (I) of the present invention can be prepared by removing a removable group out of the group defined as R ^{4 ′} and / or R ⁶ and / or the protecting group of the protected carboxy group of R ⁵ ′.
Is a process of manufacturing.

The reaction solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent,
Preferable halogenated hydrocarbons such as methylene chloride and chloroform; lower alcohols such as methanol, ethanol and isopropyl alcohol; dimethylformamide; ethers such as diethyl ether, tetrahydrofuran and dioxane; acetonitrile or water, or, for example, Chloroform-dimethylformamide-isopropyl alcohol = 2-3 such as 3: 5: 5
A mixture of the above solvents of the species is used.

The reaction temperature and the reaction time will differ depending on the conditions of the starting materials and the solvent used, but the reaction may be carried out in the sealed reaction vessel (for example, a sealed tube) under a nitrogen atmosphere in the range of 20 to 80 ° C. for 1 to 48 hours. It is suitable.

The removal of the protecting group varies depending on its type, but is generally carried out as follows by a well-known method.

Regarding the removal of the protecting group of the carboxy group, when the protecting group of the carboxy group is a lower alkyl group, it can be removed by treating with a base.
The reaction conditions are the same as the removal reaction conditions described when the hydroxyl-protecting group is a lower aliphatic acyl group or an aromatic acyl group.

When the protecting group for the carboxy group is an aralkyl group or a halogeno lower alkyl group, it can be removed by bringing it into contact with a reducing agent. As the reducing agent, zinc-acetic acid is suitable when the protecting group of the carboxy group is a halogeno lower alkyl group, and when it is an aralkyl group, catalytic reduction is carried out using a catalyst such as palladium carbon or platinum. Performed or carried out with an alkali metal sulfide such as potassium sulfide, sodium sulfide. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or acetic acid. Fatty acids such as and mixed solvents of these organic solvents and water are preferred. The reaction temperature is usually 0 ° C. to room temperature,
The reaction time varies depending on the kinds of the raw material compound and the reducing agent, but is usually 5 minutes to 12 hours.

When the protecting group for the carboxy group is an alkyloxymethyl group, it can be removed by treating with an acid. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid or the like. The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, tetrahydrofuran, ethers such as dioxane or a mixed solvent of these organic solvents and water is preferable. is there. The reaction temperature is usually 0 ° C. to 50 ° C., and the reaction time is usually 10 min to 18 hr, varying depending on the kinds of raw material compounds and acids.

Among the groups defined as R ⁴ and / or R ⁶ by the operation of removing the protecting group for the carboxy group as described above,
Removable groups may also be removed at the same time.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, after removing the insoluble matter precipitated from the reaction mixture, the organic solvent layer is washed with water and dried, the solvent is distilled off,
For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

Of the groups defined as R ⁴ and / or R ⁶ , for elimination of a removable group, when the group is a lower aliphatic or aromatic acyl group or an alkyloxycarbonyl group, It can be removed by treatment, and the reaction conditions are the same as those of the removal reaction described when the hydroxyl-protecting group is a lower aliphatic acyl group or an aromatic acyl group.

When the group is an alkenyloxycarbonyl group, it is usually eliminated by treatment with a base in the same manner as in the removal reaction when the protective group for the hydroxyl group is a lower aliphatic acyl group or an aromatic acyl group. Can be made. In the case of allyloxycarbonyl, a method of removing it particularly using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

The protective group for the carboxy group may be removed at the same time by the above removing operation.

After completion of the reaction, the target compound can be isolated from the reaction mixture by a conventional method. For example, a pure product can be obtained by purification by recrystallization, preparative thin layer chromatography, column chromatography and the like.

In addition, the reaction for removing the protecting group for the carboxy group and R ⁴
And / or the elimination reaction of the removable group of the groups defined as R ⁶ can be performed in any order, and desired reactions can be sequentially performed.

Furthermore, if desired, the carboxy group can be protected again with a protecting group that is easily hydrolyzed in vivo.

This reaction is generally carried out by methods well known in the art.

For example, aliphatic acyloxymethyl halides such as acetoxymethyl chloride, propionyloxymethyl bromide, pivaloyloxymethyl chloride, lower alkyloxycarbonyl such as 1-methoxycarbonyloxyethyl chloride, 1-ethoxycarbonyloxyethyl iodide. Oxyethyl halides, phthalidyl halides or (2-oxo-5-methyl-1,3-dioxolen-4-yl) methyl halides are added at 0 ° C to 50 ° C.
By reacting at ° C, an ester body protected by a carboxyl-protecting group which is easily hydrolyzed in vivo can be produced. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but a polar solvent such as dimethylformamide is preferably used. The reaction temperature and reaction time will differ depending on the types of starting materials, solvent and reaction reagents, but they are usually reacted in the range of 0 ° C to 100 ° C for 0.5 hours to 10 hours.

Note that Q ′ or Q ″ is a group having the formula —G (wherein —G
Has the same meaning as above. ), The compounds (X), (XIII), (XV), (XXI), (XVII), (XXI
II), (XXIV), (XXVIII), (XXX), (XXXIII),
(XXXIV), (XXXV), (XXXVII), (XXXVIII), (XX
XIX) and (XLIII) are the compound (I) of the present invention, and in this case, they were optionally defined as a protecting group for the carboxy group and / or R ⁴ and / or R ^{6 in the same} manner as in the 27th step. Of the groups, a removable group is removed, and further, if desired, protected again with a protecting group that is easily hydrolyzed in vivo, to produce the corresponding compound (I) of the present invention.

Raw material compounds (VIII), (XI), (XXV), (XXI of the present invention
X), (XXXI) or (XL) is a novel compound, for example, as shown in the following reaction formula, a known compound having a formula (XLV) (specifically, 3,4-dihydro-2H-pyran) , Dihydrofuran, 6,7-dihydrooxepin) can be stereoselectively produced as a dl form for two asymmetric carbons on the ether ring.

In the above formula, l, R ²⁰ , R ¹ ′, and Y have the same meanings as described above,
R ²¹ represents a group similar to the group defined for R ²⁰ , but R ²⁰
And R ²¹ represent groups that can be selectively and selectively removed.

The reaction conditions used in the above reaction are defined and explained below.

Reaction 1: Rubou et al., Synthesis, p. 610, 1979 [A. Lebou
c, et.al., Synthesis, 610, (1979)], the compound (XLV) is hydroxymethylated to give the compound (X
Reaction to obtain LVI).

Reaction 2: A reaction for producing a compound (XLVII) by protecting the hydroxy group of the compound (XLVI) with the above-mentioned protecting group, which is carried out according to a conventional hydroxy group-protecting reaction, preferably using benzyl halide and benzyl. The reaction that activates. As a reaction substrate, instead of the hydroxy group, for example, a compound (XL-
The mercapto group of 3) can be protected with the above-mentioned mercapto group-protecting group.

Reaction 3: Hydroboration reaction is carried out on the double bond portion of compound (XLVII) to introduce a transhydroxy group to obtain compound (XL-1), and borane is preferably used. It is also possible to carry out this reaction asymmetrically,
In that case, an optically active substance can be synthesized. The reaction is carried out according to the method of Brown et al. [J. Org. Chem., 47 , 5074 (1982)] using monoisopinocamphenylborane.

Reaction 4: The hydroxy group of the compound (XL-1) was converted to the formula R ¹ ′-
Alkylating according to the first step with a compound having the formula R ¹ ′ -Y, using a compound having the formula Y with a compound having the formula R ¹ ′ -Y, or using a compound having the formula R ³ —N═C═O with a compound having the formula 5 Carbamate conversion is carried out according to steps, but a mercapto group such as the compound (XL-3) can be similarly carried out instead of the hydroxy group.

Reaction 5: A reaction for removing a protecting group of a hydroxy group or a mercapto group, which is carried out in the same manner as the 12th step.

Reaction 6: Compound (XL-1) is a reaction in which a hydroxy group is oxidized and converted into a carbonyl group by a Jones reagent using chromic acid or pyridinium chlorochromate to obtain compound (XLVIII).

Reaction 7: A reaction for stereoselectively reducing the carbonyl group of the compound (XLVIII) using L-selectride to generate a cis-hydroxy group and obtaining a compound (XL-2).

Reaction 8: Acylation of the hydroxy group of compound (XL-1) in the same manner as in the third step, for example, by methanesulfonyl, toluenesulfonyl, trifluoromethanesulfonyl or trifluoroacetylation to synthesize an ester, and then using, for example, thioacetic acid It is a reaction in which the acyloxy group is converted into a stereo-inverted protected thiol group to obtain a compound (XL-3).

Reaction 9: a reaction in which the hydroxy group of the compound (XL-1) is protected with a protecting group of a group different from the protecting group described in the above reaction 2 to obtain the compound (XXV-1), preferably a tetrahydropyranyl group A group of protecting groups is used.

Reaction 10: is a step of producing a compound (XI-1) by converting the hydroxy group of the compound (VIII-1) into a halogen atom in the same manner as in the third step.

The table below shows in which step the above-defined reaction can be carried out.

Furthermore, the raw material compound of the present invention can specifically produce an optically active substance of d-form or l-form by using d- or 1-tartaric acid as a starting compound, as shown in the following reaction formula, for example. it can.

In the above formula, R ²⁰ and R ²¹ have the same meanings as described above, and R ²³ represents a lower alkyl group. R ^24, R ²⁶ and R ^27, which shows the definitions the same groups of R ²⁰ and ^{R 21, R 20, R 21} , R 24, of R ²⁶ and R ^27, 2 or more, in the same compound When used, they shall represent groups which may be selectively removed in distinction from other protecting groups. R ²⁵ represents the same group as the lower alkylsulfonyloxy group and the arylsulfonyloxy group in the definition of Y.

Preferably, R ²⁰ is a benzyl group, R ²¹ is a silyl group, R
²⁴ is a di- or triarylmethyl group, R ²⁶ is a lower aliphatic acyl group, and R ²⁷ is a tetrahydropyranyl group.

Ohno et al., Tetrahedron Letters, 23, 3507, 1982
Year (Ohno, et.al., Tetrahedron Lett., 23 , 3507, (198
2)], the oxygen atom at the 3-position of (2S, 3S) tartaric acid (LI), which is the starting material, has a protecting group R
A compound (LII) substituted with ²⁰ can be synthesized (step 73).

The primary hydroxy group of the compound (LII) is acylated in the same manner as in the first half of the above reaction 8, the acyloxy group is replaced with iodine, and then the compound is reacted with di-lower alkyl malonate to produce a compound (LIII). (Step 74).

The compound (LIII) can be decarbonated by heating with, for example, an aqueous solution of sodium chloride in DMSO to obtain a compound (LIV) obtained by adding 2 carbon to (LII) (step 75).

The alcohol compound (LV) can be produced by reducing the compound (LIV) with a reducing agent such as lithium aluminum hydride in an ether solvent (step 76). The hydroxy group of this compound was converted to R ²¹ (preferably diphenyl t-
Butylsilyl group) to remove the isopropylidene group, and the resulting primary hydroxy group is protected with R ²⁴ (preferably triphenylmethyl group) (step 77) to remove the secondary hydroxy group from the tertiary Acylation is carried out in the same manner as in the step to produce compound (LVII) (step 78). The hydroxy-protecting group R ²¹ (or R ²¹ is a fluorine anion when R ²¹ is a silyl group) of the compound (LVII) is removed (step 79),
By treating this with a base (for example, potassium t-butoxy in t-butanol), the optically active compound (LIX) in which the configuration at the 2-position is inverted and the ring is closed can be produced (step 80). .

Further, the compound (LIX) can be produced in the same manner as in the above Reaction 8 to produce a mercapto compound (LX) having a steric configuration (step 81).

The compound (LV) can be converted into a protected thiol group having a reversed conformation in the same manner as in Reaction 8 (steps 82 and 83).

Compound (LXII) can be produced by carrying out the compound (LXII) in the same manner as in Steps 77 to 80 (Step 84).

Compound (LXIII) can be produced in the same manner as in Step 81 to produce optically active compound (LXIV) (Step 85).

The secondary hydroxy group of compound (LVI) is protected by R ²⁷ (8th group).
(Step 6), after selectively removing the protecting group R ²¹ , the hydroxy group formed can be acylated in the same manner as in Step 3 to produce the compound (LXVI) (Step 87).

By selectively removing the protective group R ²⁷ for the secondary hydroxy group of the compound (LXVI) (step 88) and carrying out in the same manner as in step 80, ring closure in which the 2-position configuration was retained was carried out. An optically active compound (LXVIII) can be produced (step 89). Furthermore, a mercapto compound (LXIX) can be produced in the same manner as in step 81 (step 90).

Compound (LXX) can be produced using compound (LXII) in the same manner as in step 77, (step 91).

Compound (LXXI) can be produced using compound (LXX) in the same manner as in step 86 (step 92).

Compound (LXXII) can be produced by using compound (LXXI) in the same manner as in step 87 (step 93).

Compound (LXXIII) can be produced using compound (LXXII) in the same manner as in step 88 (step 94).

Compound (LXXIII) can be produced by using Compound (LXXIII) in the same manner as in Step 89 (95th step).
Process).

Compound (LXXIV) was carried out in the same manner as in Step 81,
An optically active compound (LXXV) can be produced (step 96).

As a starting material, d-tartaric acid having (2R, 3R) (LXXV
The compound (LXXVII) of (2S, 3S) can be produced by using I) in the same manner as in step 73 (step 97).

By using this compound (LXXVII) and performing steps similar to steps 74 to 96 above, the compound of the optically active form (LX
XVIII) to (LXXXV) can be produced (step 98).

On the other hand, in order to synthesize the starting material of the compound (I) of the present invention having a 5-membered ring (l = 2), a cyanide compound was synthesized using metal cyanide instead of the malonate ester, and alcohol decomposition was carried out according to a conventional method. By synthesizing an ester and further reducing the compound (LII) by using an alcohol compound (LXXXVI) which has been carbonized by 1 carbon to carry out steps 77 to 96 to produce a corresponding optically active compound. can do.

Further, in order to synthesize the starting material of the compound (I) of the present invention having a 7-membered ring (l = 4), the compound (LXXXVI) is used as a starting material, and steps 74 to 96 are carried out. An optically active compound can be produced.

One of the protecting groups of the above-prepared optically active compound is removed according to the same method as in the 13th step, and further alkylated, acylated or carbamateized according to the above Reaction 4, to give the compound of the present invention. A raw material compound can be manufactured.

〔effect〕

INDUSTRIAL APPLICABILITY The novel cyclic ether derivative of the present invention has a strong PAF antagonistic activity with excellent durability and bioavailability, and is useful as a new type of anti-shock agent, anti-thrombotic agent, anti-asthma agent and anti-allergic agent. is there.

Examples of the dosage form of the compound (I) of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories. Its usage is symptom
Depending on age etc., 0.1-200 mg / Kg body weight daily,
It can be administered once or in several divided doses.

Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples and Test Examples.

Example 1 dl-3- {7- (trans-3-hexadecyloxytetrahydropyran-2-yl) methoxy} heptyl thiazolium methanesulfonate The compound of Reference Example 55 (2.067 g) and triethylamine (1.83 g)
ml) in benzene (15 ml), a solution of methanesulfonyl chloride (0.51 ml) in benzene (5 ml) was added dropwise under ice cooling. After stirring at room temperature for 15 minutes, the reaction solution was washed with water, dried and concentrated, and crude dl-7- (trans-3-hexadecyloxytetrahydropyran-2-yl) methoxyheptyl methanesulfonate (2.406 g) was viscous. Obtained as a clear oil. This compound (1.20 g) and thiazole (1.56 ml) were dissolved in toluene (3 ml), and the mixture was heated with stirring on an oil bath at 70 ° C for 5 days. After cooling, the solvent was distilled off and the residue was washed with silica gel (40
g) was used for column chromatography. Fractions eluted with methylene chloride-methanol-water (60: 35: 5) were collected to give the title compound (0.741g) as a viscous oil.

NMR spectrum (CDCl ₃ ) ppm: Measured at 90 MHz unless otherwise specified.

0.7 to 2.45 (45H, m) 2.77 (3H, s, −OSO ₂ CH ₃ ) 2.95 to 4.05 (10H, m) 4.75 (2H, t, J = 7.5Hz) 8.4 to 8.6 (2H, m) 10.91 (1H , m) Example 2 dl-3- {7- (cis-3-hexadecyloxytetrahydropyran-2-yl) methoxy} heptyl thiazolium methanesulfonate Using the compound of Reference Example 58 (1.215 g) and operating as in the first half of Example 1, crude dl-7- (cis-3-hexadecyloxytetrahydropyran-2-yl) methoxyheptyl methanesulfonate (1.42 g) was obtained as a viscous oil. This compound (0.71 g) was treated as in the latter half of Example 1 to give the title compound (0.322 g) as a viscous oil.

NMR spectrum _{(CDCl 3) ppm: 0.75~2.30 (} 45H, m) 2.77 (3H, s, -OSO 2 CH 3) 3.1~3.75 (9H, m) 3.85~4.20 (1H, m) 4.77 (2H, t, J = 7.5Hz) 8.4~8.7 (2H, m) 10.97 (1H, m) elemental _{analysis: C 33 H 63 NO 6 S} 2 · H 2 O calculated: C, 60.79; H, 10.05 ; N, 2.15; S, 9.83 Found: C, 60.39; H, 9.94; N, 2.16; S, 9.52 Example 3 dl-3- [5-{(trans-3-hexadecyloxytetrahydropyran-2-yl) methoxycarbonylamino } Pentyl] thiazolium bromide The compound of Reference Example 47 (711 mg) was dissolved in toluene (2 ml), thiazole (1.84 ml) was added, and the mixture was heated at 80 ° C. for 86 hours. The reaction mixture was concentrated to dryness, and the residue was subjected to column chromatography using silica gel (17g). Fractions eluted with methylene chloride-methanol (19: 1 to 17: 3) were collected and subjected to medium pressure liquid chromatography using a Rover B column. Fractions eluted with the above solvent system were collected to give the title compound (480 mg) as a powder.

NMR spectrum (CD₃OD) ppm: 0.7 to 2.4 (41H, m) 2.9 to 4.5 (10H, m) 4.62 (2H, t, J = 7Hz, ▲ -CH _Two▼ N) 8.31 (1H, d, J = 4Hz) 8.52 (1H, d, J = 4Hz) IR spectrum (CHCl₃)cm^-1: 3470 (-NH), 1710 (-O
-CO-) Example 4 dl-3- [5-{(trans-3-heptadecylcarba
Moyloxytetrahydropyran-2-yl) methoxy
Carbonylamino} pentyl] thiazolium bromideDissolve the compound of Reference Example 6 (400 mg) in toluene (1 ml)
Then, add thiazole (0.47ml) and heat at 80 ℃ for 66 hours.
It was The reaction mixture was concentrated to dryness, and the residue was washed with silica gel (10 g).
Subjected to the column chromatography used. Methyl chloride
Fractions eluted with methanol-methanol (19: 1 to 4: 1) were collected.
To give the title compound (390 mg) as a powder.

mp 54-56 ° C NMR spectrum (270MHz, CD ₃ OD) ppm: Elemental analysis: Calculated as C ₃₃ H ₆₀ BrN ₃ O ₅ S ・ 1.5H ₂ O: C, 55.22; H, 8.85; N, 5.85; S, 4.47 Found: C, 55.22; H, 8.56; N, 5.73 S, 4.22 Example 5 3- [5-{(2S, 3R) -3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonylamino} pentyl] thiazolium bromide The compound of Reference Example 31 (564.0 mg), and thiazole (0.6
6 ml), and in the same manner as in Example 4, the title compound (55
3.0 mg) was obtained as a white powder. mp.97.0-99.0 ℃, ▲
[Α] _{^{25 D ▼ -27.3 ° (C =}} 1.05, MeOH) FAB- mass spectrum (m / e): 610 ( M-Br -) + Elemental _{analysis: C 33 H 60 BrN 3 O} 5 S · 1.2H 2 Calculated value as O: C, 55.63; H, 8.83; N, 5.90; S, 4.50 Actual value: C, 55.58; H, 8.62; N, 5.78; S, 4.36 Example 6 3- [5-{(2R, 3S) -3-Heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonylamino} pentyl] thiazolium bromide The compound of Reference Example 32 (540.0 mg), and thiazole (0.6
3 ml) and the title compound (523.8 m)
g) was obtained as a white powder. mp.97.0-99.0 ℃ ▲ 〔α〕
_{^{25 D ▼ + 27.2 ° (C}} = 1.05, MeOH) FAB- mass spectrum (m / e): 610 ( M-Br -) + Elementary analysis: as _{C 33 H 60 BrN 3 O 5} S · 1.5H 2 O Calculated value: C, 55.22; H, 8.85; N, 5.85; S, 4.47 Actual value: C, 55.18; H, 8.40; N, 5.86; S, 4.32 Example 7 dl-3- [5-{(cis- 3-heptadecylcarbamoylthiotetrahydropyran-2-yl) methoxycarbonylamino} pentyl] thiazolium bromide The compound of Reference Example 42 (600 mg) was dissolved in toluene (1 ml), thiazole (0.68 ml) was added, and the mixture was heated on an oil bath at 80 ° C. for 64 hours. The reaction mixture was concentrated to dryness, and the residue was subjected to column chromatography using silica gel (15g).
Fractions eluted with methylene chloride-methanol (9: 1 to 4: 1) were collected to give the title compound (595 mg) as a white powder.

m.p 122-125 ° C NMR spectrum (CD₃OD) ppm: 0.7 to 2.3 (43H, m) 2.9 to 4.2 (10H, m) 4.67 (2H, t, J = 7Hz, -CH₂ N)IR spectrum (KBr) cm^-1: 3320 (-NH), 1700 (-O-C
O-), 1640 (-S-CO-) Elemental analysis: C₃₃H₆₀BrN₃O_FourS₂・ 3 / 2H₂Calculated value as O: C, 54.01; H, 8.65; N, 5.73; S, 8.74 Actual value: C, 54.29; H, 8.21; N, 5.74; S, 8.36 Example 8 dl-3- [5-{( Cis-3-heptadecyl carbamoy
Luoxytetrahydropyran-2-yl) methoxycal
Bonylamino} pentyl] thiazolium bromideThe compound of Reference Example 67 (550.2 mg) and thiazole (0.65 m
From l) to the same compound as in Example 4 (526.9 mg)
Was obtained as a white powder. mp115-120 ° C.

NMR spectrum (CD₃OD-CDCl₃, 1: 1) ppm: 0.7 to 2.3 (43H, m) 3.0 to 3.2 (4H, m) 3.4 to 3.8 (2H, m) 3.9 to 4.2 (3H, m) 4.66 (2H, t, J = 7Hz,- CH₂ N) 4.7 to 4.9 (1H, m, C (3) -H)IR spectrum (CHCl₃)cm^-1: 3460 (-NH-), 1705,1695
(-O-CO-) Elemental analysis: C₃₃H₆₀BrN₃O_FiveS / 3H₂Calculated as O: C, 53.21; H, 8.12; Br, 13.48; N, 5.64; S, 3.30 Found: C, 53.31; H, 7.99; Br, 13.78; N, 5.51; S, 3.59 Example 9 dl -3- [6-ethoxycarbonyl-6-{(trans
-3-heptadecylcarbamoyloxytetrahydropi
Lan-2-yl) methoxycarbonylamino} hexyl
Lu] thiazolium methanesulfonateThe compound of Reference Example 64 (0.363 g) and triethylamine (0.16 g)
ml) in benzene (5 ml) and methanesulfonyl chloride.
Lido (0.099g) was added under ice cooling. Stir at room temperature for 15 minutes
After that, the reaction solution was washed with water, dried and concentrated. Oily residue (0.
357g) and thiazole (0.41ml) to toluene (2.0m
l), and heated and stirred for 4 days on a 90 ° C. oil bath. Melting
After distilling off the medium, the residue was washed with silica gel (30 g).
Rum chromatography. Methylene chloride-
Fractions eluted with methanol (3: 1 to 1: 1) are collected and labeled
To obtain the compound (0.205 g) as a white powder. mp52-60 ℃ NMR spectrum (270MHz, CD₃OD) ppm: 0.90 (3H, t, J = 7.0Hz) 1.25 (3H, t, J = 7.0Hz) 1.3 to 1.9 (39H, m) 2.01 (2H, m) 2.20 (1H, m) 2.70 (3H, s) 3.06 (2H, t, J = 6.9Hz) 3.44 (2H, m) 3.89 (1H, m) 4.0 to 4.3 (2H, m) 4.16 (2H, q, J = 7.0Hz) 4.49 (1H, m) 4.60 (2H, t, J = 7.5Hz) 8.29 (1H, d, J = 3.7Hz) 8.50 (1H, d, J = 3.7Hz) Elemental analysis: C₃₈H₆₉N₃O_TenS₂Calculated as: C, 57.61; H, 8.78; N, 5.30 Found: C, 57.57; H, 8.94; N, 5.17 Example 10 dl-cis-2- {N- (2-pyridylmethyl) carbamo
Iloxy} methyltetrahydropyran-3-yl = N
-Heptadecyl thiol carbamateA sample of the compound of Reference Example 41 (1.424 g) and pyridine (0.54 ml) was prepared.
To the solution of Tylene chloride (20 ml), phenyl chlorocarbonate
A solution of (0.778 g) in methylene chloride (8 ml) was added.
After stirring at room temperature for 1 hour, pour the reaction solution into water and
Extracted 3 times with chloride. Sequentially add 10% hydrochloric acid and
Washed with aqueous sodium hydrogen carbonate solution and saturated saline
After drying, the solvent was distilled off. Crude carbonate obtained
Dissolve (2.01 g) in chloroform (28 ml), and add 2- (a)
Minomethyl) pyridine (0.68 ml) was added and heated for 44 hours.
Shed The reaction mixture is concentrated to dryness and the residue is washed with silica gel (40
g) was used for column chromatography. Heki
Fractions eluted with sun-ethyl acetate (2: 1 to 0: 1) are collected.
Reprecipitation from hexane-methylene chloride,
The title compound (1.675g) was obtained as a white solid. m.p8
8 to 90 ° C NMR spectrum (CDCl₃) Ppm: 0.7 to 2.2 (37H, m) 3.1 to 4.3 (8H, m) 3.26 (2H, q, −SCONHCH ₂ −) 4.51 (2H, d, J = 6Hz, −CH ₂ -2-pyridyl) 5.38 (1H, m, -SCONH-) 5.82 (1H, m, -OCONH-)IR spectrum (CHCl₃)cm^-1: 3440 (-NH-), 1720 (-
O-CO-), 1670 (-S-CO-) Elemental analysis: C₃₁H₅₃N₃O_FourCalculated as S: C, 66.04; H, 9.47; N, 7.45; S, 5.69 Actual value: C, 66.12; H, 9.38; N, 7.53; S, 5.63 Example 11 dl-cis-2- {N- Acetyl-N- (2-pyridylme
Tyl) carbamoyloxy} methyltetrahydropyran
-3-yl = N-acetyl-N-heptadecyl thiol
CarbamateThe compound of Example 10 (1.632 g), 4-dimethylaminopyri
Gin (3.54g) and acetic anhydride (2.73ml) in toluene (3
2 ml) solution was heated and stirred at 80 ° C. for 65 hours. Concentrate the reaction solution
After drying to dryness, the residue was subjected to column chromatography using silica gel (40 g).
Medium pressure using Matography and Rover B column
Subjected to liquid chromatography. Hexane-methylene
Collect the fractions eluted with chloride-ethyl acetate (15: 5: 4).
Thus, the title compound (0.493 g) was obtained as an oil.

NMR spectrum (60MHz CDCl ₃ ) ppm: Example 12 dl-cis-2- {N- (2-pyridylmethyl) carbamoyloxy} methyltetrahydropyran-3-yl = N
-Acetyl-N-heptadecyl thiol carbamate The compound of Example 11 was eluted through a column of silica gel (40 g), and then eluted with hexane-methylene chloride-ethyl acetate (1: 1: 1), and the obtained fractions were collected to obtain. The oil was purified using a Rover B column. Fractions eluted with the above solvent were collected to give the title compound (0.379 g) as an oil.

NMR spectrum (60 MHz, CDCl ₃ ) ppm: 0.7 to 2.2 (37H, m) 2.41 (3H, s, NCOCH ₃ ) 3.2 to 4.6 (10H, m) 5.90 (1H, m, NH) Example 13 dl-1-ethyl-2- [N-acetyl-N- {cis-3
-(N-Acetyl-N-heptadecylcarbamoylthio) tetrahydropyran-2-ylmethoxycarbonyl} aminomethyl] pyridinium chloride Ethyl iodide (10 ml) was added to the compound of Example 11 (0.493 g), and the mixture was heated under reflux for 91 hours. The reaction solution was concentrated to dryness, the residue was dissolved in 70% methanol, and the ion exchange resin IRA-410 [C
l ^- type, manufactured by Rohm and Haas Co., Ltd.] (44 ml). The column was washed with the same solvent, and the passing liquid and the washing liquid were combined and concentrated. The obtained crude chloride was subjected to column chromatography using silica gel (10 g) and then medium pressure liquid chromatography using a Rover B column. Fractions eluted with methylene chloride-methanol (9: 1) were collected to give the title compound (0.368g).

NMR spectrum (60 MHz, CD ₃ OD) ppm: Example 14 dl-trans-2- {N- (2-pyridylmethyl) carbamoyloxy} methyltetrahydropyran-3-yl = N-heptadecylcarbamate To a solution of the compound of Reference Example 4 (1.400 g) and pyridine (0.55 ml) in methylene chloride (20 ml) was added a solution of phenyl chlorocarbonate (0.795 g) in methylene chloride (8 ml).
After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with methylene chloride three times. The extract was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and the solvent was evaporated. The obtained crude carbonate (2.04 g) was dissolved in chloroform (28 ml), 2- (aminomethyl) pyridine (0.70 ml) was added, and the mixture was heated under reflux for 49 hours. The reaction mixture is concentrated to dryness and the residue is washed with silica gel (40
g) was used for column chromatography. Fractions eluted with hexane-ethyl acetate (1: 1 to 0: 1) were collected and reprecipitated from hexane-methylene chloride,
The title compound (1.663g) was obtained as a white solid. m.p7
8 to 80 ° C. NMR spectrum _{(CDCl 3) ppm: 0.7~2.4 (} 37H, m) 2.9~3.7 (4H, m) 3.7~4.9 (7H, m) 5.87 (1H, m, -N H -CH 2 -2 -Pyridyl) Mass spectrum (m / e): 547 (M ⁺ ) Elemental analysis: Calculated as C ₃₁ H ₅₃ N ₃ O ₅ : C, 67.97; H, 9.75; N, 7.67 Found: C, 67.94; H, 9.65; N, 7.69 Example 15 dl-trans-2- {N-acetyl-N- (2-pyridylmethyl) carbamoyloxy} methyltetrahydropyran-3-yl = N-heptadecylcarbamate The compound of Example 14 (1.613 g), 4-dimethylaminopyridine (3.60 g) and acetic anhydride (2.78 ml) in toluene (3
The solution was heated and stirred at 80 ° C. for 86 hours. The reaction mixture was concentrated to dryness, and the residue was subjected to column chromatography using silica gel (40 g) and then medium pressure liquid chromatography using a Rover B column. Fractions eluted with hexane-ethyl acetate (3: 2) were collected and reprecipitated from hexane to give the title compound (0.408 g) as a solid. m.p79~81 ℃ NMR spectrum _{(60MHz, CDCl 3) ppm:} 0.7~2.4 (37H, m) 2.62 (3H, s, -COCH 3) 2.8~3.5 (4H, m) 3.7~5.2 (7H, m) _{5.11 (2H, s, -CH 2} -2- pyridyl) Elemental _{analysis: C 33 H 55 N 3 O} 6 Calculated: C, 67.20; H, 9.40 ; N, 7.12 Found: C, 66.95; H, 9.67 ; N, 7.08 EXAMPLE 16 dl-1-ethyl -2 -[N-acetyl-N- {trans-3- (N-heptadecylcarbamoyloxy) tetrahydropyran-2-ylmethoxycarbonyl} aminomethyl] pyridinium chloride Ethyl iodide (8 ml) was added to the compound of Example 15 (0.365 g) and the mixture was heated under reflux for 40 hours. The reaction solution was concentrated to dryness, the residue was dissolved in 70% methanol, and the ion exchange resin IRA-410 [C
l ^- type, manufactured by Rohm and Haas Co., Ltd.] (35 ml). The column was washed with the same solvent, and the passing liquid and the washing liquid were combined and concentrated. The obtained crude chloride was subjected to column chromatography using silica gel (10 g) and further subjected to internal pressure liquid chromatography using a Rover B column. Fractions eluted with methylene chloride-methanol (9: 1) were collected to give the title compound (0.345g).

NMR spectrum (60 MHz, CD ₃ OD) ppm: Example 17 dl-1-ethyl-2- [N- {cis-3- (N-acetyl-N-heptadecylcarbamoylthio) tetrahydropyran-2-ylmethoxycarbonyl} aminomethyl]
Pyridinium chloride Ethane iodide (8 ml) was added to the compound of Example 12 (0.379 g), and the mixture was heated under reflux for 91 hours. The reaction solution was concentrated to dryness, the residue was dissolved in 70% methanol, and the ion exchange resin IRA-410 [C
l ^- type, manufactured by Rohm and Haas Co., Ltd.] (35 ml). The column was washed with the same solvent, and the passing liquid and the washing liquid were combined and concentrated. The obtained crude chloride was subjected to column chromatography using silica gel (10 g) and then medium pressure liquid chromatography using a Rover B column. Fractions eluted with methylene chloride-methanol (9: 1) were collected to give the title compound (0.302g).

NMR spectrum (60MHz, CD₃OD) ppm: 0.7 to 2.2 (40H, m) 1.63 (3H, t, J = 7Hz, N-CH₂ CH ₃ ) 2.38 (3H, s, NCOCH₃) 3.2 to 5.0 (13H, m) 4.73 (2H, q, J = 7Hz, N-CH ₂ CH₃)Reference Example 1 6-benzyloxymethyl-3,4-dihydro-2H-pyra
The6-hydroxymethyl-3,4-dihydro-2H-pyran
Hydrogen solution of (5.71g) in dimethylformamide (100ml)
Sodium iodide (55% mineral oil suspension, 2.18g) and dimethyl
It was added dropwise to the mixture of formamide under ice cooling. 1 at room temperature
After stirring for an hour, add benzyl chloride (6.33g)
It was After stirring for 16 hours, pour the reaction mixture into 1 of water and add vinegar.
It was extracted twice with ethyl acidate. Washing, drying and concentrating the extract
The oily residue (13g) was used on silica gel (200g)
Subjected to column chromatography. Ether-hexane
Collect the fractions eluted at (4: 100 to 5: 100) and combine the indicated compounds.
The product (9.40 g) was obtained as a colorless oil. Boiling point (below bp
Is abbreviated. ) 125 ~ 130 ℃ (bath temperature) / 1mmHg.

NMR spectrum _{(CDCl 3) ppm: 1.65~2.2 (} 4H, m, C (3) -H 2, C (4) -H 2) 3.87 (2H, s, - CH 2 -OCH 2 Ph) 4.03 (2H, _{m, C (2) -H 2} ) 4.57 (2H, s, -O-CH 2 -Ph) 4.80 (1H, t, J = 3.5Hz, C (5) -H) 7.2~7.6 (5H, m, C ₆ H ₅ -) Elementary analysis: C ₁₃ H ₁₆ O ₂ calculated: C, 76.44; H, 7.90 Found: C, 76.36; H, 7.90 reference example 2 dl-trans-2-benzyloxymethyl - tetrahydro Pyran-3-ol The compound of Reference Example 1 (9.00 g) was replaced with tetrahydrofuran (30 m
l), and 1M tetrahydrofuran solution of borane (29.3 ml) was added dropwise at -5 ° C to 0 ° C. After stirring at room temperature for 3 hours, a 10% aqueous sodium hydroxide solution was added dropwise. continue
30% hydrogen peroxide solution (10.8 ml) was added dropwise at 32 to 40 ° C. After stirring at room temperature for an additional 1 hour, the organic layer was separated, washed with water,
It was dried and concentrated. The oily crude product (10.5 g) was subjected to column chromatography on silica gel (250 g). Eluted with ethyl acetate-methylene chloride (1:20).
Fractions were collected to give the title compound (8.82g). bp130 ~ 13
5 ℃ (bath temperature) / 1mmHg.

NMR spectrum _{(CDCl 3) ppm: 1.15~2.25 (} 4H, m, C (4) -H 2, C (5) -H 2) 2.83 (1H, d, J = 3Hz, -OH) 3.1~3.6 (3H , m) 3.68 (2H, d, J = 5Hz, −CH ₂ −OCH ₂ Ph) 3.75 to 4.05 (1H, m) 4.58 (2H, s, −OCH ₂ Ph) 7.2 to 7.5 (5H, m, C ₆ H ₅ −) mass spectrum (m / e): 222 (M ⁺ ).

Elemental analysis: C ₁₃ H ₁₈ O ₂ Calculated: C, 70.24; H, 8.16 Found: C, 70.07; H, 8.04 Reference Example 3 dl-trans-2-benzyloxymethyl - tetrahydropyran-3-yl = N-heptadecyl carbamate A solution of stearic acid (6.082g), diphenylphosphoryl azide (3.84ml) and triethylamine (2.48ml) in benzene (200ml) was heated to reflux for 3 hours. After cooling, the reaction was washed with aqueous sodium bicarbonate solution and brine. After drying, the solvent was distilled off and the residue was redissolved in benzene (160 ml). The compound of Reference Example 2 (1.980 g) was added, and the mixture was heated under reflux in a nitrogen atmosphere for 38 hours. After cooling, the reaction mixture was washed successively with aqueous sodium bicarbonate solution and water, dried and concentrated to dryness. The residue was subjected to column chromatography using silica gel (60 g), and hexane-methylene chloride-ether (6: 3:
The fractions eluted in 1) were collected and the indicated compound (3.904
g) was obtained as a white solid. Melting point (hereinafter abbreviated as mp) 61 to 63 ° C IR spectrum (CHCl ₃ , cm ^-1 : 3460 (-NH-), 1720 (-O
-CO-) Mass spectrum (m / e): 503 (M ⁺ ), 412 (M ⁺ -C)
₇ H ₇₎ Elemental analysis: Calculated _{C 31 H 53 NO 4: C} , 73.91; H, 10.60; N, 2.78 Found: C, 74.27; H, 10.70 ; N, 2.71 Reference Example 4 dl-(trans - 2-hydroxymethyltetrahydropyran-3-yl) = N-heptadecyl carbamate To a solution of the compound of Reference Example 3 (3.800 g) in methanol (120 ml) was added 10% palladium carbon, and the mixture was placed in a Parr apparatus at room temperature.
It was reacted with hydrogen gas at atmospheric pressure for 8 hours. After removing the catalyst, the solvent was evaporated to give the title compound (2.729 g) as a white solid. mp 84-86 ° C (ether) IR spectrum (CHCl ₃ , cm ^-1 ): 3570 (-OH), 3450 (-N
H), 1710 (-O-CO- ) mass spectrum (m / e): 413 ( M +), 382 (M + -CH 2 OH) Elemental analysis: Calculated _{C 24 H 47 NO 4: C} , 69.69 H, 11.45; N, 3.39 Found: C, 69.38; H, 11.35; N, 3.52 Reference Example 5 dl- (trans-2-hydroxymethyltetrahydropyran-3-yl) = N-octadecylcarbamate Using nonadecanoic acid (5.405 g), operating as in Reference Example 3 to react with the compound of Reference Example 2 (1.118 g) and after chromatography, dl- (trans-2-benzyloxymethyltetrahydropyran-3 -Yl) = N-octadecyl carbamate (1.417g) was obtained as a solid. This compound (1.395 g) was dissolved in tetrahydrofuran (30 ml) without further purification, and 10% palladium-carbon (700 m
Hydrogenation was carried out in the presence of g) using a Parr apparatus at room temperature and 4 atm for 7 hours. The catalyst was removed and the solvent was evaporated to give the title compound (1.128 g) as a white solid. mp84
-86 ° C. (ether) NMR spectra _{(CDCl 3) ppm: 0.7~2.4 (} 39H, m) 2.80 (1H, m, -OH) 3.0~4.2 (7H, m) 4.5~4.9 (2H, m) IR spectrum ( CHCl ₃ ) cm ^-1 : 3600 (-OH), 3460 (-NH
-), 1710 (-O-CO- ) mass spectrum (m / e): 427 ( M +), 396 (M + -CH 2 OH) Elemental analysis: Calculated _{C 25 H 49 NO 4: C} , 70.21 H, 11.55; N, 3.28 Found: C, 69.91; H, 11.55; N, 3.19 Reference Example 6 dl-trans-2- {N- (5-bromopentyl) carbamoyloxy} methyltetrahydropyran-3-yl = N-heptadecyl carbamate 6-Bromhexanoic acid (1.41 g) was dissolved in benzene (40 ml), diphenylphosphoryl azide (1.56 ml) and triethylamine (1.68 ml) were added, and the mixture was heated under reflux for 3 hours.
The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The residue was dissolved in toluene (20 ml), the compound of Reference Example 5 (1.000 g) and triethylamine (1.68 ml) were added, and the mixture was heated on an oil bath at 85 ° C. for 67 hours.
The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography using silica gel (30 g). Fractions eluting with hexane-ethyl acetate (4: 1 to 3: 1) were collected and further subjected to medium pressure liquid chromatography using a Rover B column. Fractions eluted with the above solvent were collected to give the title compound (0.815 g) as a white wax. mp71~75 ℃ NMR spectrum _{(CDCl 3) ppm: 0.7~2.4 (} 43H, m) 2.6~3.8 (6H, m) 3.38 (2H, t, J = 7Hz, -CH 2 Br) 3.8~4.9 (6H, m ) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3450 (−NH), 1720 (−OCO
NH-) Mass spectrum (m / e): 606,604 (M ⁺ ), 525 (M ⁺ -B
^{r), 524 (M + -HBr} ) Elemental _{analysis: C 30 H 57 BrN 2 O} 5 Calculated: C, 59.49; H, 9.49 ; N, 4.62 Found: C, 59.92; H, 9.44 ; N, 4.81 Reference Example 7 (2R, 3S) -3-O-benzyl-4-iodo-1,2-O-
Isopropylidene butane-1,2,3-triol (2R, 3R) -3-O-benzyl-1,2-O synthesized according to the method of Ohno et al. {Chem, Pharm. Bull., 33 , 572 (1985)}.
-Methanesulfonyl chloride (21.00 ml) benzene (100 ml) was added dropwise to a benzene (1) solution of isopropylidrethreitol (57.00 g) and triethylamine (44.10 ml) under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was washed with water,
Dry and concentrate to (2R, 3R) -2-benzyloxy-3,4-
Isopropylidene dioxybutyl methanesulfonate (74.80 g) was obtained as a colorless oil.

NMR spectrum (CDCl ₃ ) ppm: 2.92 (3H, s, -O- SO 2 -CH 3) 3.4~4.5 (6H, m) 4.65 (2H, s, -CH 2 Ph) 7.25 (5H, m, -Ph) above methanesulfonate (74.80g) , Sodium bicarbonate (113.92g) and sodium iodide (169.39g),
The mixture was heated under reflux in acetone (1.1) for 12 hours. After cooling, the reaction solution was filtered through Celite to remove insoluble materials. After the solvent was distilled off, the residue was diluted with water and extracted 3 times with ethyl acetate. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (600 g). Fractions eluted with hexane-ethyl acetate (95: 5) were collected to give the title compound (75.64g) as a colorless oil.

bp.130-150 ℃ / 1mmHg. ▲ [α] _{^{26 D ▼ + 8.40 ° (c}} = 1.2
5, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: IR spectrum (CHCl ₃ ) cm ^-1 : 518 (-I) Mass spectrum (m / e): 362 (M ⁺ ), 347 (M ⁺ -CH ₃ ) Elemental analysis: Calculated as C ₁₄ H ₁₉ O ₃ I : C, 46.22; H, 5.29; I, 35.04 Found: C, 46.47; H, 5.18; I, 35.11 Reference Example 8 (2S, 3R) -3-O-benzyl-4-iodo-1,2-O −
Isopropylidene butane-1,2,3-triol (2S, 3S) -3-O-benzyl-1,2-O synthesized according to the method of Ohno et al. {Chem, Pharm. Bull., 33 , 572 (1985)}.
-From isopropylidene threitol (48.45g), triethylamine (37.50ml) and methanesulfonyl chloride (17.80ml) in the same manner as in Reference Example 1 (2S, 3S) -2.
-Benzyloxy-3,4-isopropylidenedioxybutyl methanesulfonate (63.45g) was obtained. Furthermore, the above methanesulfonate and sodium hydrogen carbonate (96.80g)
The title compound (66.87 g) was obtained in the same manner as in Reference Example 1 from sodium iodide (143.90 g). ▲ 〔α〕 ²⁶ _D
▼ -8.40 ° (c = 1.00, CHCl ₃ ) Reference Example 9 (4R, 5R) -4-benzyloxy-2-ethoxycarbonyl-5,6-isopropylidenedioxyhexanoate ethyl A solution of diethyl malonate (40.00g) in dimethylformamide (200ml) was added to sodium hydride (55% mineral oil suspension, 1
2.00 g) and dimethylformamide (600 ml) were added dropwise at 5-8 ° C. After stirring at room temperature for 1 hour, the compound of Reference Example 7 (75.38 g) in dimethylformamide (300 m
l) The solution was added dropwise at 5-8 ° C. The mixture was heated and stirred at 100 ° C. for 2 hours, allowed to cool, poured into 2 l of water, and extracted with ethyl acetate three times. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (1 kg). Fractions eluted with hexane-ethyl acetate (9: 1) were collected to give the title compound (68.92 g) as a colorless oil. bp.170-180 ℃ / 1mmHg.

▲ [α] ²⁵ _D ▼ + 39.1 ° (c = 1.00, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 2.01 (2H, t, J = 6.5Hz, C (3) -H 2) 3.4~4.4 (5H, m) 4.15 (4H, m, -CH 2 -CH 3 × 2) 4.68 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.38 (5H, m, -Ph) IR spectrum (CHCl ₃ ) cm ^-1 : 1730 (-O-CO-) Mass spectrum (m / e): 379 (M ⁺ -CH ₃ ) Elemental analysis: Calculated as C ₂₁ H ₃₀ O ₇ : C, 63.94; H, 7.67 Found: C, 63.66; H, 7.49 Reference Example 10 (4S, 5S) -4-benzyloxy-2-ethoxycarbonyl-5 Ethyl 6,6-isopropylidenedioxyhexanoate Diethyl malonate (35.48g), sodium hydride (55%
The title compound (58.40 g) was obtained in the same manner as in Reference Example 9 from the mineral oil suspension (10.63 g) and the compound of Reference Example 8 (66.87 g). ▲ [α] ²⁶ _D ▼ -39.5 ° (c = 1.00, CHCl ₃ ) Reference Example 11 (4R, 5R) -4-benzyloxy-5,6-isopropylidenedioxyhexanoic acid ethyl ester Compound of Reference Example 9 (68.70 g), sodium chloride (12.20
g) and water (6.51 ml) were mixed in dimethyl sulfoxide (1.1), and the mixture was heated under reflux on an oil bath at 210 ° C. for 2 hours. After cooling, the reaction solution was poured into 2.5 l of water and extracted with ethyl acetate three times. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (1 kg). Fractions eluted with hexane-ethyl acetate (95: 5) were collected to give the title compound (41.79 g) as a colorless oil. bp.150-160 ℃ / mmHg. ▲ [α] ²⁶ _D ▼ + 47.6 ° (c =
1.32, MeOH) NMR spectrum _{(CDCl 3) ppm: 1.23 (} 3H, t, J = 7.5Hz, -CH 2 CH 3) 1.6~2.0 (2H, m, C ( 3) -H 2) 2.43 (2H, t, J = 7.5Hz, C (2) -H 2) 3.3~3.6 (1H, m) 3.6~4.4 (3H, m ) 4.10 (2H, q, J = 7.5Hz, - CH 2 -CH 3) 4.69 (2H, ABq, J = 12Hz, -CH 2 Ph) 7.38 (5H, s, -Ph) IR spectrum (CHCl ₃₎ cm ^-1: 1730 (-O-CO-) mass spectrum (m / e): 322 ( M +), 307 (M + -CH 3) elemental analysis: C ₁₈ H ₂₆ O ₅ calculated: C, 67.06; H, 8.13 Found: C, 67.06; H, 8.13 Reference Example 12 (4S, 5S) -4-benzyloxy-5,6-isopropylidenedioxyhexanoate ethyl The compound of Reference Example 10 (58.68 g), sodium chloride (10.43 g)
The title compound (41.79 g) was obtained from g) and water (5.56 ml) in the same manner as in Reference Example 11. ▲ 〔α〕 ²⁶ _D ▼ -47.4 °
(C = 1.30, CHCl ₃ ) Reference Example 13 (4R, 5R) -4-benzyloxy-5,6-isopropylidenedioxyhexan-1-ol The compound of Reference Example 11 (47.65 g) in tetrahydrofuran (25
0 ml) solution was added dropwise to a suspension of lithium aluminum hydride (6.75 g) in tetrahydrofuran (750 ml) at 5-8 ° C. The reaction solution was stirred at room temperature for 2 hours, and 4% aqueous sodium hydroxide solution (27.00 ml) was added dropwise at 4 to 7 ° C. The suspension was filtered through Celite, concentrated and dried. The residue was subjected to column chromatography using silica gel (800 g), and the fractions eluted with hexane-ethyl acetate (2: 1) were collected to give the title compound (37.34 g) as a colorless oil. bp.150-160 ℃ / 1mmHg. ▲ ［α］ ²⁶ _D ▼ ＋ 41.8
° (c = 1.06, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.5~1.8 (4H, m, C ( 2) -H 2, C (3) -H 2) 1.71 (1H, s, -OH) 3.4~3.8 (4H, m) 4.02 (1H, dt, J = 7.5 , 6Hz, C (4) -H) 4.25 (1H, dt, J = 7.5,6Hz, C (5) -H) 4.71 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.38 (5H, m, -Ph) IR spectrum ^{_{(CHCl 3) cm -1: 3450}} (-OH) mass spectrum (m / e): 280 ( M +), 265 (M + -CH 3) Elementary analysis: as C ₁₆ H ₂₄ O ₄ Calculated: C, 68.55; H, 8.63 Found: C, 68.23; H, 8.58 Reference Example 14 (4S, 5S) -4-Benzyloxy-5,6-isopropylidenedioxyhexan-1-ol From the compound of Reference Example 12 (41.00 g) and lithium aluminum hydride (5.78 g), the title compound (32.15 g) was obtained as a colorless oil in the same manner as in Reference Example 13. ▲ 〔α〕 ²⁶
_D ▼ -42.5 ° (c = 1.10, CHCl ₃ ) Reference Example 15 (2R, 3R) -3-benzodyloxy-6- (t-butyldiphenylsilyloxy) -1,2-isopropylidenedioxyhexane The compound of Reference Example 13 (19.27 g) and imidazole (10.2 g)
To a solution of 9 g) in dimethylformamide (300 ml) was added dropwise a solution of t-butyldiphenylsilyl chloride (20.77 g) in dimethylformamide (90 ml) at 5 to 7 ° C. After stirring at room temperature for 3 hours, the reaction solution was poured into 2 L of water and extracted with ethyl acetate three times. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (700 g). Hexane-ethyl acetate (98: 2 to 95: 5)
The fractions eluted in (1) were collected to give the title compound (32.80 g) as a colorless oil. ▲ [α] ²⁶ _D ▼ + 21.4 ° (c =
1.11; CHCl ₃₎ NMR spectrum _{(CDCl 3): ppm: 1.04} (9H, s, (CH 3) 3 -C-Si) 1.4 to 1.8 (4H, m) 3.3 to 3.8 (4H, m) 4.00 (1H, dt, J = 7.5,6Hz, C (3) -H) 4.20 (1H, dt, J = 7.5,6Hz, C (2 ) -H) 4.66 (2H, ABq, J = 12Hz, -CH ₂ Ph) 7.2-7.8 (15H, m, -Ph × 3) IR spectrum (CHCl ₃ ) cm ^-1 : 1100 (Si-O) mass spectrum (M / e): 503 (M ⁺ -CH ₃ ) Elemental analysis: Calculated as C ₃₂ H ₄₂ O ₄ Si: C, 74.09; H, 8.16 Measured value: C, 74.20; H, 8.18 Reference Example 16 (2S , 3S) -3-Benzyloxy-6- (t-butyldiphenylsilyloxy) -1,2-isopropylidenedioxyhexane Compound of Reference Example 14 (18.00 g), imidazole (9.62 g)
And t-butyldiphenylsilyl chloride (19.41g)
In the same manner as in Reference Example 15, the title compound (30.97 g) was obtained as a colorless oil. ▲ [α] ²⁶ _D ▼ -20.8 ° (c =
1.25, CHCl ₃ ) Reference Example 17 (2R, 3R) -3-Benzyloxy-6- (t-butyldiphenylsilyloxy) hexane-1,2-diol The compound of Reference Example 15 (32.49 g) was dissolved in acetic acid (300 ml) and water (30 ml), and the mixture was stirred at room temperature for 17 hours and further at 50 ° C. for 2 hours. After allowing to cool, the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (500 g).
Fractions eluted with ethyl acetate-hexane (1: 2) were collected to give the title compound (27.40 g) as a colorless oil.
▲ [α] ²⁶ _D ▼ -20.4 ° (c = 1.12, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.05 (9H, s, (CH ₃ ) ₃ -C-Si) 1.5 to 1.9 (4H, m) 1.9 to 2.3 (1H, m, -OH) 2.3 to 2.65 (1H, m, -OH) 3.4 to 3.9 (6H, m) 4.53 (2H, ABq, J = 12Hz) 7.2 to 7.8 (15H, m, Ph x 3) IR spectrum (CHCl ₃ ) cm ^-1 : 3590,3460 (-OH), 1100
(Si-O) mass spectrum (m / e): 479 (M ⁺⁺ 1) Reference Example 18 (2S, 3S) -3-Benzyloxy-6- (t-butyldiphenylsilyloxy) hexane-1,2-diol From the compound of Reference Example 16 (30.48 g), acetic acid (300 ml) and water (30 ml), the title compound (26.1
5 g) was obtained as a colorless oil. ▲ ［α］ ²⁶ _D ▼ ＋ 20.6
(C = 1.15, CHCl ₃ ) Reference Example 19 (2R, 3R) -3-Benzyloxy-6- (t-butyldiphenylsilyloxy) -1-triphenylmethoxy-
Hexan-2-ol The compound of Reference Example 17 (26.22 g) and triethylamine (18.4 g)
Triphenylmethyl chloride (18.33 g) was added to a toluene (500 ml) solution of 0 ml), and the mixture was heated under reflux for 3 hours. After allowing to cool, the reaction solution was diluted with water and extracted 3 times with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and the solvent was evaporated. The oily residue was dissolved in tetrahydrofuran (270 ml), saturated aqueous sodium hydrogen carbonate solution (90 ml) was added, and the mixture was stirred at room temperature for 1 hr. The oily product (40 g) obtained by performing the post-treatment in the same manner as above was subjected to column chromatography using silica gel (500 g). Hexane-ethyl acetate (95: 5 ~
The fractions eluted at 9: 1) were collected and the indicated compound (37.01
g) was obtained as a colorless oil.

▲ [α] ²⁵ _D ▼ −3.55 ° (c = 1.03, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.05 (9H, s, (CH ₃ ) ₃ CSi) 1.4 to 1.8 (4H, m) 2.30 (1H , d, J = 6Hz, -OH ) 3.22 (2H, d, J = 6Hz, C (1) -H 2) 3.5~3.9 (4H, m) 4.45 (2H, ABq, J = 12Hz, -CH 2 Ph ) 7.1 to 7.8 (30H, m, -Ph × 6) IR spectrum (CHCl ₃ ) cm ^-1 : 3580 (-OH), 1100 (O-S
i) Mass Spectrum (m / e): 477 ( M + -HC (CH 3) 3) Elemental analysis: C ₄₈ H ₅₂ O ₄ Si Calculated: C, 79.96; H, 7.27 Found: C, 79.71; H, 7.11 Reference Example 20 (2S, 3S) -3-Benzyloxy-6- (t-butyldiphenylsilyloxy) -1-triphenylmethoxyhexan-2-ol The compound of Reference Example 18 (25.96 g), triethylamine (18.2
(0 ml) and triphenylmethyl chloride (18.11 g) were obtained in the same manner as in Reference Example 19 to give the title compound (36.50 g) as a colorless oil.

▲ [α] ²⁵ _D ▼ + 3.56 ° (c = 1.01, CHCl ₃ ) Reference Example 21 (2R, 3R) -3-Benzyloxy-6-hydroxy-1
-Triphenylmethoxy-2-hexyl methanesulfonate The compound of Reference Example 19 (36.89 g) and triethylamine (8.56
ml) in methylene chloride (500 ml), methanesulfonyl chloride (4.75 ml) was added dropwise under ice cooling (5 ° C.). After stirring at room temperature for 1 hour, the reaction solution was poured into water. The organic layer was washed with saturated brine, dried and concentrated (2R, 3R) -3-
Benzyloxy-6- (t-butyldiphenylsilyloxy) -1-triphenylmethoxy-2-hexyl methanesulfonate (40.91 g) was obtained as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.01 (} 9H, s, (CH 3) 3 Si-) 1.3~1.8 (4H, m) 2.96 (3H, s, -O-SO 2 -CH 3) 3.0~3.9 (5H , m) 4.50 (2H ,, s, −CH ₂ −Ph) 4.6 to 4.9 (1H, m, −C H (OSO ₂ CH ₃ ) −) 7.1 to 7.8 (30H, m, −Ph × 3) above methane To a solution of sulfonate (40.91 g) in tetrahydrofuran (500 ml), 1N tetrabutylammonium fluoride (tetrahydrofuran solution) (61.4 ml) was added dropwise under ice cooling (5 ° C). After stirring at room temperature for 14 hours, the reaction solution was diluted with water and extracted with ethyl acetate three times. The extract was washed with water, dried and concentrated, and the residue was subjected to column chromatography using silica gel (700 g). Fractions eluted with hexane-ethyl acetate (4: 1 to 2: 1) were collected to give the title compound (26.45g) as a colorless oil.

▲ [α] ²⁵ _D ▼ + 21.7 ° (c = 1.22, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.37 (1H, s, -OH) 1.4 to 1.8 (4H, m) 3.00 (3H, s, -OSO ₂ CH ₃ ) 3.30 (1H, dd, J = 11,6Hz, C (6) -H) 3.4 ~ 3.6 (2H, m) 3.60 (1H, dd, J = 11,3Hz, C (6)- H) 3.6 to 3.9 (1H, m) 4.56 (2H, s, -CH ₂ Ph) 4.82 (1H, ddd, J = 6,6,3Hz, C (5) -H) 7.2 to 7.6 (20H, m, −Ph × 4) IR spectrum (CDCl ₃ ) cm ⁻¹ : 3500 (−OH), 1360,1170
(−SO ₂ −) Mass spectrum (m / e): 482 (M ⁺ −C ₆ H ₅ ), 468 (M ⁺
-C ₆ H ₅ CH ₃₎ Reference Example 22 (2S, 3S) -3- benzyloxy-6-hydroxy-1
-Triphenylmethoxy-2-hexyl methanesulfonate Using the compound of Reference Example 20 (35.60 g) and in the same manner as in Reference Example 21, the title compound (25.18 g) was obtained as a colorless oil. ▲ [α] ²⁵ _D ▼ -21.7 ° (c = 1.23, CHCl ₃ ) Reference Example 23 (2S, 3R) -3-benzyloxy-2-triphenylmethoxymethyltetrahydropyran The compound of Reference Example 21 (26.08 g) t-butanol (290 m
l) solution was added dropwise to a solution of potassium t-butoxide (7.01 g) in t-butanol (250 ml) at 25 ° C. The mixture was stirred at 40 ° C for 4 hours. After acetic acid (0.56 ml) was added to the reaction solution, the solvent was distilled off. The residue was diluted with water and extracted 3 times with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated, and the residue was washed with silica gel (43
Column chromatography using 0 g). Fractions eluted with hexane-ethyl acetate (95: 5) were collected to give the title compound (21.04 g) as crystals. mp86.0-88.0
° C (MeOH).

▲ [α] ²⁵ _D ▼ -32.8 ° (c = 1.01, CHCl ₃ ) NMR spectrum (270MHz, CDCl ₃ ) ppm: 1.41 (1H, dddd, J = 12.3Hz, 10.9Hz, 9.3Hz, 6.7Hz, C ( 4)
-Hax.) 1.70 (2H, m , C (5) -H 2) 2.26 (1H, ddddd, J = 12.3Hz, 4.2Hz, 3.9Hz, 3.9Hz, ~1Hz, C
(4) -Heq.) 3.20 (1H, dd, J = 9.8Hz, 5.0HZ, -CH-OTr) 3.37 (1H, ddd, J = 9.3Hz, 5.0HZ, 2.0Hz, C (2) -H ) 3.39 (1H, ddd, J = 11.4Hz, 9.3Hz, 5.3HZ, C (6) -Hax) 3.48 (1H, dd, J = 9.8Hz, 2.0Hz, -CH-OTr) 3.49 (1H, ddd, J = 10.9Hz, 9.3Hz, 4.2Hz, C (3) -H ) 4.00 (1H, dddd, J = 11.4Hz, 2.9Hz, 2.9Hz, ~ 1Hz, C (6)
−Heq.) 4.38 (2H, ABq, J = 11.5Hz, −CH ₂ Ph) 7.0 to 7.5 (20H, m, Ph × 4) IR spectrum (CHCl ₃ ) cm ⁻¹ : 1595,1490,1450 (C ₆ H
₅ −), 1090,1070 (C—O—C) Mass spectrum (m / e): 387 (M ⁺ −C ₆ H ₅ ), 373 (M ⁺
-C ₇ H ₇₎ Elemental analysis: Calculated _{C 32 H 32 O 3: C} , 82.73; H, 6.94 Found: C, 82.56; H, 6.83 Reference Example 24 (2R, 3S) -3- benzyloxy - 2-triphenylmethoxymethyl tetrahydropyran The title compound (20.12 g) was obtained as crystals in the same manner as in Reference Example 22 from the compound of Reference Example 22 (24.98 g) and potassium t-butoxide (6.06 g). mp.86.5-88.5 ° C. ▲
[Α] ²⁵ _D ▼ + 33.0 ° (c = 1.00, CHCl ₃ ) Reference Example 25 (2S, 3R) -3-Hydroxy-2-triphenylmethoxymethyltetrahydropyran 10% Palladium on carbon (1.852 g) was added to a solution of the compound of Reference Example 23 (3.513 g) in ethanol (120 ml), and the mixture was shaken with hydrogen in a Parr apparatus at room temperature and 4 atm for 30 hours. After removing the catalyst, the solvent was evaporated and the residue was silica gel (90 g).
It was subjected to column chromatography using. Fractions eluted with hexane-ethyl acetate (7: 1) were collected to give the title compound (2.557g) as a colorless oil. ▲ 〔α〕
²⁵ _D ▼ + 38.2 ° (c = 1.07, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 1.2 to 1.8 (3H, m) 1.9 to 2.3 (1H, m) 3.00 (1H, s, -OH) 3.1 to 3.7 (5H, m) 3.75 to 4.05 (1H, m) 7.2 to 7.7 (15H, m, Ph × 3) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3500 (OH), 1600,1490,145
0 (-Pb), 1090 (C-O-C) mass spectrum (m / e): 374 (M ⁺ ), 297 (M ⁺ -C)
₆ H ₅ ) Reference Example 26 (2R, 3S) -3-Hydroxy-2-triphenylmethoxymethyltetrahydropyran Using the compound of Reference Example 24 (2.835 g) and 10% palladium carbon (1.499 g) and in the same manner as in Reference Example 25, the title compound (2.075 g) was obtained as a colorless oil. ▲ 〔α〕 ²⁵ _D ▼
−38.0 ° (c = 1.12, CHCl ₃ ) Reference Example 27 (2S, 3R) -2- (triphenylmethoxy) methyltetrahydropyran-3-yl = N-heptadecylcarbamate A solution of stearic acid (4.782g), diphenylphosphoryl azide (3.62ml) and triethylamine (2.34ml) in benzene (100ml) was heated to reflux for 3 hours. After allowing to cool, the reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. After drying, the solvent was distilled off and the residue was dissolved in toluene (25 ml). A solution of triethylamine (2.34 ml) and the compound of Reference Example 25 (2.518 g) in triene (25 ml) was added, the mixture was heated at 100 ° C. for 90 hours, allowed to cool, and the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. 3 with ethyl acetate
It was extracted twice, the extract was dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (120 g). Fractions eluted with hexane-ethyl acetate (7: 1) were collected to give the title compound (3.131 g) as a colorless oil. ▲ [α] ²⁵ _D ▼ -28.5 ° (c = 1.04, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 0.7 to 2.4 (37H, m) 2.8 to 3.6 (6H, m) 3.8 to 4.1 (1H, m) 4.2 ~ 4.8 (2H, m) 7.1 ~ 7.6 (15H, m) Mass spectrum (m / e): 412 (M ⁺ -C ₁₉ H ₁₅ ), 396 (M
_{^{+ -C 19 H 15 O),}} 382 (M + -C 21 H 17 O) Reference Example 28 (2R, 3S) -2- (triphenylmethyl) methyl tetrahydropyran-3-yl = N- heptadecyl carbamate Using stearic acid (3.553 g), diphenylphosphoryl azide (2.69 ml) and the compound of Reference Example 26 (1.871 g), the title compound (2.491 g) was obtained as a colorless oil in the same manner as in Reference Example 27. ▲ [α] ²⁵ _D ▼ + 28.8 ° (c = 1.13, CHCl
₃ ) Reference Example 29 (2S, 3R) -2-Hydroxymethyltetrahydropyran-3-yl = N-heptadecylcarbamate P-Toluenesulfonic acid (240.0 mg) was added to a solution of the compound of Reference Example 27 (2.753 g) in methanol (55 ml), and the mixture was heated under reflux for 1 hour. After allowing to cool, sodium hydrogen carbonate (352.6m
g) was added. Methanol was distilled off, and ethyl acetate was added to remove insoluble matter. The solution was concentrated and the residue was subjected to column chromatography using silica gel (55g).
Fractions eluted with hexane-ethyl acetate (2: 1 to 1: 1) were collected to give the title compound (1.476 g) as crystals. mp.9
2.0-93.5 ° C (Et ₂ O) ▲ [α] ²⁵ _D ▼ -7.20 ° (c = 1.00, CHCl ₃ ) NMR spectrum (CDCl ₃ ) ppm: 0.7 to 2.3 (37H, m) 2.6 to 2.85 (1H, m , -OH) 2.9 to 3.8 (6H, m) 3.8 to 4.1 (1H, m) 4.4 to 4.9 (2H, m) IR spectrum (CHCl ₃ ) cm ^-1 : 3450 (-NH, -OH), 1710,1
510 (-NH-CO) mass spectrum (m / e): 414 (M ⁺ +1), 382 (M ⁺ -CH ₂
OH) Elemental analysis: C ₂₄ H ₄₇ NO ₄ Calculated: C, 69.69; H, 11.45 ; N, 3.39 Found: C, 69.33; H, 11.40 ; N, 3.53 Reference Example 30 (2R, 3S) -2 -Hydroxymethyltetrahydropyran-2-yl = N-heptadecyl carbamate Using the compound of Reference Example 28 (2.400 g) and in the same manner as in Reference Example 29, the title compound (1.305 g) was obtained as crystals. mp.92.
5-93.5 ° C, ▲ [α] ²⁵ _D ▼ + 7.25 ° (c = 1.02, CHCl ₃ ) Reference Example 31 (2S, 3R) -2- {N- (5-bromopentyl) carbamoyloxy} methyltetrahydropyran -3-yl =
N-heptadecyl carbamate 5-Bromohexanoic acid (1.706 g), diphenylphosphoryl azide (1.88 ml), and the compound of Reference Example 29 (1.206).
g) in the same manner as in Reference Example 6 (1.270
g) was obtained as a waxy solid. mp.71.0-72.0 ° C, ▲ [α] ²⁵ _D ▼ -26.4 ° (c = 1.18, CHCl ₃ ) Reference Example 32 (2R, 3S) -2- {N- (5-bromopentyl) carbamoyloxy} methyltetrahydro Pyran-3-yl =
N-heptadecyl carbamate 5-Bromohexanoic acid (1.698 g), diphenylphosphoryl azide (1.88 ml), and the compound of Reference Example 30 (1.200
g) in the same manner as in Reference Example 6 to give the compound (1.283
g) was obtained as a waxy solid. mp.71.5-72.0 ℃ ▲ 〔α〕 ²⁵ _D
▼ + 26.5 ° (c = 1.00, CHCl ₃ ) Reference Example 33 dl-cis-2-benzyloxymethyltetrahydropyran-3-ol Jones reagent (6 ml, 1.60 g of chromic anhydride) was added to a solution of the compound of Reference Example 2 (2.22 g) in acetone (20 ml) under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted twice with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained oily crude ketone (2.08 g) was dissolved in tetrahydrofuran (10 ml), and a tetrahydrofuran solution of L-selectride (1M, 12 ml) was added dropwise at 0 to 5 ° C. After stirring for 30 minutes under ice cooling and 2 hours at room temperature, 10
Aqueous sodium hydroxide solution (6 ml) was added dropwise at 5 to 15 ° C. Then, 35% hydrogen peroxide solution (6 ml) was added dropwise at 15 to 30 ° C, the organic layer was separated, dried and concentrated. The oily residue was subjected to column chromatography using silica gel (60 g), and the fractions eluted with hexane-ethyl acetate (100: 15 to 2: 1) were collected to give the title compound (1.135 g) as a colorless liquid. Obtained. bp 130-140 ℃ (bath temperature) / 1mmHg.

NMR spectrum _{(CDCl 3) ppm: 1.25~2.30 (} 4H, m, C (4) -H 2, C (5) -H 2) 2.68 (1H, d, J = 6Hz, -OH) 3.3~3.7 (4H , m) 3.80 (1H, m) 4.03 (1H, m) 4.59 (2H, s, -OCH ₂ Ph) 7.2 to 7.5 (5H, m, C ₆ H ₅ ) Mass spectrum (m / e): 222 (M ⁺ ) Reference Example 34 dl-cis-2-hydroxymethyltetrahydropyran-
3-yl = N-octadecyl carbamate Using nonadecanoic acid (2.627 g), the procedure of Reference Example 3 was repeated, and the compound (0.815 g) of Reference Example 33 was reacted. The crude product was purified using a column of silica gel (70 g) and the fractions eluted with ethyl acetate-hexane (1: 5) were collected and combined with dl
-Cis-2-benzyloxymethyltetrahydropyran-3-yl = N-octadecyl carbamate (1.05 g)
Got This compound was dissolved in tetrahydrofuran-methanol (2: 1, 30 ml), and 10% palladium carbon (0.50 g) was added.
In a Parr apparatus at room temperature and 4 atm for 8 hours. After removing the catalyst, the solvent was evaporated and the residue was subjected to column chromatography using silica gel (20 g). Fractions eluted with ethyl acetate-hexane (1: 5-1: 2) were collected to give the title compound (0.732 g) as crystals. mp 85-86 ° C (ether-hexane).

NMR spectrum _{(CDCl 3) ppm: 0.7~2.2 (} 39H, m) 2.9~3.8 (7H, m) 3.9~4.2 (1H, m) 4.65~5.1 (2H, m) IR spectrum (CHCl ₃₎ cm ^-1: 3600 (-OH), 3450 (-NH
-), 1700 (-O-CO- ) mass spectrum (m / e): 427 ( M +), 396 (M + -CH 2 OH) Elemental analysis: Calculated _{C 25 H 49 NO 4: C} , 70.21 H, 11.55; N, 3.28 Found: C, 70.27; H, 11.73; N, 3.28 Reference Example 35 dl-trans-2-benzyloxymethyl-3- (tetrahydropyran-2-yloxy) tetrahydropyran Compound of Reference Example 2 (2.22g), dihydropyran (2.65m
l) and paratoluenesulfonic acid pyridine salt (0.05g)
Was dissolved in methylene chloride (40 ml) and stirred at room temperature for 4 hours. The solvent was distilled off and the residue was subjected to column chromatography using silica gel (80 g). Fractions eluted with hexane-ether (6: 1-5: 1) were collected to give the title compound (2.93g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.1~2.4 (} 10H, m) 3.15~4.15 (8H, m) 4.57 (ABq, J = 12Hz, -CH 2 Ph) 4.78 (1H, m, -O-CH-O- ) 7.35 (5H, m, C ₆ H ₅ −) Mass spectrum (m / e): 306 (M ⁺ ) Elemental analysis: C ₁₈ H ₂₆ O ₄ Calculated value: C, 70.56; H, 8.55 Measured value: C , 70.65; H, 8.45 Reference Example 36 dl-trans-2-hydroxymethyl-3- (tetrahydropyran-2-yloxy) tetrahydropyran The compound of Reference Example 35 (2.93 g) was dissolved in tetrahydrofuran (130
10% palladium-carbon (1.30 g) was added to the solution, and hydrogenation reaction was carried out at room temperature and 4 atm in a Parr apparatus for 8 hours. After removing the catalyst, the solvent was evaporated and the residue was subjected to column chromatography using silica gel (50 g).
Fractions eluted with hexane-ether (2: 1 to 1: 1) were collected to give the title compound (1.87 g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 2.2~2.4 (} 10H, m) 2.77 (1H, t, J = 7Hz, -OH) 3.1~4.1 (8H, m) IR spectrum ^{_{(CDCl 3) cm -1: 3600,3480}} (-OH) Elemental analysis: Calculated _{C 11 H 20 O 4: C} , 61.12; H, 9.33 Found: C, 60.75; H, 9.29 Reference Example 37 dl- (trans-3-hydroxytetrahydropyran-
2-yl) methyl = N-octadecyl carbamate Operating nonadecanoic acid (6.247g) as in Reference Example 3,
The compound of Reference Example 36 (1.809 g) was reacted in an oil bath at 85 ° C for 24 hours. After cooling, the reaction solution was filtered and concentrated to dryness. The residue was subjected to column chromatography using silica gel (100 g), ether-hexane-methylene chloride (1: 5:
Fractions eluted in 5) were collected and collected as dl- {trans-3-
(Tetrahydropyran-2-yloxy) tetrahydropyran-2-yl} methyl = N-octadecylcarbamate (4.20 g) was obtained as a solid. This was purified without further purification using tetrahydrofuran-methanol (1: 2,30
ml), camphorsulfonic acid (0.20 g) was added, and the mixture was stirred at room temperature for 45 minutes. After adding a saturated sodium bicarbonate aqueous solution (10 ml), the solvent was distilled off and ether was added to the residue for partitioning. The organic layer was washed with water, dried and concentrated, and the residue (3.
57 g) was subjected to column chromatography using silica gel (70 g). Fractions eluted with hexane-methylene chloride-ether (5: 5: 1) were collected to give the title compound (3.289g) as white crystals. mp 55-56 ° C (ether-hexane).

NMR spectrum _{(CDCl 3) ppm: 0.75~2.30 (} 39H, m) 3.00~3.60 (5H, m) 3.69 (1H, d, J = 4Hz, -OH) 3.85~4.20 (2H, m) 4.76 (1H, dd , J ₁ = 13, J ₂ = 3Hz) 4.95 (1H, m, -NH-) IR spectrum (CHCl ₃ ) cm ^-1 : 3450 (-NH-,-OH), 170
0 (-O-CO-) mass spectrum (m / e): 427 (M ⁺ ), 409 (M ⁺ -H ₂ O) Elemental analysis: C ₂₅ H ₄₉ NO ₄ Calculated value: C, 70.21; H, 11.55; N, 3.28 Found: C, 70.31; H, 11.42; N, 3.27 Reference Example 38 dl-S- (cis-2-benzyloxymethyltetrahydropyran-3-yl) = thioacetate The compound of Reference Example 2 (2.00 g) and triethylamine (2.51 m
Methanesulfonyl chloride (1.04 ml) was added dropwise to a solution of l) in benzene (40 ml) under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was washed with water, dried and concentrated to obtain an oily crude methanesulfonate. Next, sodium hydride (55% mineral oil suspension, 0.47 g) was suspended in dimethylformamide (5 ml) and thioacetic acid (0.77 ml) was suspended in dimethylformamide (5 m).
l) The solution was added dropwise under ice cooling. After stirring for 1 hour at room temperature,
Dimethylformamide (10m
l) The solution was added, and the mixture was heated with stirring at 80 ° C. for 16 hours and further at 100 ° C. for 10 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (50 g). Fractions eluted with ether-hexane (3: 97-10: 90) were collected to give the title compound (1.448g) as an oil.

NMR spectrum _{(CDCl 3) ppm: 1.10~2.20 (} 4H, m, C (4) -H 2, C (5) -H 2) 2.30 (3H, s, -COCH 3) 3.20~4.20 (6H, m) 4.52 (2H, ABq, J = 12Hz, -OCH 2 Ph) 7.20~7.50 (5H, m, -C 6 H 5) Mass spectrum (m / e): 280 (M ⁺ ) Elemental analysis: Calculated as C ₁₅ H ₂₀ O ₃ S: C, 64.26; H, 7.19; S, 11.44 Found: C, 64.19; H, 6.96; S Reference Example 39 dl-cis-2-benzyloxymethyltetrahydropyran-3-thiol A solution of sodium methoxide in methanol (about 28% by weight, 1.04 ml) was added dropwise to a solution of the compound of Reference Example 38 (1.422 g) in methanol (30 ml) at -10 ° C. After stirring at −10 to 0 ° C. for 2 hours, methanesulfonic acid (0.33 ml) was added and the reaction solution was poured into water. It was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. Oily residue on silica gel (30g)
Column chromatography using
Fractions eluted with hexane (3:97 to 5:95) were collected to give the title compound (1.146g) as an oil.

NMR spectrum _{(CDCl 3) ppm: 1.10~2.40 (} 4H, m, C (4) -H 2, C (5) -H 2) 1.66 (1H, d, J = 10Hz, -SH) 2.95~3.25 (1H , m) 3.25~3.85 (4H, m ) 3.85~4.20 (1H, m) 4.55 (2H, ABq, J = 12Hz, -OCH 2 Ph) 7.10~7.50 (5H, m, -C 6 H 5) IR spectrum (CHCl ₃ ) cm ⁻¹ : 2580 (−SH) Mass spectrum (m / e): 238 (M ⁺ ) Elemental analysis: Calculated as C ₁₃ H ₁₈ O ₂ S: C, 65.51; H, 7.61; S, 13.45 Found: C, 65.62; H, 7.83; S, 13.19 Reference Example 40 dl-S- (cis-2-benzyloxymethyltetrahydropyran-3-yl) = N-heptadecylthiolcarbamate Using stearic acid (7.75 g), the procedure of Reference Example 3 was followed, and the reaction was performed with the compound of Reference Example 39 (2.60 g). The crude product was subjected to column chromatography using silica gel (120 g), and the fractions eluted with ether-hexane (1:10 to 1: 2) were collected to give the title compound (5.29 g) as white crystals. . mp 80-81 ° C (ether-hexane).

NMR spectrum (CDCl ₃ ) ppm: 0.8 to 2.2 (37H, m) 3.1 to 4.2 (8H, m) 4.57 (2H, ABq, J _AB = 12H, -CH ₂ Ph) 5.31 (1H, m, -NH-) _{7.35 (5H, m, -C 6} H 5) infrared spectrum ^{_{(CHCl 3) cm -1: 3430}} (-NH -), 1670
(-S-CO-) Elemental analysis: C ₃₁ H ₅₃ NO ₃ S Calculated: C, 71.63; H, 10.28 ; N, 2.69; S, 6.17 Found: C, 71.73; H, 10.19 ; N, 2.64 S, 6.43 Reference Example 41 dl-S- (cis-2-hydroxymethyltetrahydropyran-3-yl) = N-heptadecyl thiol carbamate Acetonitrile (200 ml) and methylene chloride (100 ml)
The mixture of was cooled in an ice-water bath and treated with aluminum chloride (6.67
g) and sodium iodide (7.50 g) were added sequentially. Then, the methylene chloride (100 m) of the compound of Reference Example 40 (5.20 g)
l) The solution was added and stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was passed through the Celite layer to remove insoluble materials. Methylene chloride was added and the layers were separated, and the aqueous layer was extracted again with methylene chloride. The organic layers were combined, washed with a sodium thiosulfate aqueous solution and water, dried and concentrated. The residue was subjected to column chromatography using silica gel (90 g), and the fractions eluted with hexane-methylene chloride-ethyl acetate (10: 10: 1 to 2: 2: 1) were collected to give the title compound (4.04 g ) Was obtained as white crystals. mp 90-91 ° C (hexane).

NMR spectrum (CDCl ₃ ) ppm: 0.7 to 2.3 (38H, m) 3.15 to 4.15 (8H, m) 5.53 (1H, m, -NH-) IR spectrum (CHCl ₃ ) cm ^-1 : 3430 (-NH-, -OH), 165
0 (-S-CO-) Elemental analysis: C ₂₄ H ₄₇ NO ₃ S Calculated: C, 67.08; H, 11.02 ; N, 3.26; S, 7.46 Found: C, 67.04; H, 10.98 ; N, 3.31; S, 7.63 Reference Example 42 dl- {cis-3- (N-heptadecylcarbamoylthio) tetrahydropyran-2-yl} methyl = N- (5
-Bromopentyl) carbamate 6-Bromhexanoic acid (1.36 g) was dissolved in benzene (40 ml), diphenylphosphoryl azide (1.50 ml) and triethylamine (1.62 ml) were added, and the mixture was heated under reflux for 3 hours.
The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The residue is toluene (20 ml)
And the compound of Reference Example 41 (1.000 g) was added, and the mixture was heated on an oil bath at 85 ° C. for 64 hours. The reaction mixture was concentrated to dryness, and the residue was subjected to column chromatography using silica gel (30 g) and then medium pressure liquid chromatography using a Rover-B-column. Hexane-ethyl acetate (4:
Collect the fractions eluted in 1) and the title compound (1.279g)
Was obtained as a waxy solid. mp 73 - 75 ° C. NMR spectrum _{(CDCl 3) ppm: 0.7~2.2 (} 43H, m) 2.9~4.3 (10H, m) 3.38 (2H, t, J = 7Hz, -CH 2 Br) 4.77 (1H, br, -OCONH-) 5.33 (1H, br, -SCONH-) IR spectrum (CHCl ₃ ) cm ^-1 : 3450 (-NH-), 1720 (-
O-CO-), 1675 (-S-CO-) Mass spectrum (m / e): 623,621 (M ⁺ +1), 541 (M ⁺
-Br) Elemental _{analysis: C 30 H 57 BrN 2 O} 4 S Calculated: C, 57.95; H, 9.24 ; Br, 12.85; N, 4.51; S, 5.61 Found: C, 57.85; H, 9.34 ; Br , 12.85; N, 4.52; S, 5.28 Reference Example 43 dl-trans-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran Sodium hydride (55% mineral oil suspension, 0.480 g) was suspended in dimethylformamide (10 ml), and a solution of the alcohol (2.22 g) of Reference Example 2 in dimethylformamide (10 ml) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, hexadecyl bromide (5.49 g) was added, and the mixture was further stirred for 4 hours. Finally, stir at 60 ° C. for 1 hour, cool and pour into 100 ml of water.
It was extracted twice with ethyl acetate, the extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (100 g). Ether-hexane (1:20
Fractions eluted at ~ 1: 10) were collected and the title compound (3.82
g) was obtained as a low melting solid.

mp28.5~29.5 ℃ (cold methanol) NMR spectra _{(CDCl 3) ppm: 0.7~2.4 (} 35H, m) 3.0~4.2 (8H, m) 4.60 (2H, ABq, J = 13Hz, -OCH 2 Ph) 7.2 _{~7.45 (5H, m, C 6} H 5 -) mass spectrum (m / e): 446 ( M +) elemental analysis: calculated _{C 29 H 50 O 3: C} , 77.97; H, 11.28 Found: C , 78.06; H, 11.31 Reference Example 44 dl- {trans-3-hexadecyloxy-tetrahydropyran-2-yl} -methanol To a solution of the compound of Reference Example 43 (3.757 g) in methanol (150 ml) was added 10% palladium carbon (1.5 g), and the mixture was shaken with hydrogen at 4 atm in a Parr apparatus at room temperature. After 20 hours, the catalyst was removed and the solvent was evaporated to give the title compound (2.749 g) as a solid. mp 41-42 ° C (cold hexane) IR spectrum (CHCl ₃ ) cm ^-1 : 3600,3470 (-OH) mass spectrum (m / e): 357 (M ⁺ +1), 356 (M ⁺ ) Elemental analysis: C ₂₂ calculated as _{H 44 O 3: C, 74.10} ; H, 12.43 Found: C, 74.12; H, 12.11 reference example 45 dl-cis-2-benzyloxymethyl-3-hexadecyloxy tetrahydropyran A mixture of the alcohol of Reference Example 33 (1.037 g), hexadecyl bromide (1.709 g), potassium hydroxide (0.77 g) and toluene (15 ml) was heated with stirring at 120 ° C for 10 hours. After cooling, the reaction solution was poured into water, and the aqueous layer was extracted twice with ether. The organic layers were combined, washed with water, dried and concentrated. The oily residue (3.3g) was subjected to column chromatography using silica gel (50g). The title compound (1.455 g) was obtained as a colorless oil from the fraction eluted with ether-hexane (1:10).

NMR spectrum _{(CDCl 3) ppm: 0.7~2.3 (} 35H, m) 3.1~3.8 (5H, m) 3.61 (2H, s, -CH 2 -OCH 2 Ph) 3.85~4.15 (1H, m) 4.55 (2H, _{ABq, J = 13Hz, -OCH 2} Ph) 7.2~7.5 (5H, m, C 6 H 5 -) mass spectrum (m / e): 447 ( M + +1) elemental analysis: calculated as C ₂₉ H ₅₀ O ₃ Value: C, 77.97; H, 11.28 Actual value: C, 77.68; H, 11.16 Reference Example 46 dl- {cis-3-hexadecyloxytetrahydropyran-2-yl} methanol The compound of Reference Example 45 (1.409 g) was dissolved in a methanol-ethanol mixture (1: 1,100 ml), and 10% palladium carbon (0.70 g) was added. Thereafter, the catalytic reduction was carried out in the same manner as in Reference Example 44, and the crude product (1.116 g) was treated with silica gel (30
g) column chromatography. Ether
The title compound (1.031 g) was obtained from the fraction eluted with hexane (1:20 to 1: 5).

mp 42-43 ° C (cold hexane) IR spectrum (CHCl ₃ ) cm ^-1 : 3600,3460 (-OH) mass spectrum (m / e): 357 (M ⁺ +1) 356 (M ⁺ ) Elemental analysis: C ₂₂ calculated as _{H 44 O 3: C, 74.10} ; H, 12.43 Found: C, 73.85; H, 12.13 reference example 47 dl-{trans-3-hexadecyloxy tetrahydropyran-2-yl} methyl = N-( 5-bromopentyl) carbamate 6-Bromhexanoic acid (985 mg) was dissolved in benzene (30 ml), diphenylphosphorine azide (1.09 ml) and triethylamine (1.17 ml) were added, and the mixture was refluxed for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The residue was dissolved in toluene (12 ml), the compound of Reference Example 44 (600 mg) and triethylamine (1.17 ml) were added, and the mixture was heated at 85 ° C. for 15 hours. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography using silica gel (20 g). Hexane-ethyl acetate (1
Fractions eluted at 7: 3-4: 1) were collected and subjected to medium pressure liquid chromatography using a Rover-B-column. Fractions eluted with the above solvent system were collected and the indicated compound (744m
g) was obtained as an oil.

NMR spectrum _{(CDCl 3) ppm: 0.7~2.4 (} 41H, m) 2.9~3.7 (7H, m) 3.38 (2H, t, J = 7Hz, -CH 2 Br) 3.96 (1H, m) 4.75 (1H, m, -NH-) Mass spectrum (m / e): 550,548 (M ⁺ +1), 468 (M ⁺
-Br) Elemental analysis: C ₂₈ H ₅₄ BrNO ₄ Calculated: C, 61.30; H, 9.92 ; Br, 14.56; N, 2.55 Found: C, 61.19; H, 9.79 ; Br, 14.24; N, 2.67 Reference Example 48 4,5-Dihydrofurfuryl alcohol Dihydrofuran (58.7g) in anhydrous tetrahydrofuran (3
50 ml) was added dropwise with a hexane solution of n-butyllithium (15.08% by weight, 358 g) in an ice-water bath at 5 to 10 ° C over 30 minutes. The reaction solution was heated and stirred at 50 ° C. for 2 hours, and the mixture was again cooled to 0 in an ice bath.
Cooled to ° C. Paraform (25.0g) was added at once, 50
The mixture was heated and stirred at 0 ° C for 2 hours. After cooling, cool the reaction mixture to ice water (500m
l) washed. The aqueous layer was extracted 5 times with methylene chloride. The organic layers were combined, dried and concentrated. The oily residue (14 g) was distilled under reduced pressure to give the title compound (8.97 g) as a colorless liquid. bp66-67 ℃ / 7mmHg. This compound is readily dimerized and used immediately in the next step.

NMR spectrum _{(C 6 D 6) ppm:} 2.21 (2H, broad t, J = 9Hz, C (4) -H 2) 2.98 (1H, broad t, J = 6Hz, -OH) 3.98 (2H, d, J _{= 6Hz, -CH 2 OH) 4.00} (2H, t, J = 9Hz, C (5) -H 2) 4.68 (1H, m, C (3) -H) mass spectrum: 200 (M × 2), 101 (M ⁺ +1), 100
(M ⁺ ) Reference Example 49 2-Benzyloxymethyl-4,5-dihydrofuran Sodium hydride (55% mineral oil suspension, 7.69 g) was suspended in dimethylformamide (150 ml), and a solution of the compound of Reference Example 48 (17.64 g) in dimethylformamide (30 ml) was cooled with ice at 5 to 10 ° C. It was dripped in 30 minutes. The reaction solution was stirred at room temperature for 1 hour, and benzyl bromide (20.93 ml) was cooled with ice for 1 hour.
It was added dropwise at 0 to 15 ° C over 30 minutes. After stirring at room temperature for 1 hour, the reaction mixture was poured into water (2l) and extracted twice with ethyl acetate. The extract is washed with water and dried, and then the solvent is distilled off. The oily residue (17.8g) was subjected to column chromatography using silica gel (400g). Fractions eluted with hexane-ether (7: 100) were collected and the title compound (3.7
1 g) was obtained as a colorless liquid.

NMR spectrum _{(CDCl 3, ppm): 2.65} (2H, tm, J = 10Hz, C (4) -H 2) 4.03 (2H, m, C (2) - CH 2 -) 4.39 (2H, t, J = _{10Hz, C (5) -H 2} ) 3.58 (2H, s, -CH 2 Ph) 4.93 (1H, m, C (3) -H) 7.35 (5H, m, C 6 H 5 -) mass spectrum (m / e): 190 (m ⁺ ) Reference Example 50 dl-trans-2-benzyloxymethyltetrahydrofuran-3-ol Hydroboration was carried out as in Reference Example 2 using the compound of Reference Example 49 (3.389 g). Crude product (3.93
g) was subjected to column chromatography using silica gel (120 g), and the fractions eluted with hexane-ethyl acetate (1: 2) were collected to give the title compound (2.012 g) as a colorless oil.

NMR spectrum _{(CDCl 3) 1.6~2.4 (2H,} m, C (4) -H 2) 2.28 (1H, m, -OH) 3.74 to 4.10 (3H, m) 4.27 (1H, m, C (3) -H) 4.58 (2H, s, -O CH ₂ Ph) 7.30 (5H, s, -C ₆ H ₅ ) Mass spectrum (m / e): 208 (m ⁺ ) Reference Example 51 dl-trans-2-benzyloxymethyltetrahydrofuran-3-yl = N-heptadecyl carbamate The compound of Reference Example 50 (1.967 g) was used, and the operation as in Reference Example 3 was carried out to obtain the title compound (3.711 g) as white crystals. mp 54-56 ° C (hexane).

NMR spectrum _{(270MHz, CDCl 3, ppm)} : 0.8~1.7 (33H, m, -C 16 H 33) 1.90~2.30 (2H, m, C (4) -H 2) 3.15 (2H, dt, J 1 = J ₂ = 6.6Hz, −OCONH− CH ₂ −) 3.59 (2H, d, J = 4.4Hz, C (2) −CH ₂ ) 3.88 (1H, m) 4.05 (2H, m) 4.56 (2H, s, _{-OCH 2 Ph) 4.67 (1H,} m, -NH-) 5.10 (1H, m, C (3) -H) 7.32 (5H, m, -C 6 H 5) IR spectrum (CHCl _3, cm ^-1) : 3450 (-NH-), 1720 (-
OCONH-) Mass spectrum (m / e): 489 (M ⁺ ), 398 (M ⁺ -C)
₇ H ₇₎ Elemental analysis: Calculated _{C 30 H 51 NO 4: C} , 73.57; H, 10.50; N, 2.86 Found: C, 73.09; H, 10.33 ; N, 2.87 Reference Example 52 dl-trans-2 -Hydroxymethyltetrahydrofuran-3-yl = N-heptadecyl carbamate Using the compound of Reference Example 51 (1.142 g), the debenzylation reaction was carried out as in Reference Example 4. Notated compound (0.841
g) was obtained as white crystals. mp 77-78 ° C (ether-hexane).

NMR spectrum _{(270MHz, CDCl 3, ppm)} : 0.8~1.7 (33H, m, -C 16 H 33) 1.95~2.25 (2H, m, C (4) -H 2) 2.41 (1H, t, J = 6.2 Hz, -OH) 3.16 (2H, dt, J ₁ = J ₂ = 6.6Hz, -OCONH- CH _2- ) 3.70 (2H, m, C (2) -CH _2- ) 3.80 to 4.10 (3H, m) 4.72 (1H, m, -NH-) 5.01 (1H, m, C (3) -H) IR spectrum ^{_{(CHCl 3, cm -1):}} 3600 (-OH), 3450 (-NH
−), 1710 (−OCONH−) Mass spectrum (m / e): 400 (M ⁺⁺ 1), 399 (M ⁺ ), 36
8 (M ⁺ -CH ₃ O) Elemental analysis: Calculated _{C 23 H 45 NO 4: C} , 69.13; H, 11.35; N, 3.50 Found: C, 68.98; H, 11.22 ; N, 3.70 Reference Example 53 6- {7- (tetrahydropyran-2-yloxy) heptyloxy} methyl-3,4-dihydro-2H-pyran A solution of 7- (tetrahydropyran-2-yloxy) -1-heptanol (4.32g) and triethylamine (5.56ml) in benzene (80ml) and methanesulfonyl chloride (2.32ml) in benzene (10ml) under ice cooling. Dropped. After stirring at room temperature for 1 hour, the reaction solution was washed with water, dried and concentrated to give 7- (tetrahydropyran-2-yloxy) heptyl methanesulfonate (5.86 g) as an oil.

Sodium hydride (55%; 0.87g) was suspended in dimethylformamide (20ml) to give 6-hydroxymethyl-3,4
A solution of -dihydro-2H-pyran (2.28g) in dimethylformamide (5ml) was added dropwise. After stirring at room temperature for 1 hour, the above methanesulfonate was dissolved in dimethylformamide (5 ml) and added. After heating and stirring on an oil bath at 70 ° C. for 1 hour, the reaction mixture was poured into water (200 ml) and extracted twice with ether. The extract was washed with water, dried and concentrated. The oily residue (6.47 g) was subjected to column chromatography using silica gel (180 g), hexane-ether (1:10).
Fractions eluted at ~ 1: 5) are collected and the title compound (5.26
g) was obtained as a colorless oil.

NMR spectrum (CDCl ₃ ) ppm: 1.1 to 2.2 (20H, m) 3.25 to 4.15 (10H, m) 4.60 (1H, m) 4.80 (1H, m) Mass spectrum (m / e): 312 (M ⁺ ), 225 (M ⁺ -C ₅ H ₉
O) Elemental analysis: C ₁₈ H ₃₂ O ₄ Calculated: C, 69.19; H, 10.33 Found: C, 69.16; H, 10.22 Reference Example 54 dl-trans-2- {7- (tetrahydropyran-2
Iloxy) heptyloxy} methyltetrahydropyran-3-ol Using the compound of Reference Example 53 (5.26 g), a hydroboration reaction was performed as in Reference Example 2. Crude product (5.
64 g) was subjected to column chromatography using silica gel (100 g), and the fractions eluted with hexane-ethyl acetate (2: 1) were collected to give the title compound (4.17 g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.1~2.3 (} 20H, m) 3.10 (1H, d, J = 2.5Hz, -OH) 3.15~4.10 (12H, m) 4.60 (1H, m) mass spectrum (m / e ): 329 (M ⁺ -1) elemental analysis: C ₁₈ H ₃₄ O ₅ calculated: C, 65.42; H, 10.37 Found: C, 65.05; H, 10.07 reference example 55 dl-7- (trans -3 -Hexadecyloxytetrahydropyran-2-yl) methoxy-1-heptanol The compound of Reference Example 54 (1.652g) in a mixture of sodium hydride (55%; 0.24g) and dimethylformamide (5ml).
A dimethylformamide (5 ml) solution of was added dropwise at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was stirred in an oil bath at 60 ° C for 30
Heated for minutes. Hexadecyl bromide (1.83 g) was added at room temperature, and the mixture was heated with stirring on an oil bath at 60 ° C for 30 minutes. The reaction was cooled and sodium hydride (55%; 0.24g) was added again at room temperature. After heating on a 60 ° C. oil bath for 30 minutes, the reaction solution was returned to room temperature and hexadecyl bromide (1.83 g) was added again. 6
After heating and stirring for 30 minutes on an oil bath at 0 ° C., the reaction solution was cooled and poured into water. It was extracted with methylene chloride three times, and the extracts were combined, dried and concentrated. The oily residue (5.74 g) was dissolved in tetrahydrofuran (15 ml), and methanol (40 m
l) and concentrated hydrochloric acid (0.5 ml) were added, and the mixture was stirred at room temperature for 30 minutes.
The solvent was distilled off, water was added to the residue, and the mixture was extracted twice with ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried and concentrated. The oily residue (5.14 g) was subjected to column chromatography using silica gel (90 g), and the fractions eluted with hexane-ethyl acetate (2: 1) were collected to give the title compound (2.123 g) as a viscous oil. I got it as a thing.

NMR spectrum _{(CDCl 3) ppm: 0.75~2.05 (} 44H, m) 2.1~2.4 (1H, m) 3.00~3.80 (12H, m) 3.80~4.10 (1H, m) mass spectrum (m / e): 471 ( M ⁺ +1) elemental analysis: C ₂₉ H ₅₈ O ₄ calculated: C, 73.99; H, 12.42 Found: C, 73.69; H, 12.30 reference example 56 dl-2- {7- (tetrahydropyran-2 Iloxy) heptyloxy} methyltetrahydropyran-3-
on Pyridine chlorochromate (2.33g), sodium acetate (1.7
Reference Example 54 in a mixture of 8 g) and methylene chloride (10 ml)
A solution of the compound of (2.387 g) in methylene chloride (10 ml) was added in one portion. After stirring at room temperature for 3 hours, ether (30 ml) was added to the reaction solution, and the mixture was passed through a silica gel (50 g) column. The column was washed with ether, and the passing liquid and the washing liquid were combined and concentrated. Oily residue (2.24g) on silica gel (60g)
It was subjected to column chromatography using. Fractions eluted with hexane-ethyl acetate (3: 1 to 2: 1) were collected to give the title compound (1.786 g) as an oil.

IR spectrum (CHCl ₃ ) cm ⁻¹ : 1730 Mass spectrum (m / e): 244 (M ⁺ −C ₅ H ₈ O), 227 (M
⁺ -C ₅ H ₉ O ₂₎ Reference Example 57 dl-cis-2- {7- (tetrahydropyran-2-yloxy) heptyloxy} methyltetrahydropyran -
3-all Using the compound of Reference Example 56 (1.718 g), a reduction reaction was carried out as in the latter half of Reference Example 33 to obtain the title compound (1.320 g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.15~2.40 (} 20H, m) 2.95 (1H, d, J = 4Hz, -OH) 3.25~4.25 (10H, m) 4.60 (1H, m) mass spectrum (m / e) ^{: 330 (M +), 329} (M + -1) elemental analysis: C ₁₈ H ₃₄ O ₅ calculated: C, 65.42; H, 10.37 Found: C, 65.22; H, 10.44 reference example 58 dl-7 -(Cis-3-hexadecyloxytetrahydropyran-2-yl) methoxy-1-heptanol The compound of Reference Example 57 (1.150 g) was used to operate as in Reference Example 55 to obtain the title compound (1.282 g) as a viscous oil.

NMR spectrum _{(CDCl 3) ppm: 0.7~2.35 (} 45H, m) 2.16 (1H, m, -OH) 3.10~3.85 (11H, m) 3.90~4.20 (1H, m) mass spectrum (m / e): 470 (M ⁺ ), 411 (M ⁺ -C ₃ H ₇
O) Elemental analysis: C ₂₉ H ₅₈ O ₄ Calculated: C, 73.99; H, 12.42 Found: C, 73.72; H, 12.31 Reference Example 59 5- (2-methoxyethoxy) methoxy-1-pentanol A solution of 1,5-pentanediol (50.00 g) in dimethylformamide (100 ml) was added to a mixture of sodium hydride (55% mineral oil suspension, 23.00 g) and dimethylformamide (300 ml) under ice cooling (5 to 5 ml). (7 ° C). After stirring at room temperature for 1 hour, a solution of 2-methoxyethoxymethyl chloride (65.79 g) in dimethylformamide (100 ml) was added dropwise under ice cooling (5 to 7 ° C). After stirring at room temperature for 3 hours, the reaction solution was poured into 2.5 l of water, and the mixture was diluted with methylene chloride to 5 times.
Extracted twice. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (850 g). Methylene chloride-methanol (98: 2-9
The fractions eluted at 5: 5) were collected and the indicated compound (48.40
g) was obtained as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.3~1.8 (} 7H, m) 3.39 (3H, s, -OCH 3) 3.4~3.8 (8H, m) 4.72 (2H, s, -O-CH 2 -O) IR spectrum (CHCl ₃ ) cm ^-1 : 3480 (-OH), 1050 (C-
O-C) Mass spectrum (m / e): 193 (M ⁺ +1), 117 (M ⁺ -C ₃
H ₇ O ₂₎ Elemental analysis: C ₉ H ₂₀ O ₄ Calculated: C, 56.23; H, 10.49 Found: C, 55.95; H, 10.28 Reference Example 60 1-Bromo-5- (2-methoxyethoxy) Methoxypentane The compound of Reference Example 59 (48.40 g) and carbon tetrabromide (100.19 g)
Triphenylphosphine (79.32 g) was added to a methylene chloride (500 ml) solution of the above under ice-cooling (5-8 ° C). After stirring at room temperature for 1 hour, the solvent was distilled off, and diethyl ether was added to the residue to remove insoluble matter. The liquid was concentrated and the residue was subjected to column chromatography using silica gel (850 g). Fractions eluted with ethyl acetate-hexane (1: 9) were collected to give the title compound (57.87 g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.4~1.8 (} 4H, m) 1.90 (2H, quintet, J = 6.5Hz, C (2) -H 2) 3.40 (3H, s, -OCH 3) 3.4~3.8 (8H , m) 4.72 (2H, s , -O-CH 2 -O-) IR spectrum ^{_{(CHCl 3) cm -1: 1045}} (C-O-C), 565
(-Br) mass spectrum (m / e): 225,223 ( M + -OCH 3), 181,179
^{_{(M + -OCH 2 CH 2 OCH}} 3) Elemental analysis: C ₁₉ H ₁₉ BrO ₃ Calculated: C, 42.37; H, 7.51 ; Br, 31.32 Found: C, 42.39; H, 7.31 ; Br, 31.13 Reference Example 61 Diethyl 2- {5- (2-methoxyethoxy) methoxypentyl} malonate Metallic sodium (3.00 g) was gradually added to anhydrous ethanol (30 ml) to dissolve it, and then diethyl malonate (37.80) was added.
A solution of g) in absolute ethanol (20 ml) was added dropwise. Further, a solution of the compound of Reference Example 60 (30.01 g) in absolute ethanol (10 ml) was added dropwise, and the mixture was heated under reflux for 21 hours. After allowing to cool, the solvent was distilled off, cold water was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was subjected to column chromatography using silica gel (850g). Fractions eluted with hexane-ethyl acetate (4: 1) were collected to give the title compound (32.78 g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.26 (} 6H, t, J = 7.0Hz, -CH 2 CH 3 × 2) 1.3~2.1 (8H, m) 3.2~3.8 (7H, m) 3.40 (3H, s, - OCH ₃ ) 4.20 (4H, q, J = 7.0Hz, -C H ₂ -CH ₃ × 2) 4.71 (2H, s, -O-CH ₂ -O-) IR spectrum (CHCl ₃ ) cm ^-1 : 1725 (−CO−), 1040 (−
C-O-C) Mass spectrum (m / e): 275 ( M + -C 3 H 7 O), 259 (M
⁺ -C ₃ H ₇ O ₂₎ Elementary analysis: Calculated _{C 16 H 30 O 7: C} , 57.47; H, 9.04 Found: C, 57.56; H, 8.98 Reference Example 62 2- {5- (2- (Methoxyethoxy) methoxypentyl} ethyl hydrogen malonate To a solution of the compound of Reference Example 61 (1.029 g) in ethanol (1.5 ml) was added a solution of potassium hydroxide (0.203 g) in water (1.5 ml) under ice cooling. The reaction solution was stirred at room temperature for 5 hours and then washed with ether. Add 10% hydrochloric acid to the aqueous layer to adjust the pH to 2,
It was extracted 4 times with methylene chloride. The extracts were combined, dried and concentrated, and the oily residue (0.94 g) was converted to silica gel (20 g).
It was subjected to column chromatography using. Fractions eluted with hexane-ethyl acetate (2: 1 to 1: 1) were collected to give the title compound (0.764g) as a colorless oil.

NMR spectrum _{(CDCl 3, ppm) 1.28 (} 3H, t, J = 7Hz, -OCH 2 CH 3) 1.15~2.10 (8H, m) 3.25~3.80 (7H, m) 3.42 (3H, s, -OCH 3) 4.24 (2H, q, J = 7Hz, -O CH 2 CH 3) 4.73 (2H, s, -O-CH 2 -O-) elemental analysis: calculated _{C 14 H 26 O 7: C} , 54.88; H , 8.55 Found: C, 54.70; H, 8.45 Reference Example 63 2-{(dl-trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonyl} amino-5-{(2-methoxyethoxy) -Methoxy} ethyl heptanoate A solution of the compound of Reference Example 62 (0.731 g), diphenylphosphoryl azide (0.51 ml) and triethylamine (0.50 ml) in benzene (15 ml) was heated under reflux for 4 hours. After allowing to cool, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried and concentrated. Oily residue (0.748g) was added to toluene (15m
l), the compound of Reference Example 4 (0.329 g) and triethylamine (0.50 ml) were added, and the mixture was heated with stirring on an oil bath at 90 ° C. for 24 hours. The solvent was distilled off, and the residue was washed with silica gel (30
g) was used for column chromatography. Fractions eluting with hexane-ethyl acetate (2: 1 to 1: 1) were collected to give the title compound (0.596g) as a wax.

NMR spectrum _{(CDCl 3, ppm) 0.8~2.5 (} 48H, m) 3.17 (2H, dt, J 1 = J 2 = 7Hz, -NH-CH 2 -) 3.43 (3H, s, -OCH 3) 3.35~4.95 (14H, m) 4.23 (2H , q, J = 7Hz, -CO-O CH 2 CH 3) 4.73 (2H, s, -O-CH 2 -O-) 5.37 (1H, m, -NH-) mass spectrum (m / e): 641 ( M + -C 3 H 7 O 2), 627
(M ⁺ -C ₄ H ₉ O ₂ ) Reference Example 64 2-{(dl-trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonyl} amino-5-hydroxyethyl heptanoate To a solution of the compound of Reference Example 63 (0.584 g) in ethanol (10 ml) was added acetyl chloride (0.2 ml) under ice cooling. After stirring at room temperature for 4.5 hours, the reaction solution was diluted with ethyl acetate (50 ml) and washed with a saturated aqueous sodium hydrogen carbonate solution and water.
After drying, the solvent was distilled off, and the waxy residue (0.479 g) was subjected to column chromatography using silica gel (20 g). Fractions eluted with hexane-ethyl acetate (1: 1 to 2: 1) were collected to give the title compound (0.405g) as a wax with mp 43-46 ° C.

NMR spectrum _{(CD 3 OD, ppm):} 0.8~2.40 (48H, m) 3.08 (2H, t, J = 7Hz, -NH- CH 2 -) 3.2~4.7 (7H, m) 3.55 (2H, t, J _{= 6Hz, - CH 2 -OH)} 4.17 (2H, q, J = 7Hz, -O CH 2 CH 3) IR spectrum ^{_{(CHCl 3) cm -1: 3500}} (-OH), 3400 (-N
H), 1720 (-O-CO-) Reference Example 65 dl-cis-2-benzyloxymethyltetrahydropyran-3-yl = N-heptadecylcarbamate Using stearic acid (2.758 g), diphenylphosphoryl azide (2.09 ml) and the compound of Reference Example 33 (0.862 g), the title compound (1.407 g) was obtained as crystals in the same manner as in Reference Example 3. mp63.0-65.0 ° C (ether-hexane).

NMR spectrum _{(CDCl 3) ppm: 0.7~2.4 (} 37H, m) 3.0~3.8 (6H, m) 3.9~4.2 (1H, m) 4.55 (2H, ABq, J = 12Hz, -OCH 2 Ph) 4.5~5.0 (2H, m) 7.2~7.4 (5H , m, C 6 H 5 -) IR spectrum ^{_{(CHCl 3, cm -1):}} 3460 (-NH -), 1715 (-
O-CO-) mass spectrum (m / e): 504 (M ⁺ +1), 396 (M ⁺ -OC _{7
^{H 7), 382 (M +}} -CH 2 OC 7 H 7) Elemental analysis: Calculated _{C 31 H 53 NO 4: C} , 73.91; H, 10.60; N, 2.78 Found: C, 73.76; H, 10.72 N, 2.79 Reference Example 66 dl-cis-2-hydroxymethyltetrahydropyran-
3-yl = N-heptadecyl carbamate Using an ethanol (30 ml) solution of the compound of Reference Example 65 (1.300 g) and 10% palladium carbon (0.819 g), the title compound (0.977 g) was obtained as crystals in the same manner as in Reference Example 4. mp 81.0-82.0 ° C (ether).

NMR spectrum _{(CDCl 3) ppm: 0.7~2.3 (} 37H, m) 2.9~3.1 (1H, m, -OH) 3.0~3.7 (6H, m) 3.9~4.2 (1H, m) 4.7~5.1 (2H, m ) IR spectrum (CHCl ₃ ) cm ⁻¹ : 3600 (−OH), 3460 (−NH
-), 1700 (-O-CO- ) mass spectrum (m / e): 413 ( M +), 382 (M + -CH 2 OH) Reference Example 67 dl-cis -2- {N- (5- bromo Pentyl) carbamoyloxy} methyltetrahydropyran-3-yl = N
-Heptadecyl carbamate 5-Bromohexanoic acid (1.245 g), diphenylphosphoryl azide (1.37 ml), and the compound of Reference Example 66 (0.880
g) in the same manner as in Reference Example 6 (0.933)
g) was obtained as a waxy solid. mp 95.0-96.0 ° C (ether).

NMR spectrum _{(CDCl 3) ppm: 0.7~2.3 (} 43H, m) 3.0~3.8 (6H, m) 3.38 (2H, t, J = 7Hz, -CH 2 Br) 4.00 (1H, m, C (2) - H) 4.13 (2H, d, J = 7Hz, -CH 2 OCO-) 4.6~5.1 (3H, m) IR spectrum ^{_{(CHCl 3) cm -1: 3460}} (-NH-) 1720 (-
O-CO-) mass spectrum (m / e): 606,604 (M ⁺ ), 524 (M ⁺ -HB
r) Elemental _{analysis: C 30 H 57 BrN 2 O} 5 Calculated: C, 59.49; H, 9.49 ; Br, 13.19; N, 4.62 Found: C, 59.61; H, 9.58 ; Br, 13.14; N, 4.74 Reference Example 68 dl-S- (cis-2-benzyloxymethyltetrahydropyran-3-yl) N-octadecylthiol carbamate Using nonadecanoic acid (3.38 g), the procedure of Reference Example 3 was repeated, and the compound (1.124 g) of Reference Example 39 was reacted. The crude product was subjected to column chromatography using silica gel (80 g), and the fractions eluted with ether-hexane (1: 5 to 1: 2) were collected to give the title compound (2.283 g) as white crystals. . mp 85-86 ° C (ether-hexane).

NMR spectrum (CDCl ₃ ) ppm: 8.0 to 2.2 (39H, m) 3.1 to 4.2 (8H, m) 4.57 (2H, ABq, J _AB = 12H, -CH ₂ Ph) 5.33 (1H, m, -NH-) _{7.35 (5H, m, -C 6} H 5) infrared spectrum ^{_{(CHCl 3) cm -1: 3450}} (-NH -), 1675
(-S-CO-) Elemental analysis: C ₃₂ H ₅₅ NO ₃ S Calculated: C, 71.99; H, 10.38 ; N, 2.62; S, 6.01 Found: C, 71.87; H, 10.30 ; N, 2.67 S, 6.17 Reference Example 67 dl-S- (cis-2-hydroxymethyltetrahydropyran-3-yl) N-octadecylthiol carbamate A mixture of acetonitrile (70 ml) and methylene chloride (35 ml) was cooled in an ice-water bath, and aluminum chloride (2.32
g) and sodium iodide (2.61 g) were added sequentially. Then, the methylene chloride (35 m) of the compound of Reference Example 68 (1.859 g)
l) The solution was added and stirred at room temperature for 7 hours. Water was added to the reaction solution, and the mixture was passed through the Celite layer to remove insoluble materials. Methylene chloride was added and the layers were separated, and the aqueous layer was extracted again with methylene chloride. The organic layers were combined, washed with a sodium thiosulfate aqueous solution and water, dried and concentrated. The residue was subjected to column chromatography using silica gel (45 g), and fractions eluted with ethyl acetate (1: 5-1: 2) were collected to give the title compound (1.200 g) as white crystals.

mp 93-94 ° C (ether).

NMR spectrum (CDCl ₃ ) ppm: 0.7 to 2.3 (40H, m) 3.15 to 4.15 (8H, m) 5.53 (1H, m, -NH-) IR spectrum (CHCl ₃ ) cm ^-1 : 3450 (-NH-, -OH), 165
0 (-S-CO-) Elemental analysis: C ₂₅ H ₄₉ NO ₃ S Calculated: C, 67.67; H, 11.13 ; N, 3.16; S, 7.23 Found: C, 67.65; H, 11.24 ; N, 2.96; S, 7.51 Reference Example 70 2-Hydroxymethyl-7- (2-methoxyethoxy)
Methoxy-1-heptanol The compound of Reference Example 61 (10.29 g) in tetrahydrofuran (10
Solution (0 ml) in a mixture of lithium aluminum hydride (2.40 g) and tetrahydrofuran (100 ml) under ice cooling (5 ml).
~ 7 ° C). After stirring at room temperature for 3 hours, 4% aqueous sodium hydroxide solution (9.60 ml) was added dropwise at 5 to 9 ° C. After stirring at room temperature for 30 minutes, the mixture was filtered through Celite, and the residue obtained by concentrating the solution was subjected to column chromatography using silica gel (105 g). Fractions eluted with methylene chloride-methanol (98: 2 to 95: 5) were collected to give the title compound (6.94g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.2~2.0 (} 9H, m) 2.52 (2H, m, -OH) 3.40 (3H, s, -OCH 3) 3.5~4.0 (10H, m) 4.71 (2H, s, - O-CH ₂ -O-) IR spectrum ^{_{(CHCl 3) cm -1: 3420}} (OH), 1040 (-C-
OC) Mass spectrum (m / e): 251 (M ⁺ +1) Elemental analysis: Calculated as C ₁₂ H ₂₆ O ₅ : C, 57.57; H, 10.47 Measured value: C, 57.46; H, 10.22 Reference example 71 (2RS) -2-benzyloxymethyl-7- (2-methoxyethoxy) methoxy-1-heptanol The compound of Reference Example 70 (3.06 g) in dimethylformamide (2
0 ml) solution, sodium hydride (55% mineral oil suspension, 5
87 mg) and dimethylformamide (40 ml) were added dropwise under ice cooling (5 to 7 ° C). After stirring at room temperature for 1 hour, benzyl bromide (1.60 ml) under ice cooling (5-7 ° C)
It was dripped at. After stirring at room temperature for 2 hours, the reaction solution was poured into 0.3 l of water and extracted 5 times with ethyl acetate. The extract was washed with water, dried and concentrated, and the oily residue was subjected to column chromatography using silica gel (60 g). Fractions eluted with hexane-ethyl acetate (2: 1 to 1: 1) were collected to give the title compound (2.37 g) as a colorless oil.

NMR spectrum _{(CDCl 3) ppm: 1.2~2.0 (} 9H, m) 2.47 (1H, t, J = 6Hz, -OH) 3.39 (3H, s, -OCH 3) 3.4~3.8 (10H, m) 4.52 (2H _{, s, -O-CH 2 -Ph} ) 4.71 (2H, s, -O-CH 2 -O-) 7.26 (5H, s, -C 6 H 5) IR spectrum ^{_{(CHCl 3) cm -1: 3500}} ( -OH), 1040 (C-
OC) Mass spectrum (m / e): 341 (M ⁺ +1) Elemental analysis: C ₁₉ H ₃₂ O ₅ Calculated value: C, 67.03; H, 9.47 Measured value: C, 66.88; H, 9.39 Test example 1 Inhibition of PAF hypotensive action Inactin (90 mg / kg ip) as a test animal
Wistar Imado rats (body weight 350-450 g) anesthetized in (1) were used. Blood pressure was continuously measured from the cannula inserted into the femoral artery, and the drug was intravenously injected from the cannula inserted into the femoral vein. First, 10 ng / kg of PAF (l-C _{16: 0} type) was intravenously injected at intervals of 5 minutes, and this was repeated until the magnitude of the antihypertensive reaction became constant. Then, the test drug was intravenously injected, and 1 minute later, the same dose of PAF was administered again. The test drug was administered cumulatively, and the 50% inhibitory dose (ID
₅₀ ) was determined and used as an index of PAF antagonistic activity. PAF and the test drug were dissolved in a physiological saline solution containing 0.25% bovine serum albumin (BSA), and only the test solution insoluble in this solvent was dissolved in a physiological saline solution containing 20% ethanol. .

Test Example 2 Inhibitory effect on platelet PAF aggregation in vitro Blood was collected from rabbits and immediately mixed with 1/9 volume of 3.8% sodium citrate. After centrifugation at 150 g for 15 minutes at room temperature, platelet-rich plasma (PRP) was obtained from the upper layer. The remaining blood was further centrifuged at 1000 g for 15 minutes to obtain platelet poor plasma (PPP) from the upper layer. Mix the appropriate amount of PRP and PPP to obtain the final platelet count of PRP in μl.
Adjusted to 600,000 pieces per item. Platelet aggregation was measured by increasing the transmitted light using an aglycometer according to the method of Bourne et al. (GVR Born J. Physiol. 62 , 67-68 (1962)).
25 μl of test drug solution was added to 250 μl of PRP, and 1 minute later, 25 μl
l of PAF (C ₁₆ , final concentration 10 ^{−8 to} 3 × ^-8 M) was added, and then observed for 5 minutes to confirm the aggregation inhibiting action. The inhibition rate was calculated based on the aggregation by PAF when physiological saline was used instead of the test solution, and the IC ₅₀ was calculated from the dose-response curve.

The results of tests 1 and 2 are shown in the table.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 405/12 207 213 215 217 233 237 239 241 257 413/12 313 417/12 307 309 313 313 // A61K 31/335 ACG 31/34 ABN 31/35 ACB 31/40 31/415 ABF 31/42 31/425 31/44 31/445 AED 31/495 31/50 31/505 31/535 31/54

Claims (1)

[Claims] 1. A general formula[Wherein l represents an integer of 2 to 4, A and B are the same or
Differently represent an oxygen atom or a sulfur atom. R¹And R²of
One of them is a straight or branched chain alkyl group having 10 to 22 carbon atoms.
Group, straight-chain or branched-chain aliphatic acyl having 10 to 22 carbon atoms
Basis orA group having³Is a straight chain having 10 to 22 carbon atoms or
Represents a branched chain alkyl group, R^FourIs a hydrogen atom, lower alk
Group, aralkyl group, lower aliphatic acyl group, aromatic acyl group
Group, alkyloxycarbonyl group or alkenyl
Indicates an oxycarbonyl group. ), The other is(Wherein X is a single bond,A group having⁶Is R^FourThe same group as above is shown. )
, M is an integer of 0 to 3, and n is an integer of 0 to 10.
Show, R^FiveIs a hydrogen atom or an optionally protected carbo
Xy group, Z Is an anion, Q isA group having⁷, R⁸And R⁹Are the same or different
Represents a hydrogen atom or a lower alkyl group. ), Or
A group having the formula -G (wherein G represents a 5- to 10-membered heterocyclic group)
You ) Is shown. ) Is shown. ] Derived cyclic ether
Body and its inner salt and its salt.