JPH02767A - Lipid derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R1 is alkyl or alkylcarbamoyl; R2 is alkyloxy, alkylcarbamoyloxy, alkylureido, cyanomethyl, hetero ring group, etc.; R2' is H or R2' and R2 are bonded to form O(CH2)m (m is 1-5); R3-R5 are H, alkyl or two or three of R3-R5 are bonded together with adjoining N to form cyclic amino; R6 is H or alkylcarbonyl and X is pair ion; Y is O or S; n is 1-10]. EXAMPLE:2-Methoxy-1-octadecylcarbamoyloxy-3-(3- trimethylammoniosulfonylamino)propane chloride. USE:An antagonist of PAF(platelet activating factor) or antitumor agent. PREPARATION:For example, an N-substituted succinimide derivative or N- substituted phthalimide derivative shown by formula V is treated as a starting substance according to the reaction formula to give a compound shown by formula I.

Description

[Detailed description of the invention] The present invention is based on the use of PAF (platelet activating factor 1) in the pharmaceutical field.
P1atalet Activating Facto
r) Concerning lipid derivatives that can serve as antagonists or antitumor agents.

More specifically, the present invention relates to a compound represented by the following formula (I).

[wherein R3 is alkyl or alkylcarbamoyl;
R1 is lower alkyloxy, lower alkylcarbamoyloxy, alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl, or a heterocyclic group or heterocyclyloxy; R1゛represents hydrogen or together with R8 forms 10(CHm)m- (wherein m represents an integer from engineering to 5); Rs, Ra and R1 independently of each other represent hydrogen or N represents lower alkyl or two or three of R3, R4 and R1 are adjacent
together to form a cyclic ammonio; R6 is hydrogen or lower alkyl carbonyl; , has the structure shown below, and is produced by basophils, neutrophils, eosinophils, macrophages, mast cells, platelets, human leukemia cells, vascular endothelial cells, etc. in response to various stimuli. It is considered.

[In the formula, m represents 16 or 18. Biological activities exhibited by PAF include platelet activation, smooth muscle contraction, n
It is known to have effects such as reducing m-flow, suppressing cardiac function, increasing vascular permeability, and lowering blood pressure. Physiological phenomena or diseases thought to be associated with PAF include inflammation, asthma, thrombosis, anaphylactic shock, endotoxic shock, allergy, hypotension, ischemic heart disease, acute tissue graft rejection, nephritis, or gastric ulcer. can be mentioned.

PAF is thus thought to be a mediator of various physiological phenomena or diseases, and for the treatment of these, PAF is
F antagonists are being developed [P.
Braquet et al., 77-7 Fu'Osical Review, Vol. 39, p. 9B-145, 1987], and PAF antagonists of PAF structural analogs are described, for example, in JP-A-5
7-65489, JP-A No. 60-243047, or JP-A No. 62-228088.

Various PAF antagonists have been developed to date, but these compounds do not act specifically on PAF receptors, and while they have PAF antagonistic effects, they also have side effects of their own. It has several problems, such as having a PAF-like effect and being rapidly metabolized, and it is desired to solve these problems.

The present inventors aimed to develop a useful PAF antagonist, and as a result of intensive research, they found that a strong PAF antagonistic effect or anti-inflammatory effect could be achieved by converting the phosphoric acid ester moiety of PAF into a sulfonamide. The present invention was completed based on the discovery that it exhibits tumor activity.

The compound of the present invention is represented by the following formula (1).

[wherein R1 is alkyl or alkylcarbamoyl i
Rm is lower alkyloxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanmethyl, or a heterocyclic group or heterocyclyloxy; R1' represents hydrogen or together with R2 forms -〇(CH,)ffi- (wherein m represents an integer from engineering to 5); R8, R6 and R1
independently represent hydrogen or lower alkyl, or two or three of R1, R4 and R6 together with adjacent N form a cyclic ammonio; R6 is hydrogen or lower alkylcarbonyl; Counterion;
Y represents oxygen or sulfur; and n each represents an integer from 1 to 10] Definitions of terms used throughout this specification are as follows.

"Lower alkyl" refers to straight-chain or branched C3-C
, alkyl, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, rt-butyl, pentyl, hexyl, and hebutyl.

"r alkyl" means a straight chain 01-CAM alkyl which may have a double bond or triple bond. Preferably, it means C0-C1, higher alkyl, for example,
Decyl;
Examples include Doriacontyl.

1-class alkyloxy, 1-class alkylcarbamoyloxy, 1-class alkylcarbonyl, r-lower alkylcarbonylamino, 1-class alkyloxycarbonylamino, 1-class alkylureido, r-lower alkyl dimethyl.
or in “lower alkylcarbonylmethyl”, “
Lower alkyl corresponds to the above-mentioned mono-alkyl.

"1 heterocyclic group" refers to a group containing 1 to 4 heteroatoms such as oxygen, sulfur and/or nitrogen, lower alkyl,
Refers to a 5- to 7-membered heterocyclic group optionally substituted with lower alkyloxy, hydroxy, halogen, or lower alkyloxycarbonyl, such as IH-
Pyrrol-1-yl, 2-methyl-IH-pyrrole-1
-yl, 3-methyl-IH-pyrrol-1-yl, IH
-imidazol-1-yl, 2-methyl-IH-imidazol-1-yl, 2,4-dimedel-IH-imidazol-1-yl, IH-pyrazol-1-yl, 5-methyl-IH-pyrazol-1-yl yl, 3,5-dimethyl-IH-pyrazol-1-yl, IH-1,2,3-triazol-1-yl, 4-methyl-IH-1,2,3
-triazol-1-yl, 4-methyl-2H-1,2
,3-triazol-2-yl,4-methyl-3H-1
,2,3-triazol-3-yl,3-methyl-I
H-1,2,4-triazol-1-yl, 3-methyl-2H-1,2,4-triazol-2-yl, 3-methyl-4H-1,2,4-triazol-4-yl, 2
H-tetrazol-2-yl, IH-tetrazol-1
-yl, 5-methyl-IH-tetrazol-1-yl or 5-methyl-2H-tetrazol-2-yl.

1 "Heterocyclyloxy" means a compound containing from 1 to 4 heteroatoms such as oxygen, sulfur and/or nitrogen, even if substituted with lower alkyloxy, hydroxy, halogen or lower alkyloxycarbonyl, etc. hydroxy substituted by a 5- to 7-membered heterocyclic group, such as 3-inxazolyloxy, 3-isothiazolyloxy, 3-pyrazolyloxy, 3-(4-methylinxazolyl) oxy, 4-(1,2,3-triazolyl)oxy or 4-
Examples include (5-p-tyl-1,2,3-triazonol)oxy.

"Cyclic ammonio" means a 5- to 6-membered mono- or bicyclic cyclic ammonio that may have a heteroatom and/or a substituent, for example, N-methyl-1
-pyrrolidinio, N-methyl-1-pyrrolidinio, 3-oxazolio, 2-isoxazolio, 3-thiazolio, 4
-Methyl-3-thiazolio, 5-hydroxyethyl-4
-Methyl-3-thiazolio, 3-imidazolio, 1-pyridinio, 3-carboxy-1-pyridinio, N-methyl-1-piperidinio, N-methyl-4-morpholio,
1-pyrimidinio, 1-pyrazinio, N-methyl-1-
piperazinio, 1-triazinio, 3-penzoxazolio, 3-benzothiazolio, 1-quinolinio, 6-medoxy-1-quinolinio, 5.6,7.8-tetrahydro-1-quinolinio, 2-isoquinolinio, 1-quinolinio or Examples include Ajirinio.

Examples of the substituent include lower alkyl, carbonyl, lower alkyloxycarbonyl, hydroxy, lower alkyloxy, acyloxy, lower alkylamino, amino, carbamoyl, and ureido.

Examples of "r counter ions" include pharmacologically acceptable ones such as halogen ions (chlorine, bromine, iodine), acetate ions, methanesulfonate ions, sulfate ions, nitrate ions, and J-phosphate ions. can. Furthermore, when the substituent of the cyclic ammonium ion is likely to be an anion, a salt may be formed within the molecule.

In the above definition, the more preferred alkyl represented by R1 includes higher alkyl of C11 to C8, such as dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or ifsanyl, and is most preferred. R
As 8, mention may be made of CtS-C1, alkyl, such as hexadecyl, heptadecyl or octadecyl.

Examples of the alkylcarbamoyl represented by R3 include those in which the alkyl moiety corresponds to the above alkyl, that is, more preferable R, alkylcarbamoyls include dodecylcarbamoyl, tridecylcarbamoyl, tetradecylcarbamoyl, and pentadecylcarbamoyltadecylcarbamoyl. and the most preferred R.

Alkyl carbamoyl Moyle Examples include tadecylcarbamoyl.

More preferred R8 lower alkyloxy such as methoxy, ethoxy or propoxy; lower alkylcarbamoyloxy such as methylcarbamoyloxy, ethylcarbamoyloxy or propylcarbamoyloxy; lower alkylcarbonylamino such as methylcarbonylaminorbonylamino; lower alkyloxy Carbonylamino such as methoxycarbonylaminoethoxycarbonylaminobonylamino; lower alkylureido such as methylureido, ethylureido or propylureido; lower alkyloxymethyl such as methoxymethyl, ethoxymethyl or propoxymethyl; and lower alkylcarbonylmethyl methylcarbonylmethyl, ethylcarbonylmethyl R, heterocyclic group means a nitrogen-containing 5- to 6-membered heterocyclic group which may have oxygen or sulfur or/and a substituent, for example, 3-Methyl-2H- 1.
2.4-triazol-2-yl, 3H-1.2.3.
4-tetrazol-3-yl, 5H- 1.2.3.4
-tetrazol-5-yl, 5-methyl-IH-tetrazol-1-yl or 5-methyl-2H-tetrazol-2-yl, and more preferably R,heterocyclyloxy means oxygen, sulfur or / and hydroxy containing a hetero atom such as nitrogen and substituted by a 5- to 6-membered heterocyclic group which may have a substituent, such as 3-isoxazolyloxy or 3
-(4-methylinxazolyl)oxy and the like.

Most preferred R. methoxy, methylcarbamoyloxy, acetamide, methoxycarbonylamino,
Methylureido, methoxymethyl, acetylmethyl, cyanomethyl, 3-methyl-2H-1.2.4-triazol-2-yl, 5-methyl-IH-tetrazol-1-yl, 5-methyl-2H-tetrazol- 2-
and 3-inxazolyloxy.

R, and R,° together form 10 (CH-m-. Preferably m is an integer of 1 to 5, more preferably m is an integer of 4 or 5. Most preferable integer , 4.

R,, R4 and R. More preferable lower alkyl groups include methyl, ethyl, and propyl, and the most preferable lower alkyl group is methyl.

More preferred cyclic ammonio is N-methy-1-
pyrrolidinio, N-methyl-1-pyrrolidinio, 3-oxazolio, 2-isoxazolio, 3-thiazolio, 4
-Methyl-3-thiazolio, 5-hydroxyethyl-4
-Methyl-3-thiazolio, 1-N-methyl-3-imidazolio, 1-pyridinio, 3-carboxy-1-pyridinio, N-mesol-1-piperidinio, N-methyl-
4-morpholinio, 1-pyrimidinio, 1-pyridinio, 1-methyl-1-piperazinio, 1-triazinio,
3-penzoxazolio, 3-penzodeazolio, 1-
Quinolinio, 6-medoxyl-quinolinio, 5.6.
Examples include 7.8-tetrahydro-1-quinolinio, 2-inquinolinio, and 1-quinoxalinio.

More preferred R. As the alkylcarbonyl, acetyl, propionyl or butyryl can be mentioned, and the most preferred R. Acetyl can be mentioned as an alkylcarbonyl.

Preferably, n is an integer from 1 to 10, more preferably from 1 to 5, and most preferably from 2 to 4.
is an integer.

Preferred examples of R, lower alkyl include the above-mentioned C1-C, alkyl, more preferred examples include methyl, ethyl, propyl, and the like, and most preferred example includes methyl.

prot-OR means a commonly used hydroxy protecting group, such as benzyl, triarylmethyl [triphenylmethyl (trityl), etc.], tonoalkylsilyl (trimethylsilyl, tart-butyldimethylsilyl, etc.), tetrahydropyranyl, Examples include acetyl-4, benzoyl, and p-nitrobenzoyl.

Prot-NH. means an amino protecting group, e.g.
acetyl, benzoyl, benzoyloxycarbonyl,
Mention may be made of tart-butoxycarbonyl or trityl.

The following abbreviations are used throughout this specification.

Me: methyl, Et: ethyl, 1-13u: tart-butyl, Ph: phenyl, Trnitriphenylmethyl (trityl), Ac: acetyl, DEAD: diethyl azodicarboxylate, THF
: Tetrahydrofuran, and MEK: Methyl ethyl ketone.

Compound (1) has two stereoisomers, R-configuration and S-configuration, and each of them, a mixture thereof, and a racemate are included in the present invention.

The compound of the present invention can be produced, for example, by the following reaction steps.

(Left below) Dake reaction process■ (First step) This step is a step in which the hydroxy of compound V is converted into an amine.

This step can be carried out by hydrolyzing the succinimide or N-substituted phthalimide of Compound V.

The reaction to obtain the N-substituted succinimide or N-substituted phthalimide is carried out using succinimide or phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent such as tetrahydrofuran, benzene or dimethylformamide (DMF) at room temperature. It can be done in several hours to several tens of hours.

Hydrolysis can be carried out using hydrazine in a solvent such as alcoholic methanol or ethanol at room temperature or by refluxing for several hours.

Alternatively, after converting hydroxy into methanesulfonyloxy or benzenesulfonyloxy, the azide compound may be obtained by reacting with sodium azide or lithium azide, and then reduced with triphenylphosphine or the like.

(Second step) In this step, the compound ■ is converted into Halo-5Ox (CH,)n
-Hal CHal and Hal' are halogens; n has the same meaning as above] to form a sulfonamide derivative ■
This is the process of obtaining

Specific examples of the sulfonyl halide include 3-chloropropanesulfonyl chloride, 3-chloropropanesulfonyl bromide, 4-chlorobutanesulfonyl chloride, 4-chlorobutanesulfonyl bromide, 5-chloropentanesulfonyl chloride, 6-bromohexanesulfonyl chloride, 7 - Bromoheptanesulfonyl bromide, 8-chlorooctanesulfonyl chloride, 9-bromononanesulfonyl bromide or 10
-Chlorodecanesulfonyl chloride sodium chloride.

The reaction is carried out, for example, in the presence of a base such as triethylamine, pyridine, or sodium hydroxide, in a solvent such as chlorinated hydrocarbons such as chloroform, dichloromethane, ethers such as ethyl ether, tetrahydrofuran, or aromatic benzene, under cooling or at room temperature. It can be done in several hours to several tens of hours.

Furthermore, if necessary, dimethylaminopyridine may be added as a catalyst.

When the compound obtained in this step is a chloride, the compound can be converted to bromide or iodide by treatment with sodium bromide or sodium iodide according to a conventional method.

In order to obtain the compound of the present invention in which R1 is alkylcarbonyl, in this step, the previously obtained compound is mixed with an acylating agent and a base (for example, triethylamine, pyridine, N,
The reaction may be carried out in the presence of N-diisopropylethylamine, etc.) in a chlorinated hydrocarbon solvent (for example, dichloromethane, chloroform) under cooling or at room temperature.

Acylating agents include acid halides, such as acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, pentanoyl chloride, hexanoyl chloride or pentanoyl chloride. or acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, bivaric anhydride, pentanoic anhydride, Examples include hexanoic anhydride and heptanoic anhydride.

(Third Step) This step is a step in which the compound (1) is converted into a quaternary ammonium to obtain the compound of the present invention.

Examples of amines used for quaternary ammonium formation include alkylamines such as trimethylamine or triethylamine, or N-methylpyrrole, N-methylpyrrolidine, oxazole, inoxazole, thiazole, 4-methylthiazole, N-methylimidazole, pyridine, Heteroatoms such as 3-carboxypyridine, N-methylpiperidine, N-methylmorpholine, pyrimidine, pyrazine, N-methylpiperazine, triazine, benzoxazole, benzodeazole, quinoline, inquinoline, quinoxaline or aziline and/or
Alternatively, 5- to 6-membered monocyclic or bicyclic cyclic amines which may have a substituent may be mentioned.

The reaction can be carried out using the amine itself as a solvent or in a solvent such as furfuric methanol, ethanol, aromatic benzene, toluene, etheric noethyl ether, tetrahydrofuran, dioxane or dimethylformamide at room temperature or under heating. It can be done in hours to tens of hours.

Alternatively, when Hal in compound (1) is chlorine, it is replaced with bromine or iodine, reacted with various amines to form quaternary amines of bromine or iodine salts, and then separated using hydrochloric acid. It may also be replaced with a chlorine salt.

Reaction Step (1) (1st Step) This step is a step in which the compound C is dehydrohalogenated to obtain the compound Wataru.

In this step, the phenylselenide or phenylthio compound obtained by replacing the halogen of compound (1) with a phenylselenium anion or phenylthio anion is oxidized with a peroxide, and the obtained oxide is further heated to produce benzeneselenium. This can be carried out by elimination as an acid or benzenesulfenic acid.

The reaction to obtain the phenylselenide compound or phenylthio compound is carried out using a reagent obtained by reducing diphenyl diselenide or diphenyl sulfide with sodium borohydride, using alcoholic methanol, ethanol, impropatol, or etheric alcohol. in a solvent such as ethyl ether, tetrahydrofuran or dioxane,
This can be carried out at room temperature or under heating for several hours.

The oxidation reaction is carried out using peroxide water, m-chloroperbenzoic acid, peracetic acid, tert-butyl peroxide, etc. as peroxides, and alcohols such as methanol, ethanol, or chlorinated hydrocarbons such as dichloromethane and chloroform. This can be carried out in a few hours at room temperature in a solvent such as.

The reaction of removing the oxide by heating may be carried out by heating in a solvent such as aromatic benzene or toluene, or chlorinated hydrocarbon dichloromethane or chloroform.

(Step 2') This step is a step in which the double bond of compound (1) is oxidatively cleaved to form an aldehyde form, and the obtained aldehyde form is reduced to obtain compound (2).

The aldehyde compound can be obtained by reductively decomposing the ocinide obtained by oxidizing compound (1) with ozone according to a conventional method.

Ozone oxidation uses chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, alcoholic methanol,
The reaction can be carried out in several hours under cooling using a mixture of solvents such as ethanol, benzene, and ethyl acetate as necessary.

In the reductive decomposition of oscinide, the reducing agents are lead powder in acetic acid, trimethyl phosphite, triphenyl phosphite or dimethyl sulfide, sodium iodide, sulfur dioxide, sodium hydrogen sulfite, and tin chloride (II). ) or iron sulfate (I[), or by catalytic reduction using a platinum, palladium, nickel catalyst, palladium-calcium carbonate, or the like.

In the reaction of reducing an aldehyde to an alcohol, a metal hydride such as lithium aluminum hydride, lithium borohydride, sodium borohydride is used as a reducing agent.
It can be carried out using lithium trimethoxyaluminum hydride or tri-tert-butoxyaluminum lithium hydride in a solvent such as alcoholic methanol, ethanol, etheric ethyl ether, or tetrahydrofuran at room temperature or under heating for several hours. can.

(3rd'' step) This step is a step of halogenating the hydroxy of compound (1).

The halogenation reaction is carried out using phosphorus halides (phosphorus pentachloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, etc.) or thionyl halides (thionyl chloride, thionyl bromide, etc.) as a halogenating agent. , the hydroxyl group may be directly halogenated, or a leaving group may be attached to the hydroxyl group, followed by halogenation.

The reaction for attaching a leaving group is carried out using a substituted sulfonyl chloride, such as methanesulfonyl chloride, benzenesulfonyl chloride or p
-Toluenesulfonyl chloride or the like may be used in the presence of a base such as triethylamine or pyridine according to a conventional method. After this, the reaction may be carried out with an alkali metal halide such as lithium chloride, sodium bromide or sodium iodide. good.

The reaction may be carried out in a conventional manner using a chlorinated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, or a ketone such as acetone, methyl ethyl ketone or dimethylformamide as a solvent depending on the nature of the halogenating agent used.

Halogenation can also be carried out using organic phosphorus compounds such as carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine, is-triphenylphosphine, or methane iodide-triphenoxyphosphine. .

(Step 4') In this step, the halogen of Compound 12 is replaced with an amine to obtain Compound 1 of the present invention, which may be carried out according to Step 3.

If necessary, the anion of the compound of the present invention obtained in the third step or this step may be exchanged with a desired anion.

(Left below) (i) When -Y-R+ is alkylthiocarbamoylthio and R1 is alkoxy, compound C can be produced as follows.

[In the formula, RI is alkylcarbamoyl; and Y represents sulfur, respectively] That is, first, compound x6 is reductively cleaved to obtain the compound, and then the hydroxy of the compound is converted to mercapto to obtain the compound It is preferable to obtain a compound B by reacting it with an isocyanate having a desired alkyl group.Compound C is preferably obtained by removing the benzyl of the compound VIA.

The reaction for obtaining compound IX from compound μ is preferably carried out using lithium aluminum hydride-aluminum chloride as a reducing agent.

In the step of obtaining a compound shadow from a compound shadow, first, compound (1) 6 is mixed with a compound forming a leaving group, such as methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride, in the presence of a base such as triethylamine, according to a conventional method. After reacting to convert hydroxy into a leaving group, use potassium thioacetate or sodium thioacetate to form thioacetate J, and then perform alkaline hydrolysis to obtain mercapto derivative Vff.
61 It is preferable to obtain the desired CI for the 0-order obtained compound μ!
The compound can be obtained by reacting an isocyanate having ~C8° alkyl, such as dodecyl isocyanate, hexadenyl isocyanate or octadecyl isocyanate, in a solvent such as pyridine.

Compound C can be obtained by cleaving the benzyl ether of compound H using trimethylsilyl iodite or aluminum chloride-sodium iodide in acetonitrile under neutral conditions at 0°C to room temperature.

(Left below) (ii) When R* is alkylcarbamoyloxy, compound VC can be produced as follows.

[In the formula, R2 is lower alkyl Hprot-OH is a hydroxy protecting group; R1% l', and Y are the same meanings as above] ■ In this step, alcohol q is added to the alkyl isocyanate.
This is the main step of adding .

Examples of the alkyl isocyanate include methyl isocyanate, ethyl isocyanate, propyl isocyanate, isobrobyl isocyanate, butyl isocyanate, and tert-butyl isocyanate.

The reaction can be carried out in a chlorinated hydrogen solvent such as dichloromethane or chloroform at room temperature or under heating for several hours to several tens of hours. If necessary, acids (boron trifluoride etherate, hydrochloric acid, aluminum chloride, etc.)
Alternatively, a base (triethylamine, pyridine, 4-dimethylaminopyridine, 4-methylpiperidine, etc.) may be used as a catalyst.

(2) This step is a step of deprotecting the 3-position hydroxy protecting group.

The deprotection reaction varies depending on the type of protecting group, but can be carried out in the presence of # (trifluoroacetic acid, acetic acid, hydrogen bromide/acetic acid or hydrochloric acid/chloroform). It can also be carried out by catalytic reduction using a palladium catalyst.

(iii) When -Y-R+ is alkylcarbamoyloxy and R1 is alkoxycarbonylamino, compound beans can be produced as follows.

[In the formula 1 R1 is alkylcarbamoyl; Y is oxygen;
prot-N is an amino protecting group; R8' and R are as defined above. ] (2) This step is a step in which alcohol (2) is added to C,, -C,, alkyl isocyanate.

Examples of the alkyl isocyanate used in this step include dodecyl isocyanate, tridecyl isocyanate, tetradecyl isocyanate, pentadecyl isocyanate, hexadecyl isocyanate, heptadecyl isocyanate, octadecyl isocyanate, nonadecyl isocyanate, and icosa The 0 reaction, which includes nyl isocyanate, can be carried out in the same manner as in (ii)-0.

(2) This step is a step of deprotecting the amine protecting group.

Deprotection reactions vary depending on the type of protecting group, but include hydrolysis (Pd catalyst, hydrogen at normal pressure, room temperature, methanol, methanol-acetic acid, or glacial acetic acid), mild acid treatment (hydrated acetic acid, 30°C; hydrated It can be carried out according to a conventional method such as trifluoroacetic acid (-5°C).

(2) This process is a process of reducing methoxycarbonyl of compound E3 to hydroxymethyl.

As reducing agent, metal hydride complexes, such as lithium aluminum hydride, lithium borohydride, sodium borohydride, lithium trimethoxyaluminum hydride, lithium tritart-phthoxyaluminum hydride or calcium chloride and sodium borohydride. Examples include calcium borohydride produced by

The reaction can be carried out in a solvent such as alcoholic methanol, ethanol, propatool, or etheric solvent such as ethyl ether, tetrahydrofuran, glyme, diglyme, etc. under cooling for several hours.

(2) This step is a step of converting the compound deaf amino into alkyloxycarbonylamino.

As reagents for alkyloxycarbonylation, alkyl haloformates, such as methyl chloroformate, methyl bromformate, ethyl chloroformate,
Propyl chloroformate, isopropyl chloroformate, butyl chloroformate, inbutyl bromoformate, tart-butyl chloroformate, tart
- butyl bromoformate, pentyl chloroformate, hexyl chloroformate or heptyl chloroformate, etc. or dialkyl dicarbonates, for example diprol carbonate, diprol carbonate, dipropyl carbonate soprobyl dicarbonate, Examples include dibutylene dicarbonate, ditertyl dicarbonate, dipentyl carbonate, diheptyl dicarbonate, and the like.

The reaction is carried out in an ethereal solvent such as ethyl ether, tetrahydrofuran, a ketone solvent such as acetone,
This can be done in a few hours at room temperature.

(iv) When -Y-R+ is alkylthio and R is alkyloxycarbonylamino, compound L can be produced as follows.

[wherein R1 is alkyl; Y is oxygen: R, ° and R,
has the same meaning as above] (1) This step is a step of converting alcohol e5 into thioacetate ester.

This step is similar to the step of obtaining ■6 from (i) (i),
After alcohol 1 is converted into a sulfonic acid ester or a halide, it can be converted into a thioacetic acid ester using potassium thioacetate, sodium thioacetate, or the like.

(2) This step is a step of converting the acetyl of compound e6 into the desired alkyl. In this process, thiol is obtained by alkaline hydrolysis of thioacetic acid ester, which is converted into deolate anion with sodium hydride etc., and then halogenated C
lm-Cl@alkyl, e.g. dodecyl bromide,
This can be carried out by reacting with tridecyl bromide, tetradecyl bromide, pentadecyl bromide, pentadecyl chromide, hexadecyl bromide, heptadecyl bromide, octadecyl bromide, octadecyl chloride, nonadecyl bromide, icosanyl bromide, etc.

This step can also be carried out using CIO-Cm@alkyl isocyanate as in the case of (i).

(2) This step is a step for removing the amino and hydroxy protecting groups of the compound Niji.

The reaction is preferably carried out using an acid such as dilute hydrochloric acid or dilute sulfuric acid.

(2) This step converts the amino of compound E8 into alkyloxycarbonylamino. It is a process.

This step can be performed in the same manner as (iii)-0.

(v) When Rm is alkylureido or alkanoylamino, compound 1[[F or II[G can be produced as follows.

(The following is a margin) [In the formula, R1, R t', R. , R, , Y and n have the same meanings as above] (1) This step is a step in which the alkoxycarbonyl of compound DIH is cleaved under acidic conditions to obtain compound 1[[E'.

Compound 111E can be obtained by reacting compound VEI or VH2 in the same manner as in reaction step I, the first step, and the second step.

This step may be carried out according to conventional methods for removing the amino protecting group of the urethane type derivative, such as treatment with hydrogen bromide or hydrochloric acid in acetic acid, treatment with hydrochloric acid or treatment with trifluoroacetic acid in ether, ethyl acetate or nitromethane.

(2) This step is a step in which an alkyl isocyanate is added to amine I[[E' to obtain compound 1[[F.

The reaction is performed with a C, -Ct alkyl isocyanate, such as methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropylisocyanate, butyl isocyanate, tart-butyl isocyanate, pentyl isocyanate, hexyl incyanate,
This can be carried out using heptyl isocyanate or the like in an inert solvent (benzene, toluene, chlorobenzene, chloroform, dichloromethane, acetone, tetrahydrofuran, etc.).

(2) This step is a step of converting amine II[E' into an acid amide.

This step is performed using an acid halide, such as acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, pentanoyl chloride, hexanoyl chloride or heptanoyl chloride. or acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, pivalic anhydride,
This is preferably carried out using an acylating agent such as pentanoic anhydride, hexanoic anhydride or hebutanoic anhydride.

The reaction can be carried out without a solvent or by heating in an inert solvent (eg, ethyl ether, benzene, etc.). If necessary, pyridine or sulfuric acid may be added to accelerate the reaction.

(vi) When Rx is a heterocyclic group or heterocycnorroquine, compound V HIJ can be produced as follows.

[In the formula, R1 is a heterocyclic group or heterocyclyloxy; R1, R8, Y and Prot-OH have the same meanings as above] (1) This step is a step of selectively protecting the hydroxyl at the 1-position.

As a group that selectively protects primary hydroxy, for example,
Mention may be made of tert-butyldimethylsilyl.

When introducing tert-butyldimethylsilyl,
The reaction can be carried out using tart-butyldimethylchlorosilane in the presence of a base such as imidazole.

(2) This step is a step in which a desired heterocyclic group or heteronyclyloxy is introduced into a compound to obtain a compound bile bean.

This reaction was carried out using Mitsunobu [Synthesis (5YNTHESIS)].
), 1, (1981)].

The reaction can be carried out using the desired heterocycle, e.g., 2-methylpyrrole, 3-methylpyrrole, imidazole, 2-methylpyrrole,
Methylimidazole, 2,4-dimethylimidazole,
Pyrazole, 5-methylpyrazole, 3,5-dimethylpyrazole, 1,2°3-triazole, 4-methyl-
1,2,3-triazole, 3-methyl-1,2,4-
triazole, 3,5-dimethyl-1,2,4-triazole, tetrazole or 5-methyltetrazo-
or 3-hydroxyinxazole, 3-hydroxyinthiazole, 3-hydroxypyrazole, 3-hydroxyinxazole, 3-hydroxyinxazole, 3-hydroxypyrazole,
- triphenylphosphine and diethyl azodicarboxylate using hydroxy-4-methylinxazole, 4-hydroxy-1,2,3-triazole or 4-hydroxy-5-methyl-1,2°3-triazole, etc. The reaction is preferably carried out in the presence of anhydrous ether, anhydrous tetrahydrofuran or anhydrous benzene.

(2) This step is a step for selectively removing the 1-position hydroxy protecting group.

The deprotection reaction can be carried out according to conventional methods such as acetic acid treatment at room temperature or tetra-n-butylammonium fluoride treatment in tetrahydrofuran.

(2) This step is a step of converting the hydroxy of compound U (2) into a desired side chain.

This step includes (i), (ii)-■ or (iv)-■,
This can be done in the same way as ①.

(2) This step is a step of deprotecting the 3-position hydroxy protecting group of compound 5HIJ.

The deprotection reaction uses reagents such as acetic acid, hydrochloric acid/chloroform, hydrobromic acid/acetic acid, p-toluenesulfonic acid, etc.
It can be done according to conventional methods.

(vii) When R* is alkaroylmethyl, compound I[M can be produced as follows.

(The following is a blank space) [In the formula, R2, R*', R1, R2, Y, m, lal and Prot-OB have the same meanings as above] (1) This step is a step of halogenating the hydroxy of compound m1.

This step can be carried out in the same manner as reaction step I and step 3'.

(2) This step is a step in which compound M3 is obtained by additionally condensing an aldehyde with the compound.

This step may be carried out according to the conventional Grignard reaction method.

As aldehydes used in the reaction, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde,
Mention may be made of C,-C,aldehydes such as pivaldehyde, hexanal, heptanal or octanal.

(2) This step is a step to protect the hydroxy of the compound.

It may be protected with a group commonly used as a hydroxy protecting group.

When introducing a triarylmethyl (e.g. trityl, etc.) aroyl (e.g. benzoyl, etc.), the corresponding halide (e.g. trityl chloride, trityl bromide or benzoyl chloride, etc.) is combined with a base (e.g. pyridine, triethylamine, etc.) present. All you have to do is react below.

When introducing a trialkylsilyl (e.g., trimethylsilyl or tart-butyldimethylsilyl), a trialkylchlorosilane (e.g., trimethylchlorosilane or tart-butyldimethylchlorosilane) is reacted in the presence of a base (e.g., pyridine). Bye.

(2) This step is a step to obtain compound group 5 by cleaving the compound.

The reaction can be carried out by treatment with an aqueous suspension of N-promofusuccinic acid containing traces of hydrobromic acid.

(2) This step is a step of converting the hydroxy of compound M5 into a desired side chain.

This step includes (i), (ii)-〇 or (iv)-■,
This can be done in the same way as ①.

(2) This step is a step in which compound M6 is subjected to base hydrolysis to obtain compound M7.

The reaction can be carried out using sodium hydroxide, potassium hydroxide, barium hydroxide, etc. as a base catalyst in water or an alcoholic solvent (eg, methanol, ethanol, etc.) according to a conventional method.

(2) This step is a step of converting the hydroxy of compound U into an amine.

This process is a reaction process! , to be carried out in the same manner as the first step,
I can do it.

(2) This step is a step in which the compound compound is sulfonylated to obtain the sulfonamide derivative M9.

This step can be performed in the same manner as the second step of reaction step 11.

(2) This step is a step for removing hydroxy protecting groups between compounds.

The deprotection reaction is carried out by acid treatment when the hydroxy protecting group is triarylmethyl, acetic acid treatment or tetra-n-in tetrahydrofuran when the hydroxy protecting group is trialkyldinol.
Butylammonium fluoride treatment, in the case of aroyl, can be carried out by hydrolysis using a basic substance such as sodium methoxide as a catalyst.

0 This step is a step of oxidizing the hydroxy of compound (1) to carbonyl.

As the oxidizing agent, use chromic acid-based Jones reagent, Frinn's reagent, pyridium chlorochromate, pyridinium dichromate, or dimethyl sulfoxide and sulfur trioxide, trifluoroacetic anhydride, methanesulfonic anhydride, thionyl chloride or oxalyl chloride. When using dimethyl sulfoxide as an oxidizing agent, it is preferable to use a tertiary amine such as tonoethylamine or pyridine as a decomposing agent.

As a solvent, depending on the properties of the reagent, chlorinated hydrocarbon 1 system (
7) Chloroform, dichloromethane, ethereal diethyl ether, tetrahydrofuran or dimethylformamide may be used. The reaction can be accomplished in several hours under cooling or at room temperature.

(viii) When R* is cyanmethyl, the compound "can be produced as follows.

[In the formula, R3 and Y have the same meanings as above]■ This step is
This is a step of converting the hydroxy of compound n1 into a desired side chain.

This step includes (i), (11)-■ or (iv)-〇,
This can be done in the same way as ①.

(2) This step is a step of cleaving the acetal of compound N3 to obtain compound N3.

This step uses N-bromosuccinimide and a chlorinated hydrogen dichloromethane solvent (e.g. carbon tetrachloride, chloroform,
This can be done by heating for several hours in dichloromethane).

(2) This step is a step in which compound N3 is cyanated to obtain compound old.

This step uses metal cyanide (e.g., sodium cyanide, potassium cyanide, m(I) cyanide),
The reaction can be carried out in a solvent such as acetone, acetonitrile, pyridine, ethyl ether, benzene, dimethyl sulfoxide or dimethyl formamide under heating. If necessary, a phase transfer catalyst (crown ether (1B-
crown-6) or tetraethylammonium cyanide) may also be used.

■ This process hydrolyzes benzoic acid ester N4,
This is a process for obtaining alcohol VN.

Similar to (vii)-0, this step can be carried out according to the conventional method of base hydrolysis.

The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention is not limited thereto.

For example, the following compounds are used as starting materials.

2-methoxy-3-octadecylcarbamoyloxyreciprobylamine 7], 3-hexadecylthio-2-methoxypropanol
er. Offen. DE 3,204.735],
3-hexadecyloxy-2-methoxypropertool [
Shimazu et al., Chemical and Pharmaceutical Plutin (Chew. Pha
rm. Bull. , Volume 30, Page 3260, 198
2 years) β-Methyl-α7-benzylidene glycol [P.E. Verkade et al., DiJw-
Reel. Tray of the Royal Netherlands Chemical Society (Reel. Tray).

Chem. Pays. -Bas. ), Volume 61, 83
1, 1942), 2-hexadecylthiomethyl-2-hydroxymethyltetrahydrofuran (USP 792095), 2-
Hydroxymethyl-2-octadecylcarbamoylmethyltetrahydrofuran (USP 792095), 1-hexadecylthio-3-trityloxy-2-propanol [Journal of Medicinal Chemistry (J. Med. Chew., Vol. 31) , p. 410, 1988], 1-ctadezylcarbamoyloxy-3-tonotyloxy-2-propatur [Journal of Medicinal Chemistry.

Mad. Chem. , Volume 31, Page 410, 1988
], N-tritylserine methyl ester [tetrahedron.
Letters (τatrahedron Letters
), Vol. 22, p. 491, 1981], 4-Hydroxymethyl-2-phenyl-2-oxacillin [J. Org. Chem., Vol. 48,
1197, 1983], 3-trityloxy-1,2-propanediol [(
ChefIl. Ber. , Volume 94, Page 812,
1961], 3-hexadecyloxy-2-methoxymethylpropanol [JP-A-58-10592], 3-hexadecylthio-2-methoxymethylpropylamine [JP-A-57-1969]
982911, 2-methoxymethyl-3-octadecylcarbamoyloxypropanol [JP-A-58-105
92], and 5-hydroxymethyl-2-phenyl-1,3-dioxane [Lipids, Vol. 22, No. 11,
947-951, 1987].

(Leaving space below) Reference Example 1 Production of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane f[[al 1.2 g (3 mM) of 2-methoxy-3-octadecylcarbamoyl Oxybropylamine IVal [JP-A-6]
0-243047 described compound] was dissolved in 24 ml of dichloromethane and 0.54 ml (3.9 mM) of triethylamine, and 0.401 ml (3.9 mM) of the compound was dissolved in the mixture under water cooling.
Add 3-chloropropanesulfonyl chloride (3mM) and stir overnight at room temperature. 6. The reaction mixture is fc-purified with an aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (3:2) as an eluent, and recrystallized from chloroform-n-hexane to give 3-(3-chloropropylsulfonylamino)- 2-Methoxy-1-octadecyl (moyloxypropane) 1.386 g (
2,56mM) is obtained as a colorless powder. Yield 85%.

NMRSS ppm (CDCIn) 0.86 (t,
3H), 1.24 (s, 30H).

1.58 (m, 2H), 2.1-2.5 (m, 2H)
, 2.9-3.6 (m, 7H).

3.44 (s, 3H), 3.67 (t, 2H, J=6
．． 0Hz), 4.18 (m, 2H).

4.87 (m, IH), 5.10 (m, IH).

IR Niji max (CHCIs) 3445.2920.
2850.1715°1510, 1460.1330.
1220.1145 am-' Elemental analysis (Cfi @H
s 5oiN*5c1) Calculated value (%) C57,70,
H9, 87, N 5.18. S 5.92°C16,
55° Experimental value (%) C57,51, H9,84, N 5.3
4. S 5.95° C16, 82° MS: 540 (M”, C13').

mp,: 64.5-66°C.

(Left below) Reference Example 2 Production of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarlebamoyloxypropane IIal 972 mg (1,8 mM) of 3-(3-colopropyl) Sulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane,! '1 was dissolved in 10ml of methyl ethyl ketone and 500mg (3.38mM
) of sodium iodide and stir with heating for 3 hours. After distilling off the solvent, the residue was diluted with n-hexane-ethyl acetate (1
:1) Separate and purify the mixed solution by silica gel column chromatography using eluting solvent and recrystallize from chloroform-n-hexane to obtain 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane. 972 mg (1,5
4mM). Yield 86%.

NMR: Sppm (CDC1,) 0.88 (t, 3
H), 1.26 (s, 30H).

1.5 (m, 2H), 2.2! r2.40 (m, 2H
), 3.1-3.3 (m, 4H).

3.31 (t, 2H, J = 6.6Hz), 3.46 (
s, 38), 3.50 (m, LH).

4.05-4.30 (m, 2H), 4.83 (m, I
H), 5.00 (t, LH.

J=6Hz).

IR Niji max (CHClm) 3450.2940.
2855, 1725° 1510, 1470.1335.
1230.1145 cm-'Elemental analysis (C**Hss
OsN*SI) Calculated value (X) C49,12,H8,4
4, N 4.56. S 5.34゜1 20.08゜Experimental value (X) C49,36,H8,44,N 4.4
3. S 5.07°I 2G, 10°MS: 505 (M-I)”.

mp: 61.5-62.5°C.

(Left below) Example 1 2-Methoxy-1-ctadezylcarbamoyloxy-
Preparation of 3-(3-trimethylammoniosulfonylamino)propane chloride Ial 420 mg (0,77
6mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane 1 [[[al]
Dissolve in toluene solution (10ml/25ml) and heat in a sealed tube at 120°C for 24 hours. After evaporating the solvent and washing several times with ahiton-ether, the product was purified by column chromatography using HP-20 to obtain 150 mg of 2-methoxy-1-octadecylcarbarimoyloxy-honylamino)propane chloride-Ia. ．． Yield 11%.

NMR: Sppm (CDC1.) 0.86 (t.3
H), 1.25 (s.30H).

1, 4-1.6 (m.2H), 2.0-2.5 (m.
．． 2H), 3.20 (s.3H).

3, 0-3.4 (m.6H), 3.46 (s.3H
), 3.4-3.8 (m.3H).

4, 15 (m. 2H).

IR: l/max (CHCIs) 3450. 2
925. 2850, 1710.

1460, 1320. 1220. 1140
am-' elemental analysis <C**Hm*OsNsSC1・1
．． 511jO) Calculated value (X) C 55.52. H
10.44, N 6.70. S 5.11.

Cl　　5.65.

Experimental value (X) C 55.49. H 10.42.
N 6.78. S 4.85.

Cl　　5.78.

mp. :60~62℃.

Example 2 Preparation of 2-methoxy-1-octadecylcarbamoyloxy-lamino)propane iodite-In2 240
Dissolve mg (0.38 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane 11al in 2 ml of thiazole and stir at 50°C overnight. After distilling off the thiazole, it was recrystallized from dichloromethane-acetone to give 2-
Methoxy-1-lactadezylcarbamoyloxy-3-
(3-thiazoliopropylsulfonylamino)propa'
/iodite-1a2 150mg (0.209mM)
obtain. Yield 55%.

NMR: Sppm (d6-DMSO) 0.6(t
．． 3H), t. 24 (s.

30H), 1.36 (m.2H), 2.2-2.4
(m.2H), 2.9-3.2 (m.

6H), 3.2 (s.3H), 3.3-3.45 (
m. IH), 3.80-4.15 (m.

2H), 4.67 (t, 2H.J=7.2Hz),
7.15 (t.LH.J=5.6Hz).

7, 33 (t.LH.J: 5.8Hz>, 8.35~
8.42 (m.LH), 8.60 (d.

ILJ: 3.8) 1z), 10.20 (s.IH).

IR Niji max (KBr) 3360. 2925.
2855, 1685.

1565, 1470, 1310. 1280. 1
145. 1130 cm” (blank below) Elemental analysis (C**HisOaNsS*I・0.2HI
O>Calculated value (%) C 48.28. H 7.88,
N 5.82. S 8.89.

I 17.59.

Experimental value (X) C 48.37. H 7.8B. N
6.00. S 9.22.

I　L7.38 mp. : 116-118°C (decomposition).

Examples 3 to 7 As shown in Table 1 below, the compounds of the present invention are obtained from compound mal in the same manner as in Example 2.

However, in Example 4, the residue after distilling off the amine was
- with hexane and in Examples 5 and 6 with ethyl ether respectively.

(Left below) Reference example 3 3-hexadecylthio-2-methoxypropylamine I
Preparation of Va2 4.356 g (12,57 mM) of 3-hexadecylthio-2-methoxypropanol Va2, [West German Patent (Ger, Offen, DE) 3, 204,
735 described compound 3.7g (25.14mM) of phthalimide and 6.59g (25.14mM) of tonophenylphosphine were dissolved in 150ml of tetrahydrofuran, and 4.37g (25.14mM) of diethyl azodical was dissolved under water cooling. Add poxylate dropwise and stir at room temperature for 3 days. After distilling off the solvent, the residue was separated and purified by silica gel column chromatography using a mixture of n-hexane-ethyl acetate-chloroform (9:1:1) as an eluent.
It is reprecipitated from dichloromethane-n-hexane to obtain 4.9 g (10.23 mM) of phthalimide.

Yield 82%.

4.678g (9.83mM) of phthalimide
Dissolved in 0ml methanol, 0.54g (10,79
(mM) of hydrazine monohydrate was added, and the mixture was heated and stirred for 5 hours. After evaporating the solvent, chloroform was added to the residue, filtered through celite to remove insoluble matter, and subjected to silica gel column chromatography using a chloroform-methanol (20:1 to 9:1) mixture (0.2% triethylamine) as the eluent. 2.98g (8,622mM) of 3-hexadecylthio-2-methoxypropylamine I
Obtain Va2. Yield 88%.

NMR: Sppm (CDC1,) 0.88 (t, 3H
), 1.26 (s, 26H).

1.6 (m, 2B), 2.5-3.0 (m, 6H),
3.30 (m, IH), 3.43 (s, 3H).

IR Niji max (CHCIs> 3380.2930.
2850, 1465° 1380, 1230.1110
allMS: 346 (MW”).

Reference Example 4 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane 1 [[Production of a2 1.018 g (2,95 mM) of 3-hexadecylthio-2-methoxypropylamine IVa2 was added to 15 ml of 3-hexadecylthio-2-methoxypropylamine IVa2. Dissolved in dichloromethane and 0.534ml (3.83mM) of triethylamine, and added 0.56ml to the mixture under water cooling.
Add 3 mg (3.24 mM) of 3-chloropropanesulfonyl chloride and stir at O''C for 3 hours. After evaporating the solvent, the residue was diluted with n-hexane-ethyl acetate (4:1
) Separation and purification by silica gel column chromatography using the mixed solution as an elution solvent, reprecipitation with chloroform-n-hexane, sealing with 3-(3-chloropropylsulfonylamine)-1-hexadecylthio-2-methoxypropane, 275 g (2.62 mM) are obtained as a colorless powder.

Yield 89%.

NMR: Sppm (CDCIs) 0.88 (t, 3H
), 1.26 (s, 26H).

1.6 (m, 2H), 2.2-2.4 (m, 2H),
2.55 (t, 2H.

J=7.41(z), 2.53~2.80(m, 2H
), 3.10-3.30 (m, 3H).

3.42 (s, 3H), 3.4=3.6 (m, 2H)
, 3.69 (t, 2H.

J:6.2Hz), 4.70(t, IH, J'6Hz
).

IR Niji max (CHCIg) 3380.2930.
2g50.1470°1410, 1330.1150.
1095 cm-' elemental analysis (CmsH-aOsNs*
c1) Calculated value (X): C56,82,H9,95,N
2.88. S 13.19° CI 7.29° Experimental value <%>: C56,76, H9,89, N 3.
18. S 12.94°C17.1g.

M5: 485 (M”, C1”).

mp,: 49-50°C.

(Left below) Reference Example 5 Production of 1-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methoxypropane 11a2, 03g (2.12mM) of 3-(3-chloropropylsulfonylamino)-1 -Hexadecylthio-2-methoxypropane IIra2 20m! was dissolved in methyl ethyl ketone, 636 mg (4.24 mM) of sodium iodide was added, and the mixture was heated and stirred for 3 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent to obtain 1-hexadecylthio-3-(
3-Iodofurobirsulfonylamino)-2-methoxyfuropane 1.06 g (1[a2 as oily substance)
1,835mM). Yield 87%.

NMR: sppm (CDCIj) 0.88 (t, 3H
), 1.26 (s, 26H).

1.6 (m, 2H), 2.22-2.40 (m, 2
H), 2.55(t, 2H.

J=7.4Hz), 2.53~2.81(m, 2H
), 3.11-3.26 (m, 3H).

3.31 (t, 2H, J=6.6Hz>, 3.43
(s, 3H), 3.41-3.56 (m, LH),
4.65 (t, IH, J=6)1z).

IR Niji max (CHCIm) 3370. 2920
．． 2850. 1460°1405, 1325.
1145. 1090 am-'Elemental analysis CC* sH
a aosNsmI) Calculated value C%'): C47,82
, H8, 38, N 2.42. S Ll, 10°I
21.97°Experimental value C%>: C47,62,H8,28,N 2.
50. S Ll, 09°I 22.18°MS: 577 (M”).

Example 8 Preparation of 1 cup of 1-hexadecylthio-2-methoxy-3-(3-trimethylammoniopropylsulfonylamino)propane iodite 500 mg (0,866 mM) of 1-hexadecylthio-3-(3-iodopropylsulfonylamino) )-2-
Methoxypropane Ira2 is dissolved in 10 ml of trimethylamine-toluene solution (10 ml/25 ml) and left in a sealed tube at room temperature for 24 hours. The solvent was distilled off, and the residue was dissolved in chloroform-methanol (5:1 to 3:1).
The mixed solution was separated and purified by silica gel column chromatography as an eluent, and reprecipitated from dichloromethane-n-hexane to obtain 8330 mg of 1-hexadecylthio-3-(3-trimethylammoniopropylsulfonylamino)-2-methoxypropane Ia (0 , 518mM)
get. Yield 60%.

NMR: 8ppm (CDC1s) 0.88 (t, 3H
), 1.26 (s, 26H).

1.58 (m, 2H), 2.3-2.5 (m, 2H)
, 2.56(t, 2H.

J=7.2Hz), 2.72(d,2)1. J-5,
81(z), 3.20-3.65(m.

5H), 3.43(s, 9H), 3.45(s, 3
8), 3.85-3.93 (m.

2H), 6.20 (t, LH, J=6Hz>.

IR Niji max (CHCl, > 3375.2925.
2850.1470°1330, 1230.1150.
1090.1055.1030 cm-'mp, :69
~71℃.

Elemental analysis (Cm Ja yOJ*stI・0.4H,O
) Calculated value (X): C48, 49, H9, 05, N 4
．． 35. S 9.96゜I 19゜71゜Actual value C%'): C48,66, H8,85, N 4
．． 47. S 10.19゜I 19.47゜Example 9 Preparation of 1-hexadecylthio-2-methoxy-3-(3-thiazoliopropylsulfonylamino)propane iodite In2 600 mg (1,04mM) of 1-hexadecylthio-
Dissolve 3-(3-iodopropylsulfonylamino)-2-methoxypropane in 5 ml of thiazole and heat at 60°C.
Stir for 6 hours. After distilling off the thiazole, it was washed with ether and reprecipitated from acetone to give 1-hexadecylthio-
2-Methoxy-3-(3-thiazoliopropylsulfonylamino)propane iodite Ia9387mg (0
゜5841TIM) is obtained. Yield 56%.

NMRr8 ppm (CDCIm) 0.88 (t, 3
H), 1.26 (s, 26H).

1.58 (m, 2H), 2.55 (t, 2H, J=7
．． 3Hz), 2.70 (d, 2H, J=5.6Hz)
, 2.5-2.7 (m, 2H), 3.1-3.5 (
m, 4H), 3.43 (s, 38), 3.55 (m
, IH), 5.04 (t, 2H, J=7.4Hz),
6.26(t,l)1. J=6Hz), 8.29~
8.32 (m, LH), 8.72-8.75 (m.

IH), 10.59-10.60 (m, IH).

IR:I, +max(CHClm)3375.2930
．． 2850.1460°1325, 1220.1140
．． 1090 cm-' elemental analysis (C*-Ha 1Os
NsSsI・O, IHIO) calculated value (x>: C46,
99, H7, 76, N 4.21. S 14.47°I 19.1G.

Experimental value (X) 2C46,79°t(7,71,N 4.
25. S L4.42°I 19.01°mp, near 0-73°C.

Reference Example 6 Production of 3-hexadecyloxy-2-methoxypropylamine IVa3 8.26 g (25 mM) of 3-hexadecyloxy-2
-Methoxypropertool V a3 [Tsushima et al., Chemical
Pharmaceutical Bulletin (CheIIl,
Pharm, Bull, ), Volume 30, Page 3260,
Compound described in 1982], 7.35g (50mM) of phthalimide, and 13.1g (50mM) of triphenylphosphine were dissolved in 300ml of tetrahydrofuran, and 8.7g (50mM) of diethyl azodicarboxylate was added under water cooling. Add dropwise and stir at room temperature for 3 days. After distilling off the solvent, ffEi was separated and purified by silica gel column chromatography using a mixture of n-hexane-ethyl acetate-chloroform (9:1:1) as an eluent.
Re-precipitated from hexane, 10.142g of phthalimide
(22.06mM) is obtained.

Yield 88%.

10.142g (22.06mM) of phthalimide was dissolved in 200ml of methanol, and 1.47g of C29,
4mM) of hydrazine monohydrate was added to the mixture and heated and stirred for 5 hours. After evaporating the solvent, chloroform was added to the residue, filtered through Celite to remove insoluble materials, and the residue was separated and purified by silica gel column chromatography using a chloroform-methanol (5:1) mixture (0.2% triethylamine) as the eluent. , 5.523 g (16.76 mM) of 3-hexadecyloxy-2-methoxypropylamine L is obtained. Yield 76%.

NMR: Sppm (CDCIs) 0.88 (t, 3H
), 1.26 (s, 26H).

1.58 (m, 2H), 2.70-2.96 (m, 6
H), 3.33 (m, IH).

3.45 (s, 3H), 3.4 (1-3,60 (m,
6H).

IR Niji max (CHCI-) 3380.2920.
2845.1580°1465, 1360.1240.
1115.860 crt-'MS: 330 (M)
1”).

(Left below) Reference Example 7 Production of 3-(3-chloropropylsulfonylamino)-1-hexadecyloxy-2-methoxypropane 3.368g (10.22mM) of 3-hexadecyloxy-2-methoxy Propylamine was dissolved in 35ml of dichloromethane and 1.85ml (13°29mM) of triethylamine, and 1.99g (
Add 3-chloropropanesulfonyl chloride (11.24 mM), stir at room temperature for 4 hours, and heat and stir for 30 minutes. After distilling off the solvent, the residue was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (3:1) as an eluent, and reprecipitated from methanol to obtain 3-(3-chloropropylsulfonyl). 34.15 g (s, 827 mM) of amino)-1-hexadecyloxy-2-methoxypropane I [[a are obtained as a colorless powder.

Yield 86%.

NMR: Sppm (CDC1,) 0.88 (t, 3H
), 1.26 (s, 26H).

1.56 (m, 2H), 2.20-2.38 (m, 2
H), 3.15-3.60 (m.

9H), 3.44 (s, 3H), 3.68 (t, 2
H, J: 6.2Hz>, 4.79 (t, LH, J=
6Hz).

IR:l/IIIax (CBCI,) 3375.29
20.2845.1465°1335, 1410.12
65.1145 am”mp,: 49-50°C.

Elemental analysis (c* sH-, O, N5C1) calculated value (X)
C58,76, H10,29, N 2.9B, S
6.82°C17,54°Experimental value (X) C58,63,H10,20,N 3.
00. S 6.72°C17,47°MS: 469 (M”, C1”).

(Left below) Reference Example 8 Production of 1-hexadecyloxy-3-(3-iodopropylsulfonylamino)-2-methoxypropane 3.845 (8.18mM) of 3-(3-chloropropylsulfonylamino) )-1-hexadecyloxy-2-
Methoxypropane IIIa3 is dissolved in 30 ml of medel ethyl ketone, 2.45 g (16.36 mM) of sodium iodide is added, and the mixture is heated and stirred for 3 hours. After distilling off the solvent, the residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent, and reprecipitated from methanol to obtain 1-hexadecyloxy-3- (3-iodopropylsulfonylamino)-2-methoxypropane 1[a33.556
g (6,332 mM).

Yield 77%.

HMR: 8ppm (CDC1s) 0.88 (t, 3H
), 1.26 (s, 26H).

1.58 (m, 2H), 2.25-2.40 (m,
2H), 3.1 (1-3.60 (m.

9H), 3.30(t, 2H, J=6.6Hz>,
3.44 (s, 3H), 4.81 (t, 18.
J: 6Hz>.

IR Niji max (CICIs) 3380. 293
0. 2855. 147G1410.1335.12
70.1150 a1' elemental analysis (C,,H,,O,N
5I) Calculated value (χ) C49,19, H8,61, N 2.49
．． S 5.71゜1 22.60゜Experimental value (χ) C49,11, H8,54, N 2.5
3. S 6.00°I 22.48°MS: 562 (M”).

mp,: 46-47 °C.

(Left below) Example 10 1-hexadecyloxy-2-methoxy-3-(3-)
600mg (1,068mM
) of 1-hexadecyloxy-3-(3-iodopropylsulfonylamine)-2-methoxypropane I[a
3 to 10ml of trimethylamine-toluene solution (10ml)
ml/25 ml) and dilute with room salt in a sealed tube.
Leave it for 4 hours. The solvent was distilled off and the residue was purified by washing with ether to give 1-hexadecyloxy-2-methoxy-3
10577 mg of -(3-trimethylammoniopropylsulfonylamino)propane iodite Ia is obtained.

Yield 87%.

NMR: εpp1n(CDCIg) 0.88(t,
3H), L 26(s, 26H).

1.58 (m, 2H), 2.3-2.5 (m, 2H
), 3.15-3.65 (m.

9H), 3.42(s, 9H), 3.47(s
, 3H), 3.8 (1-3.95 (m.

2H), 6.3 (t, LH, J=6Hz).

[R:l/max(CHCIs) 3380. 29
25. 2g50. 1470°1325.1230.
1145 cm-ri elemental analysis (CsJiyOsNtSI
) Calculated value (X) C50, 31, H9, 26, N 4.5
1. S 5.17゜I 20.44゜Experimental value (X) C50,20,H9,25,N 4.6
3. S 5.29°I 20.4g.

mp, 80.5-82.5°C.

Example 11 Production of 1-hexadecyloxy-2-methoxy-3-(3-thiazoliopropylsulfonylamino)propane iodite 1A■ 600 mg (1,07 mM) of 1-hexadecyloxy-3-(3-iodo propylsulfonylamino)-2-
Dissolve methoxypropane in 5 ml of thiazole and
Stir at ℃ for 6 hours. After distilling off the thiazole, the residue was separated and purified by silica gel column chromatography using a chloroform-methanol (5:1 to 3:1) mixture as an eluent, and reprecipitated with ether-dichloromethane to give 1-hexadecyloxy- 2-methoxy-3-(3-
Thiazoliopropylsulfonylamino)propaniotide fall 450 mg (0.70 mM) is obtained.

Yield 66%.

NMR: εppm (DMSO) 0.85 (t, 3H)
, 1.24 (s, 26H).

1.48 (m, 2H), 2.2-2.4 (m, 2H)
, 3.31 (s, 3H), 2.9-3.5 (m, 9
H), 4.65 (t, 2H, J=7Hz), 7.2
6(t, IH.

J=6Hz), 8.36-8.39 (m, IH),
8.57-8.60 (m, IH).

10, 17-10.20 (m, IH).

IR Niji max (CHCl,) 3400.2930.
2850.1460°1320, 1220.1140
cm-'mp, 52-53°C.

Reference Example 9 Production of 2-methoxy-1-octadecyJ lecarbamoyloxy-3-(3-phenylselenylpropylsulfonylamino)propane I[al' 1.52 g (4.9 m
Dissolve diphenyl diselenide (M) in 25 ml of absolute ethanol, add ice-cold F and 370 mg (9.78 mM) of sodium borohydride, and stir for 30 minutes. 0.56 ml (9.78 mM) of acetic acid was added to the mixture, and 1,0
Add 3 g (1,63 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane and stir at room temperature for 1.5 hours. Add ethyl acetate to the reaction mixture and in - Wash with hydrochloric acid, aqueous sodium bicarbonate solution, and brine, dry over anhydrous magnesium sulfate, and then evaporate the solvent. The residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (2:1) as an eluent to obtain 2-methoxy-1-octadecylcarlebamoyloxy-3-
1.06 g (1.60 mM) of (3-phenylselenylpropylsulfonylamino)propane 1[al' is obtained as a colorless powder.

Yield 98%.

R: δppm (CDCIn) 0.88 (t, 3H)
, 1.26 (s, 30H).

1.5 (m, 2H), 2.1-2.24 (m, 2H)
, 3.01 (t, 2H, J=7Hz).

3.08-3.32 (m, 6H), 3.42 (s, 3
H), 3.46 (m, IH).

4.00-4.28 (m, 2H), 4.73-4.9
0 (m, 2H), 7.24-7.34 (m, 3H),
7.45 = 7.57 (m, 2H).

IR Niji max (CHCIs) 3450.2930.
2850.1720°1515, 1460.1330.
1220.1145 cm-'MS: M" 662
(Se@O).

(Left below) Reference Example 10 2-methquine-1-year-old ctadezylcarbamoyloxy-
3-(3-propenesulfonylamino)propane ■a4
Production of 1.028 g (1,553 mM) of 2-methquin-1-
30 m
1 in a methanol-dichloromethane (5:1) mixture, add 0.25ml (3.16mM) of pyridine and 2ml of 30% hydrogen peroxide under water cooling, heat to room temperature, and stir for 5 hours. Ethyl acetate is added to the reaction mixture, washed with brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. Add 30 ml of benzene and 0.25 ml of pyridine to the residue and heat to 45-50° C. for 1 hour. After distilling off the solvent, the residue was diluted with n-hexane-ethyl acetate (2:1-1
:1) Separate and purify the mixture by silica gel column chromatography using the elution solvent, recrystallize from dichloromethane-n-hexane, and obtain 4624 mg of 2-methoxy-1-octadedylcarbamoylolixylamino)propane Wa (1.2 BmM
) is obtained as colorless crystals. Yield 80%.

NMRil; ppm (CDC1.) 0.88 (t
．． 3H), 1.26(s, 30H).

1, 5 (m.2H), 3.1-3.4 (m.4)1)
, 3.74-3.82 (m.2H).

3, 45 (s.3H), 3.50 (m.IH), 4
．． 05=4.30 (m.2H).

4, 8 (m.LH), 4.93 (t.IH.J=6)
1z), 5.35-5.50 (m.

21(), 5.82-6.04 (m.LH).

IR Niji max (CHCI-) 3460. 2930
．． 2B50. 1725.

1520, 1475. 1340. 1240. 1
150 am” elemental analysis (Cm Js *OsN*S)
Calculated value (X) C 61.87. H 10.3B.
N5.55. S 6.35.

Experimental value (X) C 61.68, H 10.34.
N 5.73. S 6.20.

mp. Near 4-75.5℃.

(Leaving space below) Reference Example 11 Production of 2-methoxy-1-octadecylcarbamoyloxy-amino)propane VIa4 600 mg (1.19 mM) of 2-methoxy-1-octadecylcarbamoyloxy-3-(3-propenesulfonylamino) ) Dissolve propane ■ a4 in 22 ml of methanol-dichloromethane (1:10) mixture and heat to -78°C.
oxidizes with ozone.

The generated oscinide was decomposed with 0.5 ml of dimethyl sulfide, the solvent was distilled off, 10 ml of methanol was added, 300 mg (7, 93 mM) of sodium borohydride was added under water cooling, and the temperature was raised to room temperature. Stir for an hour. Add ethyl acetate to the reaction mixture, wash with brine, dry over anhydrous magnesium sulfate, and evaporate the solvent. The residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (1:3) as an eluent.
2-Methoxy-1-octadecylcarbamoyloxy-
4,300 mg (0.59 mM) of 3-(2-hydroxyethylsulfonylamino)propanyl a is obtained as a colorless powder. Yield 50%.

NMR: δppm (CDCIm) 0.88 (t.3
H), 1.26 (s.30H).

1, 5 (m.2H), 2.05 (br., IH),
3.05-3.35 (m.6H).

3, 45 (s.3H), 3.51 (m.IH), 4
．． 02-4.12 (m.2H).

4, 12 = 4.27 (m.2H), 4.89 (m.I
H), 5.19 (m.IH).

IR' V max (CBCIs) 3450. 2
920.2850, 1710.

1510, 1465. 1330. 1220. 1
135 cm-'MS: 509 (MH'').

(Left below) Reference Example 12 2-Methoxy-1-year-old ctadezylcarbamoyloxy-
Production of 3-(2-methanesulfonyloxyethylsulfonylamino)propane Vfa4' 298 mg (0,58
6mM) of 2-methoxy-1-lactadezylcarbamoyloxy-3-(2-hydroxyethylsulfonylamino)propane VIa4 was mixed with 6ml of dichloromethane and 2mM
1 of tetrahydrofuran, and add 50μ to the mixture under water cooling. (0,645mM) of methane 7, Juhonyl chloride and 0. Add IQ 6 ml of triethylamine and stir at room temperature for 2 hours. After distilling off the solvent, the residue was
- Separation and purification by silica gel column chromatography using a mixture of hexane and ethyl acetate (1:1 to 1:2) as an eluent, and 2-methoxy-1-ctadezylcarbamoyloxy-3-(2-methanesulfonyloxyethyl) sulfonylamino)propane VIa4' 287 mg (
0,489mM) is obtained as a colorless powder. Yield 83%.

NMRj & ppm (CDC1,) 0.88 (t, 3
H), 1.26 (s, 30H).

1.5 (m, 2H), 3.11 (s, 3H), 3.
10 = 3.42 (m, 4H).

3.45 (s, 3H), 3.50 (t, 2H, J=6
Hz>, 4.15-4.28 (m.

28), 4.61 (t, 2H, J=6Hz), 4.
91 (m, LH), 5.19 (t.

IH, J: 6.2Hz).

IR Niji max (CHCIs) 3460.2930.
2850.1725°1520, 1470.1345.
1235.1180.1155.1000゜970 a
m” Reference Example 13 3-(2-iodoethylsulfonylamine)-2-methoxy-1-octadecylcarbamoyloxypropane
Preparation of I[a4 200 mg (0,341 mM) of 2-methoxyl-ctadezylcarbamoyloxy-3-(2-methanesulfonyloxyethylsulfonylamino)propane VIa4
' was dissolved in 5 ml of acetone and 200 mg (1,33
Add sodium iodide (mM) and heat and stir for 5 hours. After distilling off the solvent, the residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (2:1) as an eluent to obtain 3-(2-iodoethylsulfonylamine)-2-methoxy. -1-octadecylcarbamoyloxypropane 1 [a4188mg
(0,296mM) is obtained.

Yield 87%.

NMR: E ppm (CDC1,) 0.88 (t, 3
H), 1.26 (s, 30H).

1.5 (m, 2H), 3゜1 (] ~ 3.30 (m, 4
H), 3.46 (s, 3H), 3.30-3.60
(m, 5H), 4.1-4.3 (m, 2H), 4.
83 (m, LH), 5.10 (t, 1)1. J＝
6.3Hz> IR Niji max (CHCIs) 3450.2935.
2g55.1720°1515, 1460.1410.
1335.1220.1145.1090°1050
cm-' Example 12 2-methoxy-1-lactadezylcarbamoyloxy-
Production of 3-(2-thiazolioethylsulfonylamino)propane iodite Ia■ 188 mg (0,296 m
M) 3-(2-iodoethylsulfonylamino)-2
-Methoxy-1-octadecylcarbamoyloxypropane is dissolved in 2 ml of thiazole and stirred at 60°C for 12 hours. After distilling off the thiazole, the residue was separated and purified by silica gel column chromatography using a chloroform-methanol (5:1) mixture as an eluent, and reprecipitated from ether-dichloromethane-acetone to obtain 2-methoxy-1-acetone. ctadezylcarbamoyloxy-3-(
1230 mg (0,043 mM) of 2-thiazolioethylsulfonylamino)propane iodide Ia is obtained.

Yield 14%.

NMRF &ppm (CDC1, +CD, OD) 0
．． 88 (t, 3H), 1.25 (s, 30H), 1
．． 5 (m, 2H), 3.05-3.20 (m, 2H
), 3.20-3.40 (m, 2H), 3.46 (
s, 3H), 3.60 (m, LH), 3.94
(m.

2H), 4. (1-4, 3(m, 21(), 5
．． 2-5.4 (m, 2M), 5.55 (m.

IH), 6.82 (m, LH), 8.17 (d, L
H, J=3.8Hz>, 8.70 (d.

IH, J=3.8Hz>, 10.60~10.65
(m, IH).

IR: νmax(KBr) 3360. 2920
．． 2850. 1700°1535, 1460.
1335. 1255. 1150 cm-'Reference example 1
4 3-(4-chlorobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane l
1.2g (3mM) of 2-methoxy-3-octadecylcarbamoyloxybropylamine 1 was dissolved in 24ml of dichloromethane and 0.5ml (3°6mM) of triethylamine, and the mixture was cooled with water. .75g (3
, 93 mM) of 4-chlorobutanesulfonyl chloride and stirred overnight at room temperature. The reaction mixture was washed with an aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (3:2) as an eluent, and recrystallized from dichloromethane-n-hexane to give 3-(4-chlorobutylsulfonylamino)- 2-Methoxy-1-octadecylcarbamoyloxypropane I [a51.28g (2
, 305mM) is obtained as colorless crystals. Yield 77%.

NMR: εppm (CDC1, > 0.88 (t, 3H
), 1.25 (s, 30H).

1.48 (m, 2H), 1.8-2.1 (m, 4H)
, 3.0-3.4 (m, 6H).

3.45 (s, 3H), 3.4-3.55 (m, IH
), 3.58 (t, 2H.

J=6.0Hz), 4.05-4.3 (m, 2H),
4.8 (br, IH), 4.94 (t, IH, J
=6Hz).

IR: Shimax(CHCl,) 3450. 29
30. 2850. 1720°1510.1330.
1225.1140.1040 cm-'Elemental analysis (C
*yH□0INffiSC1) Calculated value (X) C58,
41, H9, 98, N 5.05. S 5.77°C
I 6.38° Experimental value (X) C58,15, H9,91, N 5.1
6. S 5.89°C16,71°MS: 554 (M”, C13').

mp: 57.5-58.5°C.

Reference Example 15 3-(4-iodobutylsulfonylamine)-2-methoxy-1-octadecylcarbamoyloxypropane
Preparation of IIa5 1.23g (2.22mM) of 3-(4-chlorooctadecylcarbamoyloxypropane Illa520ml)
of methyl ethyl ketone to give 0.67 g (4,44
Add sodium iodide (mM) and heat and stir for 3 hours. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (1:1) as an eluent.
Recrystallization from hexane yields 16 g (1.79 mM) of 3-(4-iodobutylsulfonylamine)-2-methoxy-1-octadecylcarbamoyloxypropane. Yield 81%.

NMR: &ppm(CDCIs>0.88(t.3
H), 1.26 (s.30H).

1, 5 (m.2H), 1.9-2.0 (m.4H),
3.0-3.4 (m.10) 1).

3, 46 (s.3H), 3.50 (m.LH), 4
．． 1-4.3 (m.2H).

4, 7 (br.IH), 4.87 (t.IH.J=6
．． 6Hz>.

IR: νmax(Cl(Cls) 3450.29
25. 2850. 1720.

1510, 133G. 1230. 1140cm
-'mp. Near 1-72℃.

(Left below) Butylsulfonylamino)-2-methoxy-1 elemental analysis (C1Ha60aN*SI) Calculated value (X) C50,15,H8,57,N 4.3
3. S 4.96゜I 19.62゜Experimental value (X) C50,09,H8,45,N 4.4
1. S 5.26°1 19.33°MS: 647 (M”) Example 13 2-Methoxy-1-octadecylcarbamoyloxy-
Preparation of 3-(4-thiazoliobutylsulfonylamino)propane iodite I a13 300 mg (0,46
4mM) of 3-(4-iodobutylsulfonylamino)
-2-Methoxy-1-octadecylcarbamoyloxypropane is dissolved in 3 ml of thiazole and stirred at 60°C for 6 hours. After distilling off the thiazole, the residue was washed with nityl and reprecipitated from ether-dichloromethane to give 2-methoxy-1-lactadezylcarbamoyloxy-3-(
140 mg (0,191 mM) of 4-thiazoliobutylsulfonylamino)propane iodite are obtained. Yield 41
%.

NMR: Sppm (CDC1,) 0.88 (t, 3
H), 1.25 (s, 30H).

1.5 (rn, 2H), 1.8-2.05 (m, 2H
), 2.05=2.40(m, 2H).

3.0 (1-3.40 (m, 6H), 3.44 (s,
3H), 3.60 (m, 1) 1).

4.0-4.3 (m, 2H), 4.85 (m, 2H)
, 5.38 (br, IH), 6.16 (br, IH
), 8.3-8.4 (m, IH), 8.6-8.7
(m, IH), 10.55 (s, LH).

[R: νmax(CHC1*) 3400.2930
．． 2g50.1715°1465, 1430.1320
．． 1235.1140 am-'Elemental analysis (Cs eH
i *0aNsS*I・0.5H10) Calculated value (fc)
C48,64, H8,03, N5.67, S8
．． 66°I 17.13° Experimental value (1) C4g, 46. H7,99,N5.
77, S 8.87°I 17.02°mp,: 59.5-61.5°C.

(Left below) Examples 14 to 17 As shown in the following Table 2, the compounds of the present invention are obtained from Compound IIa5 in the same manner as in Example 2.

(Left below) Example 18 2-Methoxy-1-octadecylcarbamoyl oxine-
3-(4-quinoliniobutylsulfonylamino)propane chloride! Production of a18 1.57g (2,43m
M) 3-(4-iodobutylsulfonylamino)-2
-Methoxy-1-octadecylcarbamoyloxypropane Ira5 was dissolved in 3 ml of quinoline and heated to 40°C for 30 minutes.
The reaction solution, which was stirred for several days, was dissolved in a chloroform-methanol mixture, washed twice with IN-hydrochloric acid, the solvent was distilled off, and reprecipitated from acetone to obtain 2-methoxy-1-lactadezylcarbamoyloxy-3. -(4-quinoliniobutylsulfonylamino)propane chloride 1.07g (1
, 56mM).

Yield 64%.

NMR: Sppm (CDC1, > 0.88 (t, 3
H), 1.25 (s.

30H), 1.48 (m, 2H), 2.0-2.3
(m, 2H), 2.3-2.5 (m.

2 old, 3.0~3.2 (m, 2H), 3.2~3
．． 4 (m, 41), 3.39 (s.

3H), 3.58(m, LH>, 4.0-4.3(
m, 2H), 5.40-5.65 (a3H), 6.
85 (t, IH, J=7Hz), 7.93 (t, 11
(, J Near, 2Hz).

8.0-8.4 (m, 3H), 8.65 (d, IH,
J=9Hz), 9.01(d, LH.

J=8.2Hz>, 10.35 (d, IH, J=5.
2Hz).

IR: Vmax(CHCIs) 3450.2925
．． 2850.1?15°1520, 1465.1320
．． 1220.1140゜mp,: 57.0-59.0
℃.

(Left below) Elemental analysis (CsaHsmOaNsSC14,5H*O)
Calculated value m C60,78, H9,21, N 5.91.
S 4.51° C14,98° Experimental value (X) C60,94, H9,02, N 5.9
1. S 4.78°C14, 58°mp, 57-59°C (decomposition) Example 19 3-(4-Benzothiazolibutylsulfonylamine)
-2-Methoxy-1-octadecyl carmoyloxypropane chloride Ia19 production 300 mg (0,
384 mM) of 3-(4-benzothiazoliobutylsulfonylamine)-2-methoxy,-1-octadecyl-rubamoyloxypropane iodide 1ΔI was dissolved in a chloroform-methanol mixture and treated with IN-Shiogan twice and with water. After washing once, the solvent was distilled off and reprecipitated from dichloromethane-acetone to give 3-(4-benzothiazoliobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane chloride Ia1965.
mg (0,0941 mM). Yield 25%.

NMRSppm: (CDCIm) 0.88 (t, 3
H), 1.25 (s.

30H), 1.48 (m, 2H), 2.0-2.2
(m, 2H), 2.2-2.4 (m.

2H), 3. (1~3.2 (m, 2H), 3.2~
3.4 (m, 4H), 3.38 (s.

3) 1), 3.55 (m, IH), 4.0-4.3
(m, 2H), 5.25 (m, 2H).

5.52 (br, LH), 6.80 (br, IH),
7.7 (1-7.95 (m, 2H).

8, 2-8.4 (m, 2H), 11.80 (s,
IH).

IRVmax: (CHCIm) 3450.2940
．． 2855.1715°1515, 1465.1435
．． 1330.1220.1140 am”mp,: 5
7.0-59.0°C.

Elemental analysis (C,,H,,O,N,SC1・1.5H10
) Calculated value (%): C56,92, H8,85, N5
．． 86. S 8.94゜C14,94゜Experimental value <'A''): C56,72, H8,71,N
6.05. S 8.97° CI 4.68° Examples 20 to 21 In the same manner as in Example 19, the compounds shown in Table 3 are obtained.

(Margin below) Examples 22-23 In the same manner as in Example 9, Compounds shown in Table 4 obtain.

(Leaving space below) Reference Example 16 Production of 3-benzyloxy-1-hydroxy-2-methoxypropane 1Xa6 18.98 g (0.5 mol) of lithium aluminum hydride was suspended in 400 ml of ether, and the mixture was heated to 66°C at -40°C. .69 g (0.5 mol) of aluminum chloride 2
50 ml of ether solution was added dropwise and further heated at -20°C for 3
Stir for 0 minutes. Add 48.5g (0.25m) to the above reaction solution.
ol) β-methyl-α7-benzylidene glycol 1
[P.E. Verkade et al.
, at al), Journal of the Royal Society
Navelland Chemical Society (Recl,
Trav, Chim.

Pays, -Bas, >, Volume 61, Page 831, 19
200 ml of a dichloromethane solution of the compound described in 1942 was added dropwise at a rate that kept the reaction temperature below 120°C.
Next, after gradually raising the temperature to room temperature, a saturated aqueous sodium sulfate solution is added to the reaction solution which is stirred for 2 hours under water cooling, and the white precipitate formed is filtered. The resulting filtrate is concentrated under reduced pressure and then distilled under reduced pressure to obtain 47.1 g of the title compound as a fraction with a boiling point of 133°C (2-3 mmHg).

Yield 96%.

NMR: &ppm (CDC1,) 2.44 (s, L
H), 3.38-3.52 (a.

18), 3.45 (s, 3H), 3.53=3.8
3 (m, 4H), 4.53 (s.

2H), 7.32 (s, 5H).

Reference Example 17 1-Acetylthio-3-benzyloxy-2-methoxypropane! Preparation of elms 14.7g (75mM) of dl-3-benzyloxy-
2-methoxypropyl alcohol sealed and 12.53ml (
90mM) of triethylamine is dissolved in 150ml of dichloromethane, and 6.08ml (78.75mM) of methanesulfonyl chloride is added under water cooling. After stirring at room temperature for 1 hour, the reaction solution was washed with water, dried, and concentrated to obtain crude mesylate [Xa6'. 2 of the above mesylate IXa6'
Dissolved in 00ml of acetonitrile, 8.994g (7
Add potassium thioacetate (8.75 mM) and heat under reflux for 15 hours. After cooling, the reaction solution is poured into water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated, and the oily residue was distilled under reduced pressure to obtain a boiling point of 130-137°C (2 mmHg
), 16.92 g (67 mM) of the title compound, 1-acedelthio-3-benzyloxy-2-methoxypropane ■a6, was obtained. Yield 89%.

NMRl; ppm (CDCIs): 2.34 (s, 3
H), 3.13(d,2)1゜J=5.6Hz>,
3.43-3.58 (m, 3H), 4.55 (s, 2
H), 7.33(s, 5H).

IRνmax (CHClm): 3000, 2930, 2
850.2820°1685.1450.1355.1
100 cm"Reference Example 18 3-Benzyloxy-2-methoxypropylthioalcohol! Production of cod 14.028g (55mM) of acetylthio-3-benzyloxy-2-methoxypropane ■a6 was added to 300ml
of methanol, 11.24ml (58.3mM
) of 28% by weight sodium methoxide in methanol was added dropwise at -10°C. After stirring for 2 hours at -10~0°C, 3.58ml of methanesulfonic acid was added, the reaction mixture was poured into water, extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated. The oily residue was subjected to silica gel chromatography, and the fractions eluted with a mixture of ether-n-hexane (3:97) were collected to yield 8.85 g (41.7 mM).
The title compound, 3-benzyloxydi-2-methoxypropylthioalcohol Wa6, is obtained as an oil.

NMR & ppm (CDC1m)' 1.49 (t, LH
, J=8.5Hz), 2.58~2.87(m, 2H
), 3.40-3.53 (m, IH), 3.44 (
s, 3H).

3.56-3.63 (m, 2H), 4.55 (s, 2
H), 7.34 (s, 5H).

IRv max (CHCIs): 3000.2940
．． 2860.2g20゜1455.1365.1100
cm” (blank below) Reference Example 19 Production of 3-benzyloxy-2-methoxy-1-octadecylcarbamoylthiopropane VIa6 7.258
g (34,2 mM) of 3-benzyloxy-2-methoxypropylthioalcohol and 11.65 g (39,4
(mM) of octadecyl isocyanate was dissolved in 100 ml of pyridine and heated under reflux for 1 hour. After concentrating the reaction solution, the resulting residue was subjected to silica gel column chromatography, and toluene-ethyl acetate (9:1 to 4:1 ) was collected and 17.072g (33.6mM
), the title compound of 3-benzyloxy-2-methoxy-
1-octadecylcarbamoylthiopropane Wa6 is obtained as a solid. Yield 98%.

NMR8ppm (CDC1g): 0.8g (t, 3H
), 1.25 (s, 30H).

1.40-1.60 (m, 2H), 3.10-3.
19 (m, 2H), 3.19-3.34 (m, 2H
), 3.46 (s, 3H), 3.5 (1-3.
62 (m, 3H), 4.56 (s.

2H), 5.37-5.50 (broad, IH)
, 7.33 (s, 5H).

mp, 40-41°C.

Elemental analysis (C,.H@joINs> Calculated value (X) C70,96,H10,52,N 2.
76, S 6.31° Experimental value (X) C70,90,
H10,5G, N 2.91. S 5.99° Reference Example 20 Production of 3-year-old ctadezylcarbamoylthio-2-methoxypropyl alcohol Va6 1.02g (2mM) of 3-benzyloxy-2-methoxy-1-octadecylcarbamoylthiopropane, ■a6 was dissolved in 80 ml of acetonitrile, and 0.4 ml (2.81 m
Add trimethylsilyl iodite (M) and let stand at room temperature for 15 hours. Add 50 ml of 10% hypowater to the reaction mixture, extract with dichloromethane, wash with water, dry, and concentrate.

The residue was subjected to silica gel column chromatography.
The fractions eluted with n-hexane-ethyl acetate (2:1) were collected to give 480 mg (1.15 mM) of the title compound,
3-Octadecylcarbamoylthio-2-methoxypropyl alcohol is obtained as a solid. Yield 57%.

NMR8ppm (CDC1m): 0.88(t,
3H), 1.26 (s, 301).

1.42-1.60 (m, 2H), 2.75-2.9
7 (broad, LH), 2.98=3.38 (m,
4H), 3.44 (s, 3H), 3.38-3.5
2 (m, IH).

3, 52-3.75 (n+, 2H), 5.42=5
．． 63 (broad, IH).

mp, 62-63°C.

IRvm5x (CHCIs) 3430.2920.2
850.1655°150G, 1465.1190.1
100.1045 cm-' Elemental analysis (C*sH4,N
5Os) Calculated value (%) C66,14,H11,34,N 3.
35.57.6g.

Experimental value (X) C65, 78, H11, 34, N 3.
31. S 7.50° (blank below) Reference Example 21 Production of 2-methoxy-3-octadecylcarbamoylthiopropylamine IVa6 417.7 mg (1 mM) of 2-methoxy-3-octadecylcarbamoylthiopropyl alcohol imide,
408, 6 mg (1, 5 mM) of triphenylphosphine was dissolved in 15 ml of tetrahydrofuran, -
271 after cooling to 30°C.

Add 2 mg (1.5 mM) of Diete J Reazodicarpoxylate dropwise and stir for 30 minutes, then stir at room temperature for 2 hours. After distilling off the solvent, the residue was separated and purified by silica gel column chromatography using a benzene-ethyl acetate (9:1) mixture as an eluent, and the phthalimide compound 4 was purified.
Obtain 00mg (0.732mM). Yield 73%.

1. Mix 019g (1.864mM) of phthalimide with 30ml of ethanol and 10m! of tetrahydrofuran, and add 2.5 ml of hydrazine monohydrate.
Stir at room temperature for an hour. After distilling off the solvent, the product was separated and purified by silica gel column chromatography using a chloroform-methanol (5:1) mixture (0.2% triethylamine) as an eluent.
M) 2-Methoxy-3-octadecylcarbatomoylthiopropylamine %.

NMRSppm(CDC1s+CDsOD)' 0.8
8 (t.3H), 1.26 (s.

30H), 1.40-1.62 (m, 2H), 2.
65-2.94 (m.2H), 2.95-3.17 (
m. IH), 3.17-3.30 (m.2H), 3
．． 30-3.42 (m.IH>, 3.45 (s.3H
).

IRνmax(CHCIm> 3425. 2930.
2850, 1665.

1500, 1190. 1100 cm” (blank below) Reference Example 22 93 mg (0.223 mM) of 2-methoxy-3-octadecylcarbamoylthiopropane 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane Bilamine ■a6,4
0,4μm (3,9mM) triethylamine was added to 5
ml dichloromethane and 2 ml tetrahydrofuran, and add 29.8 μl (3.3 ml) to the mixture under water cooling.
Add 3-oo propanesulfonyl chloride (M) and stir for 2 hours, and further stir for 30 minutes at room temperature. Wash the reaction solution with an aqueous sodium bicarbonate solution and brine, dry over anhydrous magnesium sulfate, and then evaporate the solvent. The residue was separated and purified by silica gel column chromatography using a benzene-ethyl acetate (4:1) mixture as the eluent.
3 mg (0.149 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIIa6 are obtained as a colorless powder.

Yield 67%.

NMR: Sppm (CDC1.) 0.88 (t.3H
), 1.26 (s.30H).

1, 40-1.60 (m.2H), 2.20-2.3
7 (m.2H), 2.93-3.40 (m.8H),
3.40-3.55 (m.IH), 3.43 (s.
3H), 3.69 (t.

J: 5.3Hz. 2H), 5.17-5.35 (br
oad, LH>, 5.37-5.54 (broad.
18).

It is maximum (CHCIm> 3420. 2930
．． 2850. 1670.

1495, 1460. 1335. 1185. 1
150. 1090 am” Reference Example 23 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecyJ and carbamoylthiopropane I [a6 production (hereinafter blank) 197 mg (0,354 mM) of 3-(3- [70propylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane 1
Add sodium iodide (M) and heat and stir for 3 hours.

After distilling off the solvent, the residue was diluted with n-hexane-ethyl acetate (
3:1) Separation and purification by silica gel column chromatography using the mixture as an elution solvent yielded 197 mg of 3-(3-iodopropylsulfonylamine)-2-methoxy-1-octadecylcarbamoylthiopropane I [a6.
(0,304mM) is obtained. Yield 86%.

NMR: δppm (CDC1*) 0.88 (t, 3H
), 1.26 (s, 30H).

1.42-1.62 (m, 2H), 2.25-2.4
2 (m, 2B), 2.95-3.50 (m, 88),
3.44 (s, 3H), 3.50-3.58 (m,
LH), 5.18-5.34 (broad, 11()
, 5.38-5.57 (broad, LH).

IR Niji max (CHCIm> 3425.292
5. 2850. 1670°1500, 1460.
1325. 1185. 1140. 1100 a
m-' Example 24 2-methoxy-1-octadecylcarbamoylthio-3
-(3-N-methylimidazoliobrobylsulfonylamino)propane iodite Production of Mt.D Dissolve in N-methylimidazole and stir overnight at 25°C. After distilling off the solvent, the mixture was washed with ether to obtain 102 mg of 2-methoxy-1-octadecylcarbamoylthio-dazoliopropylsulfonylamino)propane iodite I24. Yield 91%.

NMR: & ppm (CDCIs) 0.88 (t.3
H), 1.26 (s. 301().

1, 4! lr1.65 (m.2H), 2.40-2.
63 (m, 2H), 2.95-3.40 (m, 8H)
, 3.43 (s.3H), 3.45-3.60 (m
．． LH), 4.06 (s.

3H), 4.63 (m.2H), 5.96=6.2
4 (broad.2H), 7.38 (s.IH),
7.71 (s.IH), 9.66 (s.Hl).

IR Niji max (CHCIs) 3430. 3150
．． 2920. 2850.

1670, 1495. 1460. 1320, 1
140. 1095 cm-' (hereinafter blank) Example 25 2-methoxy-1-year-old ctadezylcarbamoylthio-3
-(4-quinoliniopropylsulfonylamino)propane iodite I Production of a25 88 mg (0.136
3-C3-E-dobropylsulfonylamine)
-2-Methoxy-1-octadecylcarbamoylthiopropane was dissolved in 1 ml of quinoline and heated to 45°C.
Stir for 2 days. The reaction solution was dissolved in a chloroform-methanol mixture, washed twice with 5.7% hydroiodic acid and once with water, the solvent was distilled off, and reprecipitated from acetone to obtain 2-
Methoxy-1-ctadezylcarbamoylthio-3-(
3-quinoliniopropylsulfonylamino)propane iodite I a25 is obtained.

NMRz & ppm (CDC1, > 0.88 (t, 3H
), 1.25 (s, 30H).

140-1.62 (m, 2H), 2.62-2.85
(m, 2H), 2.90-3.65 (m, 9H),
3.39 (s, 3H), 5.56 (t, 2H, J=8
．． 1Hz), 5.80-6.25(broad, 2H
), 7.99 (t, LH, J=7.4Hz>, 8.
13-8.37 (m, 3H), 8.67 (d, LH,
J:8.8Hz), 9.07(d, IH.

J=8.2Hz), 10.14(d, IH, J:5.
2Hz).

IR Niji max (CHClm) 3430.2930.
2855.1670°1500, 1465.1330.
1150 cm-' (hereinafter blank) Example 26 2-methoxy-1-year-old ctadezylcarbamoylthio-3
-(3-Thiazoliopropylsulfonylamino)propane iodite I Production of a26 76m17) 3-(3
-iodopropylsulfonylamino)-2-methoxy-
1-Octadezylcarbamoylthiopropane is dissolved in 1 ml of thiazole and heated at 60° C. for 6 hours. After distilling off the solvent, washing with ether and then acetonitrile gave 2-methoxy-1-ctadezylcarbamoylthio-
2632 mg of 3-(3-thiazoliopropylsulfonylamino)propane iodide FIa is obtained. Yield 37%.

NMR: Sppm (CDC1, > 0.88 (t, 3
H), 1.25 (s, 30H).

1.40-1.62 (2H), 2.50-2.75 (
m, 2H), 2.95-3.60 (a+.

9H), 3.42 (s, 3H), 4.95-5.2
0 (m, 2H), 6.07-6.29 (m, 2H),
8.2 (1-8.30 (m, IH), 9.70-9
．． 80 (m, IH).

10, 20-10.32 (m, IH).

IR: νmax(CHCl,) 3420.2925
．． 2850.1670°1500, 1465.1330
．． 1150 am” (blank below) Example 27 2-methoxy-1-octadecylcarbamoylthio-3
Preparation of -(4-quinoliniopropylsulfonylamino)propane chloride I a27 The title compound is obtained in the same manner as in Example 19.

NMRz &ppm (CDC1m) 0.88(t, 3
H), 1.25 (s, 30H).

1.48(m, 2H), 2.15=2.35(m, 2H)
H), 3.0-3.2 (m, 2H).

3.2-3.35 (m, 2H), 3.37 (, s, 3
H), 3.3! lr3.50 (m, IH).

3.5 (1~3.70 (m, 2) 1), 4.0 (1~
4.30 (m, 2H), 5.55-5.80 (m, 3
H), 7.75 (t, IH, J: 6Hz>, 7°9
4 (t, 18. J=7.6Hz), 8.15~
8.40 (m, 3H), 8.74 (d, IH, J=
9.0Hz).

8.97 (d, IH, J=8.2Hz), 10.4
8 (d, IH, J=5.6Hz).

ER: νmax(CHCIs) 34ss,
2930. 2855. 1715°1530.147
0.1325.1220.1140 am”mp,
57-59℃ Elemental analysis (CsaHs*0JsSC14,2H*0) Calculated value (X) C60,75, H9,09, N 6.07
．． S 4.63° C15,12° Experimental value (X) C60,66, H9,09, N 6.2
3. S 4.51° C14,89° Example 28 1-(N-n-octadecylcarbamoyloxy)-2
-Methoxy-3-[4-(3-carboxylatepyridinio)butylsulfonylaminocopropane 13 production (blank below) 600 mg (0,928 mmol) of 3-(4-iodobutylsulfonylamino)-2- Methoxy-1-octadecylcarbamoyloxypropane and 230 mg (1,
Dissolve 87 mmol of 2'=+tinic acid in 10 ml of dimethyl sulfoxide and heat at 80°C for 3 days. 1. Wash the reaction solution once with IN hydrochloric acid, once with aqueous sodium bicarbonate solution, and once with saturated brine. After that, it was reprecipitated from dichloromethane-acetone to give 279 mg (0,435 mmol 1).
1-(N-n-octadecylcarbamoyloxy)-
2-Methoxy-3-[4-(3-carboxylatepyridinio)butylsulfonylaminocopropane is obtained. Yield 47%.

NMR: Sppm (CDCIn) 0.88 (t, 3
H), 1.25 (s, 30H).

1.48 (m, 2H), 1.65-1.95 (n+,
2H), 1.95-2.25 (m.

2H), 2.9-3.3 (m, 6H), 3.36 (
s, 31), 3.50 (m, IH).

3.9-4.3 (m, 2H), 4. flr4.9
(a+, 2H), 5.65-5.80 (m.

IH), 7.20-7.50 (m, IH), 7.
90-8.10 (m, IH), 8.7Ch8.90
(m, IH), 8.90-9.10 (m, IH),
9.25-9.50 (m.

IR: l/maX (CHCIs) 3450, 2920
．． 2850, 1710° 1640, 1615.151G
, 1460.1360.1210°1135 am-
' Elemental analysis (CmJieOJJ4.2HmO) calculated value (X
) C59,74,H9,33,N 6.33. S
4.83° Experimental value (X) C59,61, H9,36,
N 6.26. S 4.63° (blank below) Reference Example 23 Production of 2-aminomethyl-2-n-hexadecylthiomethyltetrahydrofuran IVbl bt Using 2-n-hexadecylthiomethyl-2-hydroxymethyltetrahydrofuran IVbl, reference example 23. 4 Phthalimide compound m, reacted and post-treated in the same manner as in Example 3.
p, 54.5-55.5°C, the amount charged and the physical properties of the product are shown in Tables 5 and 6.

Reference example 24 2- (3-chloropropylsulfonylaminomethyl)
Table 7 shows the amount of charge and the physical properties of the product.

Reference Example 25 2-n-hexadecylthiomethyl-2-(3-iodopropylsulfonylaminemethyl)tetrahydrofuran
(2) Production of b1 Vb1 11b1 Using 2-aminomethyl-2-n-hexadecylthiomethyltetrahydrofuran IVbl, allow reaction in the same manner as in Reference Example 4, and perform post-treatment, m, p, 44.5-2-
(3-chloropropylsulfonylaminomethyl) -
The reaction was allowed to proceed in the same manner as in Reference Example 5 using 2-n-hexadecylthiomethyltetrahydrofuran, followed by post-treatment. Table 8 shows m, p, 36-37°C, charge amount and physical properties.

Example 29 Production of 2-n-hexadecylthiomethyl-2-(3-trimethylammoniopropylsulfonylaminomethyl)tetrahydrofuran-Ibl Reference Example 26 2-Aminomethyl-2-n-octadecylcarbamoyloxymethyltetrahydrofuran Kanbu Production of bt Using 2-hexadecylthiomethyl-2-(3-iodopropylsulfonylaminemethyl)tetrahydrofuran, the reaction is carried out in the same manner as in Example 8, followed by post-treatment, m
, p, 79-84° C1 Charge amount and physical properties of the product are shown in Table 9.

Using 2-hydroxymethyl-2-n-octadedylcarbamoyloxymethyltetrahydrofuran, the reaction was carried out in the same manner as in Reference Example 3, and the post-treatment was carried out. The physical properties are shown in Tables 5 and 6.

Reference example 27 2- (3-chloropropylsulfonylaminomethyl)
-2-n-octadecylcarbamoyloxymethyltetrahydrofuran I[[b2 Using 2-aminomethyl-2-n-octadecylcarbamoyloxymethyltetrahydrofuran IVb2, react and post-process in the same manner as in Reference Example 4. The amounts and physical properties of the products are shown in Table 7.

Reference example 28 2-(3-iodopropylsulfonylamine methyl)
-2-n-octadecylcarbamoyloxymethyltetrahydrofuran 1 side production Vb2 b2 2- (3-chloropropylsulfonylaminomethyl)
Using -2-n-octadecylcarbamoyloxymethyltetrahydrofuran, react in the same manner as in Reference Example 5,
Table 8 shows the post-treatment m, p, 66.5-67.5°C, charge amount, and physical properties of the product.

Example 30 2-n-octadecylcarbamoyloxymethyl-2-
(Production of (3-quinoliniopropylsulfonylaminomethyl)tetrahydrofuran iodite Ib2) Using -2-n-octadecylcarbamoyloxymethyltetrahydrofuran 1, react in the same manner as in Example part and perform post-treatment. , p, 57-62°C, the amount charged and the physical properties of the product are shown in Table 10.

(Left below) 2-(3-iodobrobylsulfonylaminomethy) Reference Example 29 3-n-hexadecylthio-2-methylcarbamoyloxypropanol 1-n-hexadecylthio-3-trityloxy-2-
4.6 g (8.0 mmol) of propatool cl was dissolved in 100 ml of dichloromethane, and 1.17 g (9.6 mmol) of 4-dimethylaminopyridine and 4.4 mmol of methyl isocyanate were dissolved. Add 72 ml (80 mmol). The solution is left at room temperature for 72 hours and then concentrated.
This was applied to a column containing 46 g of silica gel and eluted with ethyl acetate-hexane (1:5) to obtain 5.6 g of an oily crude product of 1-n-hexadecylthio-2-methylcarbamoyloxy-3-trityloxypropane C2. Dissolve this directly in 100ml of dichloromethane,
1.68 ml of boron trifluoride/methanol complex at 0°C
(15.5 mmol) is added. The resulting yellow solution is stirred at 0°C for 15 minutes and then at room temperature for 1.5 hours, resulting in the formation of a precipitate. After neutralizing by adding sodium carbonate aqueous solution,
The organic layer was applied to a column containing 80 g of silica gel and eluted with ethyl acetate-hexane (1:1) to obtain crude crystals. 0
Obtain 7 g. Add pentane to this, grind and wash to obtain 1.205 g of the title compound Vat. The mother liquor was separated and purified by Roper column chromatography using the above solvent as an eluent to obtain additional VclO. 321g (total rate 49%)
) is obtained. m. p. 53-55°C.

NMR: 8 (CDCIm) 0.80-1.70
(m, 31H), 2.22 (br.s.LH), 2.
50=2.75 (m.4H), 2.80 (d.J
=5Hz.

3H), 3.82 (m.2H), 4.85 (b
r. m. 2H).

(The following is a blank space) Reference Example 30 3-n-Hexadecylthio-2-methylcarbamoyloxypropylamine The reaction is carried out in the same manner as in the production of Ncl, and post-treatment is performed. The amount charged and the physical properties of the product are shown in Tables 5 and 6.

The crude phthalimide compound was prepared by methanol-dichloromethane (1
0:l).

Reference Example 31 3-(3-chloropropylsulfonylamino)-1-n
-Hexadecylthio-2-methylcarbamoyloxypropane Vc1 React in the same manner as in Reference Example 4 using 3-n-hexadecylthio-2-methylcarbamo 3-hexadecylthio-2-methylcarbamoyloxypropanoloxypropylamine ■c1 Forgive me, I'll do post-processing, m, p, 84.5-8
Table 7 shows the temperature at 5.5°C, the amount charged, and the physical properties of the product.

Reference Example 32 Table 8 shows the physical properties of 1-n-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methylcarbamoyloxypropanoic acid product.

Example 31 Preparation of 1-n-hexadecylthio-2-methylcarbamoyloxy-3-(3-quinoliniopropylsulfonylamino)propane iodite Icl 3-(3-chloropropylsulfonylamino)-1-n-hexadecylthio-2 -Methylcarbamoyloxypropane III
Using Cl, the reaction was carried out in the same manner as in Reference Example 5, followed by post-treatment. Charge amount and raw 1-n-hexadecylthio-3
Using -(3-iodopropylsulfonylamino)-2-methylcarbamoyloxypropane I [cl, the reaction is carried out in the same manner as in Example 25, followed by post-treatment. Preparation amount and raw.

Table 10 shows the physical properties of the acid.

Example 32 Production of 1-n-hexadecylthio-2-methylcarbamoyloxy-3-(3-trimethylammoniopropylsulfonylamino)propane iodite Ic2 The physical properties of the acid product are shown in Table 9.

Reference Example 33 Production of 2-methylcarbamoyloxy-1-ctadezylcarbamoyloxy-3-trityloxypropane 1-n-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methylcarbamoyloxypropane I[ Using Cl, reaction preparation and post-treatment are carried out in the same manner as in Example 8.
Dissolve 1.26 g (2.0 mmol) of -n-year-old ctadezylcarbamoyloxy-3-trityloxy-2-propatool c3 in 20 ml of dichloromethane, add 0.293 g (2.4 mmol) of 4-dimethylaminopyridine and methyl Isocyanate 1. Add 18 ml (20 mmol). After stirring this solution at room temperature for 24 hours,
The solvent was distilled off and the residue was diluted with ethyl acetate-hexane (1:1).
was purified by silica gel column chromatography using as an eluent to obtain the title compound c40, 789 g (yield 59%).
). m, p, 89-91°C.

NMRES (CDCIs>0.86 (t, J=6
Hz, 3H)-1,28(br, s, 32H), 2.
74 (d, J=6Hz, 3H), 2.90-3.4
5 (m.

4) 1), 4.24 (d, J=6Hz, 2H),
4.70 (m, 2H), 5.10 (m, IH),
7.15”7.65 (m, 15H).

Reference Example 34 4.5 g (6.68 mmol) of the compound c4 obtained from the manufacturer of 2-methylcarbamoyloxy-decylcarbamoyl Vc2 was dissolved in 45 ml of dichloromethane, and boron trifluoride. Methanol complex 1. 08ml (9.96
millimoles). After stirring this solution at room temperature for 4 hours, it is washed with an aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from methanol-ether to obtain the title compound L62.04.
g (69% yield), rn. p. 92-93°C.

NMR: l; (CDC1.>0.86 (t.J
=6Hz. 3H), 1.26 (br.s.32H),
2.75 (d.J:6Hz.3H), 2.80~
3.45 (m.

3H), 3.68 <m. 2H), 4.25 (d
．． J=6Hz. 2H), 4.75-5,25 (m.
3H).

IR: νIIIax (Nujol) 3340,
3290.

1685, 1520. 1375. 1285. 1
150. 1065 am-'Reference Example 35 Production of 2-methylcarbamoyloxy-3-n-octadecylcarbamoyloxypropylamicine (blank below) c2 Reference Example 36 3- (3-chloropropylsulfonylamine/)-2
-Production of methylcarbamoyloxy-1-n-octadecylcarbamoyloxypropane c2 Using 2-methylcarbamoyloxy-3-n-octadecylcarbamoyloxypropanol Vc2, react in the same manner as in Reference Example 3 and perform post-treatment. ．． Amine Nc
2 m. p. 91-92℃. The amount charged and the physical properties of the product are shown in Tables 5 and 6.

Using 2-methylcarbamoyloxy-decylcarbamoyloxybropylamine (c2), the reaction was carried out in the same manner as in Reference Example 4, followed by post-treatment. m.
Table 7 shows the p, 102-104°C, charge amount, and physical properties of the product.

Reference Example 37 3-(3-iodopropylsulfonylamino)-2methylcarbamoyloxy-1-n-octadedylcarbamoyloxypropane I [shown in the production table of c2.

Example 33 Preparation of 2-methylcarbamoyloxy-decylcarbamoyloxy-3-(3-quinoliniopropylsulfonylamino)propane iodite Ic3 1 [[c2 1[c2 3- (3-chloropropylsulfonylamino)-2-
Reference Example 5 Using methylcarbamoyloxy-1-n-octadecylcarbamoyloxypropane I [[c2
Allow the reaction to proceed in the same manner as above, and perform post-processing.

m. p. 97-99℃. The amount of charge and the physical properties of the product were determined using 83-(3-iodopropylsulfonylamino)
-2-Methylcarbamoyloxy-1-n-octadecylcarbamoyloxypropane I[c2 was used to react in the same manner as in Example 25, followed by post-treatment. Table 10 shows the amount charged and the physical properties of the product.

Example 34 2-Methylcarbamoyloxy-1-n-octadenylcarbamoinooxy-3-(3-trimethylammoniopropylsulfonylamino)propane iodite I
C4 was reacted and post-treated in the same manner as in Example 8. Table 9 shows the amount charged and the physical properties of the product.

(Left below) I[c2 3- (3-iodopropylsulfonylamino)-2-
Using methylcarbamoyloxy-1-n-octadecylcarbamoyloxypropane I [c2, Reference Example 3
8 Production of 〇-octadecylcarbamoyl-N-triphenylmethylserine methyl ester 3.16 (2Lm
), 3.19 (31(,s), 3.58 (I
H, m), 4.21<LH, dd, J=11.61
(z), 4.37 (LH, dd, J=11.5Hz
).

4.69 (LH, t, J=11Hz), 7.1-7
．． 3 (9) i, m), 7.45-7.6 (6) 1
．． m).

Reference example 39 0-octadecylcarbamoylserine methyl ester N
-triphenylmethylserine methyl ester 1.67
g and stearyl isocyanate 2. Og's N. Heat 10 ml of N-dimethylformamide solution at 85°C for 16 hours. Pour the reaction mixture into ice water and extract with ethyl acetate.
The extract was washed with water, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by flash chromatography (silica gel, hexane: ethyl acetate 3:2) to obtain the title compound as an oil in 2.46 sections (yield 82.6%).

NMR (CDC1s) δppm F 0.88 (3
H. t, J=7Hz>, 1.25(30)1,s),
1.46 <2H. m), 2.78 (IH.d.
J=10Hz).

Add 573 mg of 10% dilute hydrochloric acid to 15 ml of acetone.
Add to the solution and leave at room temperature overnight. After making alkaline with aqueous sodium carbonate solution, extract with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue a was subjected to flash chromatography (silica gel 15 g, ethyl acetate:methanol 9:1) and then recrystallized from ethyl acetate-hexane to obtain the title compound e.
3 276 mg (yield 74, 9%) was obtained. mp. 7
0-71℃; NMR' (CDClm) & p9fn
O. 89 (3H.t.J"6Hz), 1.26 (
30H,s), 1.49 (2H.m), 1.78
(2H.s), 3.16 (21.

m>, 3.73 (IH.m), 3.76 (3H
．． s), 4.31 (2H.d.

J:5)1z), 4.76 (ILs>.

Reference Example 40 Production of 2-amino-3-octadecylcarbamoyloxypropanol e4 Extract with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silicageno LT, chloroform:methanol 9:1) and then recrystallized from hexane to obtain 41.57 g (yield 80.9%) of the title compound e.
mp 103-105°C.

NMR: (CDC1.)&ppm O. 88
(3Lt.J=6)%z), 1.26(30H
,s), 1.49 (2H.m), 1,73 (3
8,s), 3.06 (IH.

m), 3.17 (2H.m), 3.51 (2H.m), 3.17 (2H.m), 3.51 (2H.
．． m>, 4.08 (2H.d.

J=5Hz), 4.75 (1) 1. s).

Reference Example 41 2-methoxycarbonylamino-3-octadecylcarbamoyloxydibrobanol 1 Production of sweetfish Calcium chloride 1. Add 11 g to a mixture of 760 mg of sodium borohydride and 30 ml of ethanol at -40°C. Stir the mixture for 1 hour at -20°C. Above ester 2.
Add a solution of 0.8 g in 50 ml of ethanol dropwise at -20°C. Stir the mixture at -20°C for 3 hours. Add water and add a solution of 117 mg of methyl chloroformate in 8 ml of acetone to the above amino alcohol e4, 120 mg (7) 3.
Add to a suspension of 3 ml of 3% aqueous sodium carbonate solution. After stirring the mixture for 6 hours, water was added and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is subjected to flash chromatography (10 g of silica gel, 1 ethyl acetate) and then recrystallized from hexane to give 115 mg (82.3% yield) of the title compound Yet. mp 84-85°C.

NMR (CDCIs) sppm 0.89 (3H, t
, J=6Hz), 1.26 (30H,s), 1.5
0 (2H, m), 1.61 (IH, s), 3.
07 (IH.

br, s), 3.18 (2H, m), 3.69
(3H,s), 3.86 (IH.

br, s), 4.20 (2H, d, J=5Hz),
4.83 <ILs), 5.23 (LH, d, J=
7Hz>.

(Leaving space below) Reference Example 42 'Production of 1-tart-butoxycarbonylamino-3-octadecylcarbamoyloxybrobanol - Using ditart-butyl dicarponate instead of methyl chloroformate in the synthesis of Vel Synthesized in the same manner, yield 93.4% mp 73-75°C.

NMR: (CDCIm) & ppm 0.87 (
3H. t. J=5Hz>, 1.26 (30H.s),
1.44 (9H.s), 1.56 (2H.rn
>, 3.18 (2H.

m>, 3.63 (2H.m), 3.81 (LH
．． br. s), 4.18 (2H.d.

J=5Hz), 4.78 (IH.br.s), 5
．． 20 <IH. br. s) Reference Example 43 Production of 2-methoxycarbonylamino-3-octadecylcarbamoyloxypropylamine IVel m. p. 85-8fi℃. The amount charged and the physical properties of the product are shown in Tables 5 and 6.

Reference example 44 'l-tart-butoxycarbonylamino-3-
Production of octadecylcarbonyloxyprobylamine e2 Reference Example 3 Using 2-methoxycarbonylamino-3-octadecylcarbamoyloxybrobanol Vel
React and post-process in the same manner as above. Phthalimide m
．． p. 128-129℃; Amine body! Wind 2-t
Reference Example 3 using art-butoxycarbonylamino-3-octadecylcarbamoyloxypropane Ve2
React and post-process in the same manner as above. Phthalimide m
．． p. 127 (29°C; amine IVe269-7
0℃.

The amount charged and the physical properties of the product are shown in Tables 5 and 6.

(Left below) Reference Example 45 Reference Example 46 Production of 4-acetylthiomethyl-2-phenyl-2-oxacillin e6 Production of 4-hexadecylthiomethyl-2-phenyl-2-oxacillin e7 4-hydroxymethyl-2- Phenyl-2-oxacillin was reacted in the same manner as in Reference Example 17, and the extract was purified by flash chromatography (silica gel, hexane: ethyl acetate 2:1) and then crystallized from hexane to obtain the title compound e6 as needle crystals. obtain. mp59-60
℃6 NMR (CDC1,) & ppm 2.37 (3H,s
), 3.23 (2H, m).

4.11 (IH, m), 4.33-4.62 (2
H), 7.36-7.55 (3H).

7.95 (2H, m) - (blank below) To a solution of 613.28 g of the above thiol ester e in 70 ml of methanol is added 60 ml of a 10% aqueous sodium hydroxide solution while stirring at 0°, and the mixture is stirred at room temperature for 2 hours. Add water and extract with ether. The heavy equipment layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude thiol r, 6 sg.
(yield 70.4%).

To a solution of this residue in anhydrous tetrahydrofuran (40 ml) is added portionwise 1.6 g of 60% sodium hydride at room temperature. After stirring the mixture for 30 minutes, a solution of 12.22 g of quinadecane bromide in 10 ml of anhydrous tetrahydrofuran is added and stirred overnight at room temperature. 6. The reaction mixture is diluted with ether, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to flash chromatography (
silica gel, hexane:ethyl acetate 4:1) and then purified by crystallization from hexane to obtain the title compound e714.68.
g (62.3% yield) as needles. mp39
-41℃ NMR (CDCIs) Sppm 0.88 (
3H,t,J:6.5Hz>, 1.25(26H,s
), 1.59 (2H, m>, 2.53-2.67
(3H), 2.99 (IH, m), 4.30 (
IH, m), 4.43-4.59 (2H), 7.
36-7.54 (38), 7.95 (2)t, turtle).

Reference Example 47 Production of 2-amino-3-hexadecylthiopropanol e8 715.0 g of the above oxazoline e was mixed with 55 m of 6N-sulfuric acid.
1 and stirred at 105°C for 24 hours. After cooling 10
% water and extract with ethyl acetate. After washing with water and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to flash chromatography (silica gel,
Chloroform→Chloroform:methanol 10:1)
It is then purified by crystallization from dichloromethane-hexane to obtain 11.16 g (yield 93.7%) of the title compound as fine plate crystals. mp 70-71℃.

NMR (CDC1s) & 1) pm 0.88 <
3Lt, J=6.5)1z), 1.26(26H,
s), 1.58 (2H, m), 1.85 (38
, s), 2.46 (IH.

dd, J=8.2.13.3Hz), 2.52 (2
H, t, J = 7.3 Hz), 2.66 (IH, dd,
J=4.8.13.3Hz>, 3.02 (IH, m
), 3.42 (LH, dd, J: 6.5.10.7H
z＞, 3.67 (IH, dd, J=4.1°10.
7Hz).

Reference Example 48 Production of 3-hexadecylthio-2-methoxycarbonylaminopropanol e9 The reaction was carried out in the same manner as in Reference Example 41, with the aqueous sodium oxide solution made slightly alkaline. (Yield 94.6%) mp
55-56°C.

NMR (CDCIs) & ppm 0.88 (31(
, t, J=6.4) 1z>, 1.26 (26H, s)
, 1.58 (2H, m), 2.55 (2H, t
, J=7.2Hz).

2.73 (2H, d, J=5.7Hz), 3.69
(38,s), 3.67-3.88(3H), 5
．． 21 (br, S).

Reference Example 49 Production of 3-hexadecylthio-2-tert-butoxycarbonylaminoprobanol elO The reaction is carried out in the same manner as in Reference Example 42.

Yield 95.9%, mp 48-50°C NMR (CDC
1s) & ppm 0.88 (31(, t, J=6.
411z), 1.26 (26H, s), 1.45
(9H, s), 1.58 (2H, m), 1.96
(IH.

s), 2.55 (2H, tJ=7.0Hz), 2
．． 71 (2H, d.

J=4.0Hz>, 3.69-3.82 (3H),
5.02 (LH, br, s).

Reference example 50 1-hexadecylthio-3-methanesulfonyloxy-
Alcohol e92.727g dichloromethane 3
A solution of 0.96 g of methanesulfonyl chloride in 5 ml of dichloromethane was added dropwise to a 4 ml solution of triethylamine at -10°C and stirred for 2 hours at the same temperature.The reaction solution was diluted with ether and mixed with water, 10% hydrochloric acid, and sodium bicarbonate. Wash sequentially with water and then dry with anhydrous sodium sulfate.

The solid obtained by distilling off the solvent under reduced pressure was recrystallized from benzene-hexane to obtain 3.133 g of the title compound elf.
(Yield 95.7%) is obtained as a crystalline powder. mp
82-83℃.

NMR (CDCIs) # ppm O, 88 (3H, t
, J=6.5Hz), 1.26(26)1. s),
1.58 (2H, m), 2.55 (2H, t
, J=7.2Hz).

2.68 (IH, dd, J=7.3. 13.5Hz
>, 2.78 (IH, dd.

J=5.2.13.5Hz), 3.05 (3H,s
), 3.70 (3)1. s).

4.05 (LH, m), 4.34 (LH, dd
J=4.3. 10.2Hz).

4.45 (L)1. dd, J=4.2. 10.21
(z), 5.10 <11(, d.

J=8.0Hz).

Reference Example 51 Production of 2-tert-butoxycarbonylamino-1-hexadecylthio-3-methanesulfoxypropane e12 (IH, dd, J = 5.6. 13.5 Hz>, 3
．． 05 (3H, s), 4.00 (IH, m),
4.32 (IH, dd, J=4.3.10.2Hz)
, 4.45(1)1. dd,,c4.1. 10.2
Hz>, 4.90 (1)1. d, J=7.8Hz
>: Reference Example 52 Production of 3-azido-1-hexadecylthio-2-methoxyluponylaminopropane The reaction was carried out in the same manner as in Reference Example 50.

Yield 97.9%, mp 90-91°C.

NMR (CDCIs) Sppm 0.88 (3H, t
, J=6.4Hz), 1.26(26H,s), 1
．． 45 (9H, 9), 1.58 (2H, m),
2.55 (2H.

t, J=7.1Hz), 2.67 (LH, dd, J
= 7.2.13.5Hz), 2.76 To a solution of all 4.677 g of the above mesylate in 25 ml of hexamethylphosphoric triamide, add 1 g of sodium azide and
Stir at 0°C for 4 hours. After cooling, the reaction mixture was diluted with ether, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash chromatography (silica gel, hexane: ethyl acetate 8:1) followed by crystallization from hexane to give the title compound e133.92.
5 g (yield 94.6%) are obtained as fine needles.
mp 44.5-45.5℃ NMR (CDCIs) Sl) m O, 88 (3H, t
, J=6.5Hz), 1.26(261,s),
1.58 (2H, m), 2.54 (2H, t
, J=7.3Hz>.

2.64 (IH, dd, J near, 3. 13.9Hz
), 2.73 (IH, dd.

J=6.0. 13.9Hz), 3.52 (LH
, dd, J=5.0. 12.3Hz).

3.65 (LH, dd, J=4.5. 12.3Hz
), 3.69 (3H,s).

3.91 (LH, m), 4.98 (LH, dJ=
6.5)1z).

Reference example 53 3-azido-2-tart-butoxycarbonylamino (LH.dd., C6.1. 14.0Hz),
3.50 (IH.dd., C5.1.

12,2Hz), 3.64 (LH, dd., C
4.2. 12.2Hz>, 3.86 (IH.m
), 4.81 (IH.d.J=6.5Hz>.

Reference Example 54 Production of 3-hexadecylthio-2-methoxycarbonylaminopropylamine L The reaction was carried out in the same manner as in Reference Example 52. Yield 93.6%, m
p 63-64°C.

NMR (CDCIs) ff ppm 0.88 (3
H. tJ=6.4Hz), 1.26(26H,s),
1.45 (9H.s), 1.58 (2H.m>
, 2.54 (2H.

t. J=7.3Hz>, 2.63 (IH.dd.J
=7.4, 14.0Hz), 2.71 3.875g of the above azide a13, triphenylphosphine 3
．． A solution of 19 g in 40 ml of tetrahydrofuran was added to 20
Stir for an hour. Add 10 ml of water and heat under reflux for 30 minutes. After cooling, dilute with ether, wash with water, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform→chloroform:methanol 25:2) and then crystallized from hexane to give 3.532 g of the title compound L (yield 97.
．． 2%) as a crystalline powder, mp 49-50
．． 5℃.

NMR (CDCIs) & ppm 0.88 (3H
．． t. J=6.4Hz), 1.25(, 26H.s)
, 1.45 (2H,s), 1.58 (2H.m
), 2.54 (21.

t. J=7.3Hz), 2.62 (IH.dd.
J=6.9. 13.2Hz), 2.74(1)1
．． dd, J=5.7, 13.2Hz>, 2.87
(2H.d.J=5.5Hz).

3,68 (3H.s), 3.76 (LH,m),
5.14 (IH.d.

J=7.6Hz).

Reference Example 55 Production of 3-hexadecylthio-2-tart-butoxycarponylaminobrobylamine IVe4 2, 72 (
IH. dd. J=5.5. 13. IHz), 2
．． 86 (2H.d.

J=5.1Hz), 3.71 (IH.m),
4.94 (IH, d, J=7.5Hz).

Reference Example 56 Preparation of 3-(3-chloropropylsulfonylamino)-2-methoxycarbonylamino-carbamoyloxypropane I[[el e4 The reaction is carried out in the same manner as in Reference Example 54. Yield 95.3%.

mp 46-47”C NMR (CDCIs)Spfffi O.88 (3
H. t. J=6.4Hz>, 1.26 (26H.s)
, 1.45 (9H.s), 1.50-1.66
(4H), 2.54 (2H.t.J=7.3Hz),
2.62 (IH.dd.J=6.7.13.1H
z＞.

Using 2-methoxycarbonylamino-3-octadecylcarbamoyloxypropylamine, the reaction is carried out in the same manner as in Reference Example 4, followed by post-treatment.

m. p. Table 7 shows the temperature, charge amount, and physical properties of the product.

(Left below) Reference Example 57 '1-tert-Butoxycarbonylamino-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane IIIe2 Reference Example 58 3-<3-chloropropylsulfonylamino)-1-hexadecylthio-2- Production of methoxycarbonylaminopropane (Ve2) Using 2-tart-butoxycarbonylamino-3-octadecylcarbamoyloxypropylamine Ne2, allow reaction in the same manner as in Reference Example 4, and perform post-treatment.
+. p. 112-115℃. Table 7 shows the amount charged and the physical properties of the product.

Using 3-hexadecylthio-2-methoxycarbonylaminopropylamine ffe3, the reaction is carried out in the same manner as in Reference Example 4, followed by post-treatment. m. p. 67-69℃.
Table 7 shows the amount charged and the physical properties of the product.

(Left below) Reference Example 59 2-tart-i toxycarbonylamino-3-(3-
Reference example 60 for the production of chloropropylsulfonylamino)-1-hexadecylthiopropane me4 2-amino-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane 1
Preparation of a filtrate Using fe4 11e4 3-hexadecifrethio-2-tart-ptoxycarbonylaminopropylamine and chlorine, react in the same manner as in Reference Example 4, and perform post-treatment. p.

Too. s-tot. s℃. Table 7 shows the amount charged and the physical properties of the product.

(Left below) 11 [e2 Trifluoroacetic acid 0. 5ml dichloromethane 2ml
The solution was added dropwise to a suspension of 252 mg of the above BOCi conductor 11 [e2 in dichloromethane glaze 1] at room temperature. The mixture is stirred at room temperature for 2 hours. After making alkaline with sodium bicarbonate water, separate the organic layer. Extract the aqueous layer with dichloromethane. The organic layers were combined, washed with water, dried over aqueous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform:methanol and recrystallized from ethyl acetate-hexane) to give the title compound mel' 190 mg (yield: 8
9.7%) as a crystalline powder, mp 8fr8
8°C; NMR (CDCIs) 5ppm o. ss (
3H. t. J=5Hz), 1.26 (30H.s),
1.50 (2H.m), 2.20 (2H.br
．． s), 2.30 (2H.m), 3.16 (6H.
．． m), 3.69 (2H, t.J=6Hz), 4
．． 09 (3H.br.s), 4.88 (LH.br.s)
．． s) (blank below) Reference Example 61 2-Amino-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane I[Ie2'1[
C4 Carry out the reaction in the same manner as in Reference Example 60. Yield 98.4%.

mp7 low 77℃.

NMR (CDC1n) Sppm O. 88 (3)1
．． t. J=6.4Hz), 1.26 (26H.s),
1.58 (2Lm), 2.20 (3Lbr.s
), 2.30 (2H.m), 2.44-2.55
(38), 2.65 (IH.dd, J=5.0.

13.3Hz), 2.97 (IH.dd, J=7.
5. 11.8Hz>, 3.07 (LH.m), 3
．． 19-3.33 (3H), 3.70 (2H.t
．． , C6.2Hz).

Reference Example 62 2-acetamido-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane 1 Salmon Itral' Tsch chromatography (silica gel, chloroform:methanol lo: 1), then recrystallized from ethyl acetate The title compound L&! 459 mg (yield 84
．． 8%), mp 110 (12°C; NMR (
CDC1. ) & ppm O. 88 (3)1. t. J
=61(z), 1.26(30H.s), 1.50
(2H.m), 2.02 (3)1. s), 2,
28 (2H.

m), 3.1-3.3 (6H), 3.69 (2
H. t. , J=6Hz>, 4.1-4.3 (3H),
4.91 (IH.t.J=6Hz>, 5.72
(IH.br.s).

6, 48 (IH.d.J=6Hz>.

(Left below) Pyridine 0. Add 1 mg of the above amine 5Q and 1 ml of acetic anhydride to a solution of 77 ml of dichloromethane at room temperature.
Add to 15 ml of dichloromethane solution of 94. After stirring at room temperature for 2 hours, wash sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, and dry over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was converted into Fura Reference Example 63 3-(3-chloropropylsulfonylamino)-2=
(3-Methylureido)-1-octadecylcarbatomoyloxypropane 1
mg (yield 88.0%). fflp 87-9
0°C.

NMR (CDC1.>Sppm 0.88 (3H.
t. J=6Hz), 1.26 (30H, s), 1.
50 (2H.m), 2.28 (2H.m), 2
．． 77 (3H.

s), 3.1-3.3 (68), 3.68 (2
8,t. J'7Hz), 4.05 (IH, br.s)
, 4.15 (2)1. m>, 5.04 (171
,br. s), 5.51 (lH.br.s), 6.
11 (LH.br.s).

(Left below) Add 0.2 ml of methyl isocyanate to the above amine N e
1L480mg N,N-dimethylformamide 5ml
Add to the solution. After stirring at room temperature for 1 hour, pour into water and extract with ethyl acetate. The extract was dried with anhydrous sodium sulfate (1) ram, and the solvent was distilled off under reduced pressure, and the resulting residue was subjected to flash chromatography. Preparation of 1-hexadecylthiopropane l- Purified with 1[[e2':1] and crystallized from hexane to obtain the title compound 1.
Obtain 924 mg (yield 88.2%). mp86
-88℃.

NMR (CDCIs>Sppm 0.88 (3H.
t. J=6.5Hz), 1.26 (26H.s),
1.58 (2) t. m), 2.03 (3
H. s), 2.28 (21.

m), 2.54 (2H.t.J=7.3Hz),
2.65 (IH.dd.

J=7.0. 13.5Hz), 2.76 (IH.
dd. J=5.9. 13.5Hz).

3, 18-3.37 (4H), 3.69 (2H.
t. J=6.2Hz), 4.13(lH.m), 5
．． 36 (LH.t.J=6.1Hz>, 6.23
(IH.d.

J=7. 9Hz).

(Left below) 962 mg (2.042 mmol) of the above amine
) in 20 ml of dichloromethane solution and 0.0 mL of acetic anhydride. 5m
Add 161.1.l of pyridine to it. 5mg (2.0
A solution of 42 mmol) in 2 ml of dichloromethane was added dropwise at room temperature, and the mixture was stirred for 1 hour. After distilling off the solvent under reduced pressure, flash chromatography (chloroform→chloroform-methanol 2.

Reference Example 65 3-(3-chloropropylsulfonylamino)-1hexadecylthio-2-(3-methylureido)-propane mf2 111e2' Recrystallized from xane to obtain the title compound 11 [f21.107 g
(yield 97.8%). mp 79-80°C.

NMR (CDC1m>δpriffi: 0.88 (
3H, t, J = 6.4Hz).

1.26 (26H, s), 1.57 (2H, m)
, 1.88 (LH, br, s).

2.28 (2H, m), 2.54 (2H, t, J
=7.0Hz), 2.70 (2H.

m), 2.78 (3H, s), 3.17-3.4
1 (4H), 3.68 (2H, t.

J=6.2Hz), 3.99 (IH, m), 5.
12 (IH, br, s), 5.78 (IH, br,
s).

(Left below) Amine above! ”32 1.01 g (2,143 mmo
Add 0.2n+1 of methyl isocyanate to 20ml of dimethylformamide solution of l).
Add l solution and stir at room temperature for 3 hours. Dilute the reaction solution with ethyl acetate, wash successively with water and saturated brine, and dry with anhydrous sodium sulfate. Distill the solvent to obtain crystals. Reference Example 66 Preparation of 2-acetamido-3-(N-acedel-3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane m 1 [eL''; L chromatography (silica gel, chloroform:
Methanol 20:1) and then purified by recrystallization from ethyl acetate to obtain the title compound L&! 342 mg (yield 81.7%
). mp 116 (17℃.

NMR (CDCIs) δppm 0.88 (3H, t
, J=5Hz), 1.26 (30H, s), 1.5
0 (2H, m), 1.99 (3H, s), 2.
33 (2)1゜m), 2.46 (3H,s),
3.17 (2H, m), 3.58 (2H, t.

J-7Hz), 3.69 (2H, t, J=7Hz)
, 3.90 (2H, m), 4.10 (IH, dd
, J:12.5Hz), 4.22 (IH, dd, J
= 12.5Hz).

4.47 (IH, m), 4.81 (LH, t, J
=5Hz), 6.08 (LH, d.

J=7Hz).

(Left below) A solution of 0.5 ml of acetic anhydride in 2 ml of dichloromethane is added to the above solution of 361 mg of amine Nel' in 2 ml of triethylamine and 210 ml of dichloromethane. - After being left at room temperature overnight, it is washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, and dried over anhydrous sodium sulfate.

The solvent is distilled off under reduced pressure and the resulting residue is flashed. Reference Example 67 Production of 3-(3-iodopropylsulfonylamino)-2-methoxycarbonylamino-1-octadecylcarbamoyloxypropane 11 Reference Example 68 2-Butoxycarbonyl Preparation of amino-propylsulfonylamino)-1-octadedylcarbamoyloxypropane IIe2 1 m. p.

93℃. Table 8 shows the amount charged and the physical properties of the product.

2-Ptoxycarbonyleaamino-3-(3-chloropropylsulfonylaminolbamoyloxypropane I
-98°C. Table 8 shows the amount charged and the physical properties of the product.

Reference Example 69 Production of 2-acetamido-3-(3-iodopropylsulfonylamino)-1-octadecylcarbamoyloxypropane l Salmon Reference Example 70 3-(3-iodopropylsulfonylamino)-2-(
Preparation of 3-methylureido)-1-octadedylcarbamoyloxypropane nfl 11 [gl 2-acetamido-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane l Using salmon, Reference Example 5 Allow the reaction to proceed in the same manner as above, and perform post-processing. m. p. IQl (02°C. The amount charged and the physical properties of the product are shown in Table 8.

3- (3-chloropropylsulfonylamino)-2-
Using (3-methylureido)-1-octadecylcarbamoyloxypropane f1, react in the same manner as in Reference Example 5 and perform post-treatment, m. p. 87-89℃
．． Table 8 shows the amount charged and the physical properties of the product.

Reference Example 71 Production of 1-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methoxycarbonylaminopropane IIe3 Reference Example 72 2-Butoxycarbonylamino-1-hexadecylthio-3-(3-iodopropylsulfonylamino) Production of propane 11e3 e4 3- (3-chloropropylsulfonylamino)-1-
React hexadecylthio-2-methoxycarbonylaminopropane and perform post-treatment, m. p. 79-81°C
．． The preparation details and physical properties of the product are shown in Table 8.

Using 2-butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane me4, the reaction is carried out in the same manner as in Reference Example 5, followed by post-treatment. m. p. 82-83℃. Table 8 shows the amount charged and the physical properties of the product.

Reference Example 73 2-acetamido-1-hexadecylthio-3-(3-
Reference Example 74 Production of 1μ of 1-hexadecylthio-3-(3-iodopropylsulfonylamino')-2-(3-methylureido)propane] 11g2 f2 2-acetamido-3-(3 -chloropropylsulfonylamino)-1-hexadecylthiopropane, react in the same manner as in Reference Example 5, and perform post-treatment, m.
p. 75-76°C. Table 8 shows the amount charged and the physical properties of the product.

3-(3-chloropropylsulfonylamino)-1
-Hexadecylthio-2-(3-methylureido)propane I [If2 is used to react in the same manner as in Reference Example 5, followed by post-treatment, m. p. 70-71℃. Table 8 shows the amount charged and the physical properties of the product.

Reference Example 75 Production of 2-acetamido-3-(N-acetyl-3-iodopropylsulfonylamino)-1-octadedylcarbamoyloxypropane jLH=A m, 9.118
Table 8 shows the amount of 119°C1 charged and the physical properties of the product.

Example 35 1-year old ctadezylcarbamoyloxy-2-methoxycarbonylamino-3-(3-trimethylammoniopropylsulfonylamino)propane iodite-Iel
Production of 2-acetamido-3-(N-acetyl-3-iodopropylsulfonylamino)-1-octadecylcarbamoyloxypropane is reacted in the same manner as in Reference Example 5, followed by post-treatment.

3- (3-iodopropylsulfonylamino)-2-
Using methoxycarbonylamino-1-octadedylcarbamoyloxypropane I[el, the reaction was carried out in the same manner as in Example 8, and the post-treatment was carried out. Table 9 shows the amount charged and the physical properties of the product.

Example 36 Production of 2-tart-butoxycarbonylamino-1-octadecylcarbamoyloxypropane (ammoniobrobylsulfonylamino) iodite-C1 The reaction is carried out in the same manner as in Example 8, and the post-treatment is carried out. Table 9 shows the amount charged and the physical properties of the product.

Example 37 2-acetamido-1-octadecylcarbamoyloxy-3-(3-trimethylammoniopropylsulfonylamino)furopane Production of iodite sweetfish 1e2 g1 2-tert-phthoxycarbonylamino-3
-(3-iodopropylsulfonylamino)-1-octadecylcarbamoyloxypropane-1[e2] 2-acetamido-3-(3-iodopropylsulfonylamino)-1-octadecylcarbamoyloxypropane 1st edition , the reaction was carried out in the same manner as in Example 8, and the post-treatment was carried out. Table 9 shows the amount charged and the physical properties of the product.

Example 38 Preparation of 1-octadecylcarbamoyloloxy-methylureido)-3-(3-trimethylammoniopropylsulfonylamino)propane iodite If. , perform post-processing. Table 9 shows the amount charged and the physical properties of the product.

Example 39 Production of 1-hexadecylthio-2-methoxycarbonylamino-sulfonylamino)propane Yodai FI@3 e3 3-(3-iodopropylsulfonylamino)-2-(
3-methylureido)-1-old ctadezylcarba 1-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methoxycarbonylaminopropane was used to react in the same manner as in Example 8, followed by post-treatment. ．． Table 9 shows the amount charged and the physical properties of the product.

Example 40 Production of 2-tert-butoxycarbonylamino-l-hexadecylthio-3-(3-trimethylammoniopropylsulfonylamino)propaneiotite Ie4 Using ruamino)propane ffe4, the reaction was carried out in the same manner as in Example 8, and the subsequent reaction was carried out in the same manner as in Example 8. Perform processing. Table 9 shows the amount charged and the physical properties of the product.

Example 41 2-acetamido-1-hexadecylthio-3-(3-
Preparation of trimethylammoniopropylsulfonylamino)propane iodite I Using 1G of -iodopropylsulfonylamino)propane, the reaction was allowed to proceed in the same manner as in Example 8, and the post-treatment was carried out. Table 9 shows the amount charged and the physical properties of the product.

Example 42 1-hexadecylthio-2-(3-methylureido)-
Table 9 shows the productivity of 3-(3-trimethylammoniopropylamino)propane iodite 1B.

Example 43 2-acetamido-3-(N-acetyl-3-trimethylammoniopropylsulfonylamino)-1-octadecylcarbamoyloxypropane Preparation of iodite 1G 1[f2 1-hexadecylthio-3-(3-iodopropylsulfonyl Amino)-2-(3-methylureido)propane The reaction was allowed to proceed in the same manner as in Example 8 using f2, and the post-treatment was carried out. 3-iodopropylsulfonylamino)-1-octadedylcarbamoyloxypropane-1] was reacted and post-treated in the same manner as in Example 8. The preparation and physical properties of the product are shown in Table 9. .

Example 44 Preparation of 1-year-old ctadezylcarbamoyloxy-2-methoxycarbonylamino-3-(3-quinoliniopropylsulfonylamino)propane iodite Ie5 3-(3-iodopropylsulfonylamino)-2-methoxycarbonylamino Using -1-octadecylcarbamoyloxypropane 11, the reaction was allowed to proceed in the same manner as in Example 25, and the post-treatment was carried out. Table 10 shows the amount charged and the physical properties of the product.

(The following is a blank space) Example 45 Production of 2-tert-butoxycarbonylamino-tadecylcarbamoyloxy-3-(3-quinoliniopropylsulfonylamino)propane iodite Ie6 ℃, React in the same manner as in Example 25, Post-treatment Do the following. Table 10 shows the amount charged and the physical properties of the product.

Example 46 Preparation of 2-acetamido-1-ctadezylcarbamoyloxy-3-(3-quinoliniopropylsulfonylamino)propane iodite 1 e2 2-tert-butoxycarbonylamino-3-(3
-Iodopropylsulfonylamino>-1-octadecylcarbamoyloxypropane-1[e2 using 2-acetamido-3-(3-iodopropylsulfonylamino)-1-octadecylcarbamoyloxypropane J
The reaction was allowed to proceed in the same manner as in Example 25 using Lm, and post-treatment was performed. Table 10 shows the amount charged and the physical properties of the product.

Example 47 Preparation of 1-year-old ctadezylcarbamoyloxy-2-(3-methylureido)-3-(3-quinoliniopropylsulfonylamino)propane)'If3 3-(3-iodopropylsulfonylamino)- 2-(
3-Methylureido)-1-octadecylcarbatomoyloxypropane and post-treatment. Table 10 shows the amount charged and the physical properties of the product.

Example 48 1-hexadecylthio-2-methoxycarbonylamino-3- (3-quinoliniopropylsulfonylamino)
Propane iodite 1 Rainbow production e3 1-hexadecylthio-3-(3-iodopropylsulfonylaminopropane I [e3 was used, the reaction was allowed to proceed in the same manner as in Example 25, and the post-treatment was carried out. Amount charged and physical properties of the product are shown in Table 10.

(Leaving space below) Example 49 Production of 2-tart-butoxycarbonylamino-1-hexadecylthio-3-(3-quinoliniopropylsulfonylamino)propane iodite Ie8 e4 2-tert-butoxycarbonylamino-1-hexadecylthio-3 - Using (3-iodopropylsulfonylamino)propane IIe4, react in the same manner as in Example 25, and perform post-treatment. The amount charged and the physical properties of the product are shown in Table 1O.

Example 50 2-acetamido-1-hexadecylthio-3-(3-
Using the year of manufacture of quinoliniopropylsulfonylamino)propane iodite 1C, the reaction was carried out in the same manner as in Example 25, and the post-treatment was carried out. Table 10 shows the amount charged and the physical properties of the product.

Example 51 1-hexadecylthio-2-(3-methylureido)-
Production of 3-(3-*noliniopropylamino)propane iodite 1 g2 f2 2-acetamido-1-hexadecylthio-3-(3-
Iodopropylsulfonylamino)furopane l-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-(3-methylureido)propane Using Mf2, react in the same manner as in Example 25, and perform post-treatment. Table 10 shows the amount charged and the physical properties of the product.

(Left below) Example 52 Production of 2-acetamido-3-(N-acetel-3-quinononiopropylsulfonylamino)-1-octadecylcarbamoyloxypropane on iodite Using 3-iodopropylsulfonylamino)-1-octadedylcarbamoyloxypropane IC, the reaction was carried out in the same manner as in Example 25, and the post-treatment was carried out. Table 10 shows the charge amount and the product.

(Hereafter - blank space) Reference Example 76 1-tert-Butyldimethylsilyloxy-3-triphenylmethoxypropan-2-ol Production of tart-butyldimethylsilyl chloride 14.2g (
94mM) and imidazole 12.8g (198mM
) in 200 ml of dimethylformamide and stirred at room temperature. After 30 minutes, 3-triphenylmethoxy-1,2-propanediol th 3
1°45g (94mM) dimethylformamide 10
After dropping 0 ml of the solution, the mixture is stirred at room temperature for 2 hours.

Pour the reaction solution into a mixture of ice water and dichloromethane and extract. The dichloromethane solution was further washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was separated and purified by silica gel chromatography to obtain 40.7 g of the title compound 2h as an oily substance, eluent: toluene-toluene-ethyl acetate (9:1) in a yield of 96. NMR: l;ppm (CDC1,) 0.02
& 0.03 (s, 3H each).

0.84 (s, 9H), 2.46 (d, J=5H
z, LH).

3.14 (ABX, J=9.2 & 5.84H2,
IH), 3.22 (ABX, J=9.2 & 5.7
6Hz, LH), 3.67 (ABX.

J=9.40. & 4.91Hz, LH>, 3.70
(ABX.

J:9.40 & 3.09Hz, LH), 3.75
-3.9 (m.

IH), 7.1-7.5 (m, 15H) (blank below) Reference Example 77 1-tart-butyldimethylsilyloxy-2-(5
-Methyl-2H-tetrazol-2-yl)-3-triphenylmethoxypropane and 1-tart” butyldimethylsilyloxy-2-(5-methyl-LH-tetrazol-1-yl)-3-triphenyl Preparation of methoxypropane 31 1-tart-butyldimethylsilyloxy-3-triphenylmethoxypropan-2-ol zht, og(
2,23mM), triphenylphosphine 877n+g
(3,35mM), and diethyl azodicarboxylate 0.
53ml (3,35mM>) was dissolved in 30ml of THF, and 281mg of 5-methyltetrazole was stirred at 0°C.
(3.35mM) was added little by little. The reaction solution was stirred at room temperature for 15 hours, then poured into a mixture of saturated aqueous sodium bicarbonate solution and dichloromethane and extracted. The obtained residue was subjected to silica gel chromatography to obtain the title compound 3hO, 74 g (yield: 64%) and 3i, 0.36 g.
(Yield 31%) is obtained.

[Elution solvent: n-hexane-toluene (1:1) to toluene-ethyl acetate (9: t) co-compound 3h oily substance NMR: Sppm (CDC1,) -0,10 (s
, 38), -0,08 (s, 3H), 0.74 (
s, 9H), 2.54 (s, 3H), 3.57 (A
BX, J=9.8 & 4.6Hz, IH), 3.6
3 (ABX.

J:9.8 & 7.6Hz, IH), 4.0-4.
15 (m, 2H).

4.95-5.15 (m, IH), 7.1-7.3
5 (m, 15H)'.

Compound oil NMRs Spm (CDC1,) -0,
16 (s, 3H), -0,09 (s, 3H), 0
．． 73 (s, 9H), 2.56 (s, 3H),
3.59 (ABX, J=9.8 & 5.6Hz, LH
), 3.67 (ABX.

J=9.8 & 9.4Hz, IH), 3.9
1 <ABX, J=10.4 &9.9Hz, LH
), 3.97 (ABX, J=LQ, 4 & 5.9
%%2゜LH), 4.35-4.5 (m, IH
), 7.15-7.4 (m, L5H).

(Left below) Reference Example 78 2-(5-Methyl-2H-tetrazol-2-yl)-
Preparation of 3-triphenylmethoxypropatol 4h 1-tart-butyldimethylsilyloxy-2-(5
-Methyl-2H-tetrazol-2-yl)-3-triphenylmethoxypropane 17.2g (33.4m
After dissolving M) in 300 ml of tetrahydrofuran, 1
M Tetra-n-butylammonium fluoride solution in tetrahydrofuran 36.8+++1 (36.7m
Drop M). After stirring for 10 minutes at room temperature, the reaction solution was poured into a mixture of ice water and dichloromethane and extracted. The dichloromethane layer was washed once with water and once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue is separated and purified by silica gel chromatography using toluene-ethyl acetate (9:1) as an eluent to obtain 12.8 g (yield 96z) of the title compound 4h. Melting point 126 (27°C (recrystallized from dichloromethane-methanol) NMR: εppm (CDCIs) 2.49 (s
, 3H), 2.94 (t, J=6.5Hz, LH),
3.6-3.75 (m, 2H).

3.95-4.3 (m, 2H), 4.9-5.1
(m, LH).

7.15-7.45 (m, 15H).

Reference Example 79 2-(5-methyl-IH-tetrazol-1-yl)-
Preparation of 3-triphenylmethoxypropatool 41 1-tart-butyldimethylsilyloxy-2-(5
-Methyl-IH-tetrazol-1-yl)-3-triphenylmethoxypropane 3i 5.92g (12m
12.7 ml of tetrahydrofuran solution of IM tetra n-butylammonium fluoride (12.7 ml)
, 7mM) in 100ml of tetrahydrofuran and post-treated in the same manner as in Reference Example 78 to obtain the title compound 4i4.
17 g (yield 911) was obtained. m, p, 148-15
0°C NMR: Sppm (CDC1,) 2.49
(s, 3H), 3.5-3.65 (m, 3H),
3.9-4.2 (m, 2H), 4.35-4.5 (
m, LH), 7.1-7.35 (m, 15H).

(Left below) Reference Example 80 1-n-hexadecylthio-2-(5-methyl-IH-
Preparation of 2-(5-methyl-IH-tetrazol-1-yl)-3-triphenylmethoxypropane 51
3-Triphenylmethoxypropertool 4i 1.86
g (4.6mM) and triethylamine 0.71ml
(5.1mM) was dissolved in 50ml of dichloromethane and
°C, under stirring, 0.38 ml of methanesulfonyl chloride
(4.8mM) was added dropwise, the mixture was gradually returned to room temperature and left overnight.

The reaction solution is poured into a mixture of ice water and dichloromethane and extracted. The dichloromethane layer was washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the methanesulfonate. 204 mg (5.1 m) of sodium hydride (60% oily suspension) and n-hexadecyl mercaptan (98% purity) 1
．． 75ml (5.5mM) in 20ml of benzene
After cooling the reaction solution, which was reacted at 0°C for 30 minutes, 20 ml of the above methanesulfonate benzene was added. Add liquid J dropwise, then dicyclohexyl-18-crown-61
After adding 00 mg, react at room temperature for 4 hours.
The reaction solution was poured into a mixture of ice water and ethyl acetate and extracted. The ethyl acetate layer was washed once with water and once with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was separated and purified by silica gel chromatography using toluene-ethyl acetate (9:1) as an eluent, to obtain 2.97 g of the title compound 5i (yield: 1
00%) as an oil.

NMR: Sppm (CDC1,) 0.88 (
t, J=6) 1z, 3H).

2.21 (t, 7.5Hz, 2H), 2.56
(s, 3H).

2.99 (d, J=7.2Hz, 2H), 3.62
(ABX, J: 10 & 4.9Hz, IH), 3.6
8 (ABX, J=10 & 8.2Hz.

1) 1), 4.2-4.4 (-11>, 7.
1-7.4 (m, 15H).

Reference Example 81 3-n-hexadecylthio-2-(5-methyl-IH-
Tetrazol-1-yl) propatool Vil (7) Preparation 1-n-hexadecylthio-2-(5-methyl-IH-
2.90 g (4.5 mM) of tetrazol-1-yl)-3-triphenylmethoxypropane in methanol.
170 mg of p-toluenesulfonic acid hydrate (0,9
The reaction solution was poured into a mixture of ice water and ethyl acetate containing 151 mg (1.8 mM) of sodium bicarbonate and extracted. After washing the ethyl acetate once with saturated brine, drying over anhydrous magnesium sulfate, and distilling off the solvent. The resulting residue is separated and purified by silica gel column chromatography to obtain the title compound Lt, 4ag (yield: 81%). (Elution solvent: toluene-ethyl acetate (4:l~1:1>,',;
Chloromethane-methanol Yosu recrystallization mp 77-7
8℃) NMR: Sppm (CDCIs) 0.88 (
t, J=7Hz, 3H).

1.4-1.6 (+n, 2H), 2.34 (t,
, c7.4Hz, 2H).

2.59 (s, 3H), 3.03 (ABXJ=1
4.4 &10.1Hz, IH), 3.07 (AB
X, J=14.4 &5.9Hz, IH), 4.08
(ABX, J=IQ, a & 3.2Hz.

LH>, 4.15 (ABX, J=10.8 & 7
．． 6Hz, IH).

4.35-4.55 (m, IH).

(Left below) Reference Example 82 2-(5-Methyl-IH-tetrazol-1-yl)-
Preparation of 3-n-octadecylcarbamoyloxypropanol 2-(5-methyl-IH-tetrazol-1-yl)-
3-triphenylmethoxypropan-1-ol 4i
1.9g (4,7mM) and n-octadecyl isocyanate 20ml (5,6mM) in pyridine 40f
f11, stirred at room temperature for 60 hours, and heated at 60°C for 2 hours. After cooling the reaction solution, the solvent was distilled off, and the residue was poured into a mixture of ice water and dichloromethane and extracted. After washing the dichloromethane station once with saturated saline,
Dry over anhydrous magnesium sulfate and evaporate the solvent. The obtained residue was separated and purified by silica gel column chromatography using toluene-ethyl acetate (9:1 to 2:1) as an eluent to obtain 1.84 g of 1-n-octadecyl carbamate containing some impurities. obtain. 1-n-octadecyl carbamate obtained above 1.84
g was dissolved in 50 ml of methanol-tetrahydrofuran (1:1) mixture to obtain 1 p-toluenesulfonic acid hydrate.
Add 50 mg (0,79a+M) and leave overnight at room temperature.6. Add 132 mg of sodium bicarbonate to the reaction solution.
Pour into a mixture of ice water and dichloromethane containing (1.6mM) and extract. The dichloromethane layer is washed once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off.The resulting residue is transferred to a silica gel column. Separation and purification by chromatography yielded the title compound 6i1.05&
<Yield 49% from ■> Elution solvent: Toluene-ethyl acetate-1/1~l/~ethyl acetate; Recrystallized from dichloromethane-methanol Melting point 80-83°C] NMR: Sppm (CDCIs) 0.88
(t, J=6.4Hz, 3H).

1.4-1.6 (m, 21(), 2.54 (s
, 3H), 3.13 (quartet, J=6.4
Hz, 21 (), 4.0-4.25 (m.

2M), 4.38 (ABX, J=11.8 &
8.3) 1z, IH).

4.56 (ABX, J=11.8 & 4.5Hz,
IH), 4.65-4.8 (m, IH),
5.01 (t, J=5.7) 1z, IH) Reference Example 83 Production of 1-n-hexadecylthio-2-(5-methyl-gotetrazol-2-yl-3-triphenylmethoxypropane 5h 2- (5-methyl-2H-tetrazol-2-yl)-
3-triphenylmethoxypropertool 4h 6.50
g (16mM), triethylamine 2.5ml (18
mM) and methanesulfonyl chloride 1.3 ml (
17mM) in 150ml of dichloromethane, Reference Example 80
The reaction and post-treatment are carried out in the same manner as above to obtain the methanesulfonate compound. Subsequently, 0.71 g (1
8-) and n-hexadecyl mercaptan (purity 98
%) 4.70g (18mM) in 150ml of benzene and post-treated in the same manner as in Reference Example 80 to obtain the title compound. However, although the obtained product contains a small amount of impurities, it can be purified after deprotecting the trityl group.

NMR: Sppm (CDC1,) 0.88 (
t, J=7Hz, 3H).

2.34 (t, J=7.5Hz, 2H), 2.55
(s, 3H).

3.05 (d, J=7.2Hz, 2H), 3.60
(ABX, 10 & 5.0Hz, LH), 3.6
6 (ABX, J=10 & 7.3Hz.

LH), 4.9-5.1 (m, IH), 7.15
-7.5 (m.

15H).

(Left below) Reference Example 84 Production of 3-n-hexadecylthio-2-(5-methyl-4-tetrazol-2-yl)propatool Vhl 1-n-hexadecylthio-2-(5-methyl-4-tetrazol- 10.2 g of crude product of 2-yl)-3-triphenylmethoxypropane 5h, 500 mg of p-toluenesulfonic acid hydrate (2.6 mM)
) /-tetrahydrofuran (1: l) 200m
1, the reaction and post-treatment were carried out in the same manner as in Reference Example 81 to obtain 3.17 g of the title compound (yield: 49% from Compound X).
get.

NMR8ppm (CDCIs) 0.88 (t,
J=7Hz, 3H).

1.45-1.65 (m, 2H), 2.48 (t
, J=7.4Hz, 2B).

2.52 (s, 3H), 3.08 (ABX, J=
14.6 & 7.6Hz.

IH), 3.12 (ABX, J: 14.6 & 7
．． 4Hz, LH).

4.16 (ABX, J=12.4 & 4.3Hz,
1) 1), 4.19 (ABX, J=12.4 & 7
．． 7Hz, IH), 4.9-5.1 (m, LH)
.

(Left below) Reference Example 85 2-(5-methyl-2H-tetrazol-2-yl)-
Preparation of 3-n-octadecylcarbamoyloxypropanol Vh2 2-(5-methyl-2H-tetrazol-2-yl)-
3-Triphenylmethoxypropertool 6h 5.71
g (14mM) and 5.9ml (17mM) of n-octadecyl isocyanate in 120ml of pyridine are reacted and post-treated in the same manner as in Reference Example 82 to obtain a carbamate. However, a small amount of Although it contains some impurities, it can be purified after deprotecting the trityl group.

2-(5-methyl-2H-tetrazol-2-yl)-
5.74 g of crude product of 1-n-year-old ctadezylcarbamoyloxy-3-triphenylmethoxypropane, 400 mg of p-toluenesulfonic acid hydrate (2.1 mM)
methanol-tetrahydrofuran (L:L) 150m
The reaction and post-treatment were carried out in the same manner as in Reference Example 82 to obtain 23.39 g of the title compound Vh. (The yield is 5% based on the compound color.
2%) m, p, 7 lo-77°C1 NMRF 8 pp
m (CDC1,) 0.88 (t, J=7)1z
, 3) 1).

1.35-1.55 (m, 2H), 2.54 (s
, 3H), 3.14(quartet, J=6.5H
z, 2H), 4.14 (d.

J=5.8Hz, 2H), 4.55-4.7 (m,
2H), 4.8-4.95 (m, IH), 5.0
-5.2 (m, 1)1).

(Left below) Reference Example 86 3-n-hexadecylthio-2-(5-methyl-IH-
Tetrazol-1-yl)butyramine IVi13-
Using n-hexadecylthio-2-(5-methyl-IH-tetrazol-1-yl) propatool 5i, the reaction was allowed to proceed in the same manner as in Reference Example 3, and the amount of charge and physical properties of the product were Shown in Table and Table 6.

The obtained phthalimide compound is directly subjected to the next reaction.

Reference Example 87 3-(3-chloropropylsulfonylamino)-1-n
-hexadecylthio-2-(5-methyl-IH-tetrazol-1-yl)propane 1[[il Preparation 3-n
Using -hexadecylthio-2-(5-methyl-IH-tetrazol-1-yl)propylamine Nil, react in the same manner as in Reference Example 4 and perform post-treatment, m, p,
62-62.5℃, the amount of charge and the physical properties of the product
Shown in the table.

The yield is that of the 3-hydroxy compound 51.

(Margin below) 1ril Reference Example 88 1-n-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-(5-methyl-IH-tetrazol-1-yl)propane I[1lya, p,
63.5-65.5°C, the amount charged and the physical properties of the product are shown in Table 8.

Example 53 1-n-hexadecylthio-2-(5-methyl-IH-
Tetrazol-1-yl)-3-(3-trimethylammonioprobylsulfonylaminopropane iodide 1
Production of u 11i1 3- (3-chloropropylsulfonylamino)-1-
A reaction is carried out in the same manner as in Reference Example 5 using n-hexadecylthio-2-(5-methyl-IH-tetrazol-1-yl)propane Iil, and post-treatment is performed.

A reaction was carried out in the same manner as in Example 8 using 1-n-hexadecylthio-3-(3-iodopropylsulfonylamino")-2-(5-methyl-IH-tetrasily-1-yl)propane f[il, Table 9 shows the amount of charge and the physical properties of the product for post-treatment.

Reference Example 89 2-(5-methyl-IH-tetrazol-1-im)-
Production of 3-n-octadecylcarbamoyloxypropylamine L■i2 2-(5-methyl-IH-tetrazol-1-yl)-
3-n-octadecylcarbamoyloxypropanol Vi 21.02g (2,25mM), triphenylphosphine 885mg (3,38mM), and 1.8
1.9 ml of mM hydrogen azide benzene solution (3.38 m
M) was dissolved in 50 ml of tetrahydrofuran and heated to -50°C.
Under cooling, diethyl azodicarboxylate 0.53 ml (3
, 3B+nM).

The temperature of the reaction solution is raised to 0° C. over 2 hours. Next, 150 mg of 10% Pd carbon powder is added to the reaction solution and reacted for 30 minutes under a hydrogen stream. After filtering off the 10% Pd carbon powder, the solvent is distilled off. The obtained residue was separated and purified by silica gel column chromatography using ethyl acetate - chloroform - methanol (9:1) as an eluent, to give 20.82 g of the title compound IVi (yield 8).
1%).

NMR: δppm (CDCIn) 0.88 (
t, J=7Hz, 3H).

2.52 (s, 3H), 3.13 (quarte
t, J = 6.6Hz.

28), 3.15-3.45 (m, 2H), 4.
23 (ABX, J=12.6 & 9.8Hz, IB
), 4.52 (ABX, J=12.6 &4.2H
z, 11), 4.5-4.65 <m, 1% (),
5.07 (t.

J=6Hz, IH).

Reference Example 90 3-(3-chloropropylsulfonylamino)-2-
(5-methyl-IH-tetrazol-1-yl)-1-
Preparation of n-octadecylcarbamoyloxypropane 1 Using amine ff12, the reaction was carried out in the same manner as in Reference Example 4, and the post-treatment was carried out. Shown in the table.

Reference Example 91 3-(3-iodopropylsulfonylamino)-2-
(5-methyl-IH-tetrazol-1-yl)-1-
n-octadecylcarbamoyloxypropane! [i2
Production fi2 (hereinafter blank) 2-(5-methyl-IH-tetrazol-1-yl)-
3-n-ktadecyl rubamoyl xypropylene 111
i2 Example 54 2-(5-methyl-IH-tetrazol-1-yl)-
1-n-octadecylcarbamoyloxy-5-(3-
Preparation of quinoliniopropylsulfonylamino)propane iodite Ii3 3-(3-chloropropylsulfonylamino)-2-
(5-methyl-IH-tetrazol-1-yl)-1-
n-octadecylcarbamoyloxypropane lff1
Table 8 shows the m, p, 82.5-83.5°C, charge amount, and physical properties of the product.

(Left below) 3-(3-iodopropylsulfonylamino)-2-(
3-Methyl-IH-tetrazol-1-yl)-1-n
--Octadecylcarbamoyloxypropane 1[i2
Table 10 shows the amount charged and the physical properties of the product.

Reference Example 92 Production of 3-n-hexadecylthio-2-(3-methyl-4-tetrazol-2-yl)propylamine yht Reference Example 93 3-(3-chloropropylsulfonylamino)-1-
〇-Hexadecylthio-2-(3-methyl-2H-tetrazol-2-yl)propane Ii [hl Production Vh1 3-n-hexadecylthio-2-(3-methyl-anti-tetrazol-2-yl)propane Using tool vh1,
Tables 5 and 6 show the phthalimide m, p, 82-83°C, charge amount, and physical properties of the product, which were reacted and post-treated in the same manner as in Reference Example 3.

Using 3-n-hexadecylthio-2-(3-methyl-4-tetrazol-2-yl)propylamine, reaction and post-treatment were carried out in the same manner as in Reference Example 4. The amount charged and the physical properties of the product were determined. It is shown in Table 7.

Reference Example 94 Production of 1-n-hexadecylthio-5-(3-iodopropylsulfonylamino)-2-(5-methyl-2H-tetrazol-2-yl)propane l1hl Reference Example 5
React and post-process in the same manner as above.

Table 8 shows m, p, 50-51°C, charge amount, and physical properties of the product.

Example 55 1-n-hexadecylthio-2-(3-methyl-4-tetrazol-2-yl)-3-(3-trimethylammoniopropylsulfonylamino)propane iodite
Ih1 ht 3- <3-chloropropylsulfonylamino)-1-
Using n-hexadecylthio-2-(3-methyl-2H-tetrazol-2-yl)propane II [hl, 1
-n-hexadecylthio-5-(3-iodopropylsulfonylamino)-2-(5-methyl-2H-tetrazol-2-yl)propane was reacted in the same manner as in Example 8, and after-treatment was carried out. Table 9 shows the amount of charge and the physical properties of the product.

Reference Example 95 2-(5-methyl-2H-tetrazol-2-yl)-
Preparation of 3-n-octadecylcarbamoyloxypropylamine lbutyrolysis h2 2-(5-methyl-2H-tetrazol-2-yl)-
3-n-octadecylcarbamoy J leoxypronol 2.57g (5.7m old, triphenylphosphine 2
．． 23g (8.6mM), 4.7ml (8.6mM) of a 1.8mM hydrogen azide benzene solution, and 1.44g (8.6mM) of diethyl azodicarboxylate were reacted in tetrahydrofuran in the same manner as in Reference Example 89. Get a body. To the above reaction solution of the azide compound, 350 mg of 10% Pd/C is added without post-treatment, and the reaction and post-treatment are carried out in the same manner as in Reference Example 89 to obtain the title compound IVh2.

However, the obtained product contains a small amount of impurities,
After 3-chloropropylsulfonylamination, it can be purified.

NMR: sppm (CDC1m) 0.88 (
t, J=6.5Hz, 3H).

1.4-1.65 (m, 2H), 2.55 (s,
3H), 3.12(quartat, J=6.61(
z, 2H), 3.25-3.35 (m, 2H), 4
．． 47 (ABX, J=11.6 & 8゜OHz.

LH), 4.59 (ABX, J=11.6 & 4
．． 1Hz, LH).

4.8-4.95 (m, IH), 4.95-5.1
(m, IH).

Vh2 Reference Example 96 3- (3-chloropropylsulfonylamino)-2-
(5-methyl-2H-tetrazol-2-yl)-1-
〇-octadecylcarbamoyloxypropane I [h2
Allow the production of, perform post-processing, m, p, 70-70.5℃,
Table 7 shows the amount charged and the physical properties of the product.

The yield is the yield from the hydroxy form Vh2.

Reference Example 97 3-(3-iodopropylsulfonylamino)-2-(
5-methyl-2H-tetrazol-2-yl)-1-n
-Octadezylcarbamoyloxypropane Vh2 11h3 2-(5-methyl-2H-tetrazol-2-yl)-
The reaction 3-(3-
Using chloropropylsulfonylamino)-2-(5-methyl-2H-tetrazol-2-yl)-1-〇-octadedylcarbamoyloxypropane 111h3,
React and post-process in the same manner as in Reference Example 5, n+,
Table 8 shows p, 53.5-54°C, charge amount, and physical properties of the product.

Example 56 2-(5-methyl-2H-tetrazol-2-yl)-
Preparation of 1-n-octadecylcarbamoyloxy-(3-quinoliniopropylsulfonylamino)propane iodite Ih3 3-(3-iodopropylsulfonylamino)-2-(
5-methyl-2H-tetrazol-2-yl)-1-n
- Using octadecylcarbamoyloxypropane 1[h2, the reaction is carried out in the same manner as in Example 25, followed by post-treatment. Table 10 shows the amount charged and the physical properties of the product.

Reference Example 98 1-tart-butyldimethylsilyloxy-2-(3
-inxazolyloxy)-3-triphenylmethoxypropane production 1-tart-butyldimethylsilyloxy-3-triphenylmethoxypropan-2-ol 2h6.72g
(15mM), 3-hydroxyinxazole 1.53
g (18mM>, triphenylphosphine 4.71g
(18mM) and diethyl azodicarboxylate 3.
10g (18mM) was reacted and post-treated in the same manner as in Reference Example 77 in 100ml of tetrahydrofuran to obtain 7.24g (yield 94%) of the title compound.

NMRr 8ppm (CDC1,) 0 & 0.
01 (s, 3H each).

0.82 (s, 9H), 3.36 (ABX, J=
10.2 & 5.31Hz, 18), 3.47 (A
BX, J=10.2 & 4.09゜IH), 3.9
6 (d,,c5.2Hz, 21(), 4.85-5
．． 0 (m, LH), 6.01 (d, J=1.6Hz
, LH), 7.15-7.6 (m, 15H), 8
．． 13 (d.
-isoxazolyloxy)-3-triphenylmethoxypropay 3J 7.24 g (1,4 mM>) and 15.4 ml (15 mM) of a tetrahydrofuran solution of IH tetra-n-butylammonium fluoride in 100 ml of tetrahydrofuran, Reference Example 78 Reacts similarly to,
After post-treatment, 45.37 g of the title compound J (yield 95%) was obtained.
).

NMR! Sppm (CDCIm) 2.31 (
t,, c6Hz, IH).

3.40 (ABX, J=10.2 & 4.89Hz
, LH), 3.50 (ABX, J=10.2 & 4
．． 51Hz, IH), 3.94 (quartet, J
=4.6Hz, IH), 3.96 (quartet
.

J=4.6Hz, IH), 4.85-4.95 (m
, IH), 6.01 (d, J=1.8Hz, IH),
7.15-7.55 (m, L5H).

8, 12 (d, J=1.81Hz, 1)1).

(The following is a blank space) Reference Example 100 1-n-hexadecylthio-2-(5-isoxazinoloxy)-3-1-liphenylmethoxybroban phantom production 2-(3-isoxazolyloxy)-3- ) Riphenylmethoxyprobanol ij0.17 g (0.42m
M), triethylamine 65μm (0,46mM) and methanesulfonyl chloride 34μm (0,44mM)
) in 4 ml of dichloromethane and post-treated in the same manner as in Reference Example 80 to obtain methanesulfonate. Subsequently, the above methanesulfonate, 18 mg (0.46 mM) of sodium hydride (60% oily suspension) and f
i-hexadecyl mercaptan (purity 98%>0.1
2g (0.46mM) in 6ml of benzene, Reference Example 8
The reaction and post-treatment were carried out in the same manner as in 0, and the title compound 540.1
9 g (70% yield) are obtained. Crane, 9.41-44℃
.

NMR: εppm (CDCIm) 0.88 (t
, J=7Hz, 3H).

2.48 (t,,c7.3Hz, 2B), 2.96
(d.

, C7,8Hz, 2H), 3.38 (ABX, J=
10.2 & 4.78Hz, IR), 3.52 (A
BX, C10, 2 & 3°98Hz, IH), 4.9
-5.05 (m, LH), 6.00 (d, J=1.
8Hz, IH), 7.15-7.5 (m, 15H)
.

8.11 (d, J=1.8Hz, LH>Reference Example 101 Production of 3-n-hexadecylthio-2-(5-inxazolyloxy)propanol XU 1-n-hexadecylthio-2-<3-iso xazolyloxy)-3-triphenylmethoxypropane 547,
30 g (11 mM), 433 mg (2.3 mM) of p-toluenesulfonic acid-hydrate in 150 ml of methanol-tetrahydrofuran (1:1) Example 81
The reaction and post-treatment were carried out in the same manner as in 4.25.
g (yield: 94%).

NMRil; ppm (CDC1m) 0.88
(t,, C6, 2Hz, 3H).

1.45-1.7 (m, 2H), 2.5 (bro
ad, IH).

2.60 (t, J=7.4Hz), 2.87 (A
BX, J=12.8 & 6.48Hz, IH), 2.
95 (ABX, J=12.8 &3.52Hz, LH
), 3.92 (ABX, J=13.0 &4
．． 8Hz, LH), 4.01 (ABX,, C13,
0 & 3.2Hz.

18), 4.8-4.9 (m, IH), 5.99
(d.

J=1.8Hz, LH), 8.13 (d, J=1.
Reference Example 102 Production of 3-n-hexadecylthio-2-(5-inxacinoloxy)propylamine 3-n-hexadecylthio-2-(5-inxacinoloxy)propylamine Tables 5 and 6 show the phthalimide m, p, 73-74°C, the amount charged, and the physical properties of the product, which were subjected to reaction preparation and post-treatment in the same manner as in Reference Example 3 using Tool Island.

Reference example 103 3-(3-'70 propylsulfonylamino-1-n
-Hexadecylthio-2-(5-inxazolyloxy)propane Reference Example 104 1-n-hexadecylthio-5-(3-iodopropylsulfonylamino)-2-(3-isoxazolyloxy)propane One-time production Ij1 3-n-hexadecylthio-2-(5-inxacinoloxy)propylamine is reacted in the same manner as in Reference Example 4, and post-treatment is performed. Charge amount and physical properties of the product. are shown in Table 7.

3-(3-chloropropylsulfonylamino)-1-n
-Hexadecylthio-2-<3-isoxazolyloxy)propane", was reacted and post-treated in the same manner as in Reference Example 5.
Shown in the table.

Example 57 1-n-hexadecylthio-2-(5-isoxazinoloxy)-3-(3-trimethylammoniopropylsulfonylamino)propane Produced by Iodite Co., Ltd. Using the oxy)propane reaction Example 8 Table 9 shows the amount charged and the physical properties of the product, which was reacted and post-treated in the same manner as above.

Reference example 105 3- (3-chloropropylsulfonylamino)-2-
(3-Isoxazolyloxy)-1-n-octadecylcarbamoyloxypropane production Vj2 1-n-hexadecylthio-5-(3-iodopropylsulfonylamino)-2-(3-isoxazolyl 2-(
3-Inxazolyloxy)-1-n-octadecylcarbamoyloxypropylamine, react in the same manner as in Reference Example 4, and perform post-treatment, m, p, 63
．． 5-65°C, charge amount and physical properties of the product are shown in Table 7.

Reference Example 106 3-(3-iodopropylsulfonylamino)-2-(
Production of 3-(3-chloropropylsulfonylamino)-2-(3-inxazolyloxy)-1-n-octadecylcarbamoyl Oxypropane! Table 8 shows the amount of charge and the physical properties of the product.

Example 58 2-(3-Inxazolyloxy)-1-n-old ctadezylcarbamoyloxy-5-(3-trimethylammoniopropylsulfonylamino)propane Production of Iodite 1 song I [j2 ■j2 3-( 3-iodopropylsulfonylamino)-2-(
Table 9 shows the amount of charge and the physical properties of the product. Shown below.

(Left below) Example 59 Production of 2-(3-isoxazolyloxy)-L-tt-octadenylrubamoyloxy-5-(3-quinoliniopropylsulfonylamino)propane iodite-IW 3-(3- iodopropylsulfonylamino)-2-(
3-Isoxazolyloxy)-1-n-octadecylcarbamoyloxypropane was reacted and post-treated in the same manner as in Example 25. The amount charged and the physical properties of the product are shown in Table 10. .

(Left below) Reference Example 107 Production of 3-n-hexadecyloxy-2-methoxymethylpropylamine L■K1 Same as Reference Example 3 using 3-n-hexadecyloxy-2-methoxymethylpropanol vht react to,
Post-processing, phthalimide m, p, 49-5
Table 5 and 6 show the charging amount and physical properties of the product at 1°C.
Shown in the table.

Reference Example 108 3-(3-chloropropylsulfonylamino)-1-
Production Reference Example 109 of 1-n-hexadecyloxy-5-(3-iodopropylsulfonylamino)-2-methoxymethylpropane
Production of Ikl Vkl fik1 Using 3-n-hexadecyloxy-2-methoxymethylpropylamine IVkl, reaction is carried out in the same manner as in Reference Example 4, followed by post-treatment, m, p, 44-46.5°C.

Table 7 shows the amount charged and the physical properties of the product.

3- (3-chloropropylsulfonylamino)-1-
Using n-hexadecyloxy-2-methoxymethylpropane II [kl, allow reaction and post-treatment in the same manner as in Reference Example 5. m, p, 42.5-44°C, amount charged and physical properties of product. are shown in Table 8.

Reference Example 110 Production of 3-(N-acetyl-3-iodopropylsulfonylamino)-1-n-hexadecyloxy-2-methoxymethylpropane I 10
ml and added 0.39 ml (2.2 mM) of N,N-diisopropylethylamine under stirring at 0°C.
The 0 reaction solution, which was reacted at 0°C for 3 hours, was poured into ice water.
Extract. The dichloromethane layer was washed once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was separated and purified by silica gel column chromatography using toluene-ethyl acetate (9:1) as an eluent to obtain the title compound 1 [kl'0.81 (yield 99%).

NMRS ppffi (CDCL)' 0.88
(t, J: 6Hz, 3)1).

1.95-2.15 (m, IH), 2.2-2.4
5 (m, 2B>.

2.38 (s, 3H), 3.29 (t, J: 5H
z, 2H), 3.32 (s, 3H), 3.59 (
t, J=8Hz, 2H), 3.82 (d.

J=6Hz, 2H).

(Left below) 1-n-hexadecyloxy-5-(3-iodopropylsulfonylamine)-2-methoxymethylpropane
I[kl O, 76g (1,3mM), acetylchlora Example 60 3-(N-acetyl-3-trimethylammoniopropylsulfonylamino)-1-n-hexadecyloxy-
2-Methoxymethylpropane iodite The amount of charge and the physical properties of the product that can be reacted and subjected to post-treatment in the production of Ikl are shown in Table 9.

Example 61 1-n-1\xadecyloxy-2-methoxymethyl-
3-(3-Trimethylammoniopropylsulfonylamino)propane iodite Preparation of Ik2c 11kl' 1[kl 3-(N-7cetyl-3-iodopropylsulfonylamino)-1-n-hexadecyloxy-2-methoxymethyl Using propane, react in the same manner as in Example 8 using 1-n-hexadecyloxy-5-(3-iodopropylsulfonylamino)-2-methoxymethylpropane I[kl, Table 9 shows the amount of charge and the physical properties of the product for post-treatment.

Example 62 1-n-hexadecyloxy-2-methoxymethyl-3
-(3-quinoliniopropylsulfonylamino)propane iodite Preparation of Ik3 1-n-hexadecyloxy-5-(3-iodopropylsulfonylamino)-
Example 25 using 1 u of 2-methoxymethylpropane
Table 10 shows the amount charged and the physical properties of the product, which was reacted and post-treated in the same manner as above.

Reference Example 111 Production of 3-n-hexadecylthio-2-methoxymethylpropylamine IVk3 Phthalimide compound, which is reacted and post-treated in the same manner as in Reference Example 3 using 3-hexadecylthio-2-methoxymethylpropylamine IVk3. m, p, 45°C6 Charge amount and physical properties of the product are shown in Tables 5 and 6.

Reference Example 112 3-(3-chloropropylsulfonylamino)-1-n
Reference Example 113 Production of 1-n-hexadecylthio-5-(3-iodopropylsulfonylamino)-2-methoxymethylpropane Vk3 11[k3 3-n-hexadecylthio Using -2-methoxymethylpropylamine IVk3, the reaction was carried out in the same manner as in Reference Example 4, and the post-treatment was performed. m, p, 41.5-43°C, the amount charged and the physical properties of the product are shown in Table 7. .

3-(3-chloropropylsulfonylamino)-1-n
-hexadecylthio-2-methoxymethylpropane I
[K3 was used to react and post-process in the same manner as in Reference Example 5. Table 8 shows the amount charged and the physical properties of the product.

Example 63 1-n-hexadecylthio-2-methoxymethyl-5-
(3-Trimethylammoniopropylsulfonylamino)propane iodite-1 was subjected to the post-production treatment of 4, and the amount charged and the physical properties of the product are shown in Table 9.

Reference Example 114 Production of 2-methoxymethyl-5-n-octadecylcarbamoyloxyprobylamine 1Vk2 k3 k2 1-n-hexadecylthio-5-(3-iodopropylsulfonylamino)-2-methoxymethylpropane I [
k3 to react in the same manner as in Example 8, 2-methoxymethyl-5-n-octadecylcarbamoyloxypropanol Vk2 to react in the same manner as in Reference Example 3, and post-treatment. p, 84-
Tables 5 and 6 show the temperature, charge amount, and physical properties of the product at 85°C.

Reference Example 115 3-(3-Chloropropylsulfonylamino)-2methoxymethyl-1-n-octadecylcarbarimoyloxypropane Reacted in the same manner as in Reference Example 4 and post-treated m. p
．． 72-73℃. The amount of charge and the physical properties of the product are
Shown in the table.

Reference Example 116 3-(3-iodopropylsulfonylamino)-2-
3- (3
-chloropropylsulfonylamino)-2-methoxymethyl-1-n-octadecylcarbamoyloxypropane, react in the same manner as in Reference Example 5, and perform post-treatment, m, p. 69-70℃.

Table 8 shows the amount charged and the physical properties of the product.

Reference Example 117 Production of 3-(N-acetyl-3-iodopropylsulfonylamino)-2-methoxymethyl-1-n-octadenylcarbamoyloxypropane IIk2' 1[k2 3-(3-iodofurobylsulfonylamino) -2-methoxymethyl-1-n-octadecylcarbamoyloxypropane-1 [k2 0.72g (1.1mM),
Acetyl chloride 88μm (1.2mM) and N,
N-diisopropylethylamine 0.25ml (1.
4mM) in dichloromethane and post-treated in the same manner as in Reference Example 110 to obtain 0.65g of the title compound -Lηl'.
(yield 85%), m. p. 71-73℃.

NMR: Sppm (CDC1.) 0.88
(t.J=6Hz.3H).

1, 4-1.6 (m.2H), 2.25-2.5
(m.3H).

2, 40 (s. 3H), 3.15 (q, J=6H
z. 21 (>, 3.30 (t.J=7Hz.3H),
3.32 (s.3H), 3.35-3.5 (m.
2H), 3.56 (t.J=8Hz.2H), 3
．． 84 (d.

J=7Hz. 2H), 4-4.2 (m.2H),
4.79 (t.

J=6Hz. IH).

(Margin below) COC)I.

1[k2 Example 64 2-Methoxymethyl-1-n-old ctadezylcarbamoyloxy-3-(3-quinoliniopropylsulfonylamino)propane Reacted in the same manner as in the production of iodite and post-treated. Charge amount Table 10 shows the physical properties of the products.

Example 65 3-(N-acetyl-3-quinoliniopropylsulfonylamino)-2-methoxymethyl-1-n-octadecylcarbamoyloxypropane Preparation of Ik6 1[k2 3-(3-iodopropylsulfonylamino)- Example 25 and 3-(N
-acetyl-3-iodopropylsulfonylamino)-
2-Methoxymethyl-1-n-octadecylcarbamoyloxypropane I[k2' was reacted and post-treated in the same manner as in Example 25. Table 10 shows the amount charged and the physical properties of the product.

(Left below) Reference Example 118 Production of 5-bromomethyl-2-phenyl-1,3-dioxane m2 119.4 g (0.1 mol) of 5-hydroxymethyl-2-phenyl-1,3-dioxane m and tetrabromination Carbon 33.
26.2 g (0.1 mol) of triphenylphosphine are added to a solution of 60 ffi1 of anhydrous benzene (1 g < 0.1 mol) at 70° C. over a period of 45 minutes with vigorous stirring. 3 more
After reacting for 0 minutes, the reaction solution was concentrated under reduced pressure. Add 200 ml of ether to the obtained residue and filter out the precipitated triphenylphosphine oxyto. After repeating this operation twice, the obtained filtrate was concentrated under reduced pressure and then distilled under reduced pressure to obtain 19.391 g ( The title compound m2 is obtained with a yield of 75.4%.

B, P, lmmHg 145-158°C Reference Example 11
9 Preparation of 5-(2-hydroxypropan-1-yl)-2-phenyl-1,3-dioxane m3 A crude product of the title compound m3 is obtained.

IR: vmax (CHCIs) 3620~31
50 am-' (broad) Reference Example 120 5- (2-hendiyloxypropan-1-yl)-
Preparation of 2-phenyl-1,3-dioxane 5-bromomethyl-2-phenyl-1,3-'; oxane rn21
Magnesium 1.923 g (75.4 mmol) in a solution of 200 ml of tetrahydro-7
9.17 mmol) and reacted at 40°C for 7 hours using an Ultrasonicator. The resulting reaction solution was heated to -78°C.
Add 21.27 ml (377 mmol) of acetaldehyde and let stand at 0°C for 15 hours. 1. Pour the reaction mixture into ice-cooled ammonium chloride water and extract with ethyl acetate. After washing the ethyl acetate with saturated brine, drying with magnesium sulfate and concentrating under reduced pressure. The resulting residue was subjected to short-path silica gel column chromatography to remove nonpolar substances, resulting in 11.353 g of the previously obtained 5-(2
-hydroxypropan-1-yl)-2-phenyl-1
, 10.829 of the crude product of 3-dioxane m3
g is dissolved in 200 ml of dichloromethane, and then 11.3 ml (97.4 mmol) of benzoyl chloride, 20.5 ml (146.1 mmol) of triethylamine, and 100 mg of dimethylaminopyridine are sequentially added under water cooling.

The reaction solution was stirred at room temperature for 15 hours, then poured into 2N hydrochloric acid and extracted with dichloromethane. The dichloromethane layer is washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue was subjected to short-path silica gel column chromatography using n-hexane-ethyl acetate (4:1) as the elution solvent.
17.125 g of the crude title compound m4 is obtained by removing the polar substances using a solvent.

IR: vmax(CHCIs) 1715 am-'
Reference example 121 2-(2-benzoyloxypropan-1-yl)-3
-Hydroxy-propatur Preparation of benzoic acid ester m5 N-bromosuccinimide 9.344 g (52,5
mmol) and 250ml of water! ! ! Drops of hydrobromic acid were added to the cloudy solution under water cooling, and with vigorous stirring, the previously obtained 5-
Crude product suspended in (2-benzoyloxypropan-1-yl)-2-phenyl-1,3-dioxane 17.125
Slowly add g. After reacting for 1 hour under water cooling,
22 g (260 mmoles) of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was further stirred for 1 hour and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was eluted using a mixture of n-hexane and ethyl acetate (1:1). By separating by silica gel column chromatography, 7.401g (yield 29.7% based on compound size)
The title compound 1115 is obtained as an oil.

IR Niji wax (CHCl,) 3600-3250
(broad).

1700 cm-' NMR: Sppm (CDCIm) 1.40 (
d, J = 2.6Hz.

1.5H), 1.43 (d, J=2.6Hz, 1.
5H), 1.67-1.99 (m, 2H), 2.
01-2.24 (m, IH), 2.51-1.52
(br, IH), 3.57-3.82 (m, 2H
), 4.32-4.60 (m, 2H), 5.26
-5.47 (m, IH), 7.37-7.67 (
m, 6H), 7.93-8.13 (m, 4H).

Reference example 122 2-(2-benzoyloxypropan-1-yl)-
Preparation of 3-octadecylcarbamoyloxypropanol benzoate ester m6 3.70 g (11,2 mmol) of 3-hydroxy-2
-(2-Benzoyloxypropan-1-yl)propatur Add 4.964 g (16.8 mmol) of octadecyl isocyanate to a solution of benzoic acid ester 1 in 74 ml of pyridine and heat at 70°C for 15 hours. 6. Heat the reaction mixture under reduced pressure. After concentration, cooled 2N hydrochloric acid solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography using n-hexane-ethyl acetate (4:1) as an eluent to obtain 6.28 g (yield: 87.8%) of the title compound m6.

IRi νmax (CHCIs) 3440.170
5 am″1NMR: Sppm (CDCIs)
0.88 (t, J=6.4Hz, 3H).

1.10-1.35 (m, 30H), 1.36-1
．． 55 (m, 5H).

1.68-2.07 (m, 2H), 2.22-2.
45 (m, IH).

2.97-3.21 (m, 2H), 4.10-4.
27 (m, 2H).

4.27-4.45 (m, 2H), 4.62-4.
83 (br.

IH), 5.28-5.50 (m, IH), 7.3
8-7.64 (m.

6H), 7.97-8.13 (m, 4H).

Reference example 123 2-(2-benzoyloxypropan-1-yl)-
Preparation of 3-methanesulfonyloxypropatur benzoate ester m11゛1.85 g (5.60 mmol) of 3-hydroxy-
2-(2-benzoyloxypropan-1-yl)propatur benzoate m5 dichloromethane 40m
Add 607 μm of methanesulfonyl chloride to the solution of 1 under water cooling.
(7.84 mmol) and triethylamine 1.34 ml
(9.52 mmol) was added and stirred. After 30 minutes, the reaction solution was poured into water-cooled 2N hydrochloric acid, washed with dichloromethane, saturated sodium bicarbonate, and then saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give the title compound m11. A crude product is obtained.

NMR: Sppm (CDC1s) 1.43 (
d, J=6.2Hz, 3H).

1.74-2.08 (m, 2H), 2.27-2.
53 (m, IH).

3.01 (s, 3) 1), 4.25-4.54 (
m, 4H), 5.27-5.47 (m, LH),
7.37-7.65 (m, 6H), 7.9! r8.
11 (m, 4H).

(The following is a blank space) Reference Example 124 2- (2-benzoyloxypropan-1-yl)-
Preparation of 3-n-hexadecylthiopropanol benzoic acid ester ml 3,858 g (14,92 mmol) of 6 ml of hexadecyl mercaptan in 100 ml of anhydrous benzene solution
Add 554 mg (13.86 mmol) of 0% oily sodium hydride and heat and stir at 50°C. After 1 hour, a solution of the previously obtained crude product 2-(2-benzoyloxypropan-1-yl)-3-methanesulfonyloxypropatur benzoate m11' in anhydrous benzene 5Il11 was added to the reaction solution. The reaction solution was heated and stirred at ℃ for 1 hour, and after cooling, it was extracted with ethyl acetate.

The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by chromatography using n-hexane-ethyl acetate (95:5) as an eluent to obtain 4.4 tags (yield 71.1%) of the title compound (ml).
get l.

NMR: δppm (CDC1,) 0.88 (t
, J=6.4Hz, 3H).

1.12-1.38 (m, 26H), 1.40 (
d, J = 6.2Hz.

3H), 1.45-1.65 (m, 2)1), 1
．． 67-2.31 (m.

3H), 2.49-2.53 (m, 2H), 2.
57-2.82 (m.

2H), 4.29-4.55 (m, 2H), 5.
26-5.45 (m.

LH), 7.36-7.63 (m, 6H), 7.
97-8.11 (m, 4H).

(Left below) Reference Example 125 2- (2-benzoyloxypropan-1-yl)-
Preparation of 3-n-octadecylcarbamoyloxypropanol m7 2,879 g (4,51 mmol) of 2-<2-benzoyloxypropan-1-yl)-3-n-octadecylcarbamoyloxybrobanol ben is ester m6 25 ml of methanol and 2 ml of tetrahydrofuran
Add 4.5 ml of 2N sodium hydroxide to 5 ml of solution under water cooling.
Add 1 ml (9.02 mmol) and stir for 2 hours.
The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate,
The solvent is distilled off. The residue was dissolved in n-hexane-ethyl acetate (2
:1) 1.72g was obtained by separating and purifying the mixture using silica gel column chromatography as an elution solvent.
The title compound m7 (yield 71.4%) is obtained.

NMR: l; ppm (CDC1,) 0.88
(t, J=6.4Hz, 3H).

1.10-1.39 (m, 30H), 1.37 (
d, J = 6.2Hz.

3H), 1.38-1.53 (m, 2H), 1.
60-1.81 (m, 2H), 1.85-2.02
(m, LH), 2.92-3.24 (m, 2H),
3.39-3.70 <m, 2H), 4.05-4.
32 (m, 2H), 4.68-4.88 (m, IH
), 5.20-5.40 (m, LH), 7.35-
7.66 (m, 3H), 8.04 (d.

J=6.8Hz, 2H) (Hereafter the margin) Reference example 126 2-(2-benzoyloxypropan-1-yl)-
Preparation of 3-n-hexadecylthiopropanol ml 4.017 g (6,89 mmol) of 2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropanol ml of benzoic acid ester methanol 38 ml and 43 ml of tetrahydrofuran, 6.89 ml of 2N sodium hydroxide (13,
78 mmol) was added, and the reaction and post-treatment were carried out in the same manner as in Reference Example 125 to obtain 2.071 g (yield 62.8%) of the title compound m12.

NMR: δppm (CDCIs) 0.88 (
t, J=6.4Hz, 3H).

1.12-1.38 (m, 26H), 1.38 (
d, J = 6.2Hz.

3) 1), 1.45-1.63 (m, 28), 1
．． 63-2.01 (m.

31 (>, 2.47 (t, J=7, OHz, 2
)%), 2.51-2.75(m, 2H), 3
．． 62-3.82 (m, 2H), 5.15-5.
42 (m, LH), 7.39-7.61 (m, 3
H), 8.04 (d.

J=7.2Hz, 2B>.

Reference Example 127 2-(2-benzoyloxypropan-1-yl)-
3-n-octadecylcarbamoyloxypropanol methanesulfonic acid ester self-produced alcohol m72.0
59 g (3.86 mmol), methanesulfonyl chloride 359 μm (4.63 mmol), and triethylamine 814 μm (5.79 mmol) were reacted and worked up in the same manner as in Reference Example 50 in dichloromethane to give the crude product of the title compound m7a. get something

NMRr Sppm (CDCIs) 0.88 (
t, J=6.4Hz, 3H).

1.14-1.35 (m, 30H), 1.39 (
d, J = 6.2Hz.

38), 1.36-1.56 (m, 2H), 1.
59-2.01 (m, 2H>, 2.15-2.37
(m, LH), 3.02 (s.

3H), 3.05-3.22 (m, 2H), 3.
99-4.37 (m.

4H), 4.63-4.84 (m, LH), 5.
20-5.45 (m, IH), 7.35-7.66
(m, 3H), 8.04(d, J=6.8Hz,
2H).

(Left below) 2- (2-benzoyloxypropan-1-yl)-
3-n-octadecylcarbamoyloxypropane Reference Example 128 1-azido-2-(2-benzoyloxypropane-1
Preparation of -yl)-3-n-octadecylcarbamoyloxypropane m7b 92.0%) to obtain the title compound (1).

NMR: δppm (CDCIn>0.88 (
t, J=6.4) 1z, 3H).

1.17-1.36 (m, 30H), 1.38 (
d,,C6,2Hz.

3Hz), 1.39-1.53 (m, 2H), 1
．． 55-1.98 (m, 2H), 1.99-2.17
(m, IH), 3.02-3.03 (m, 28)
, 3.32-3.53 (m, 2H), 3.93-
4.22 (m, 2H), 4.60-4.80 (br
,,IH), 5.20-5.42 (m, 18),
7.39-7.64 (m, 3H), 8.04 (d,
J=6.8Hz, 21).

(Left below) The previously obtained 2-(2-benzoyloxypropane-1)
-yl)-3-n-octadecylcarbamoyloxybrobanol Methanesulfonic acid ester m7a crude product and lithium azide 1.889 g (38.6 mmol)
was reacted and post-treated in the same manner as in Reference Example 52 in 50 ml of dimethylformamide, yielding 1.986 g (yield Reference Example 129) 2-(2-benzoyloxypropan-1-yl)-
A crude product of 3-n-octadecylcarbamoyloxypropylamine m8 is obtained.

NMR; l; ppm (CDC1,) 0.88
(t,,c6.4Hz, 3H).

1.17-1.36 (m, 30)1), 1.37
(d, J=6.2Hz.

38), 1.39-1.53 (m, 2H), 1.
55-1.96 (m, 5H), 2.59-2.85
(m, 2H), 2.98-3.27 (m, 2H),
4.00-4.27 (m, 2H), 4.65-4.
87 (br,, IH), 5.20-5.46 (m,
IH), 7.36-7.65 (m, 3) 1), 8
．． 04 (d, J=6.8Hz, 2H).

(Left below) 1-azido-2-(2-benzoyloxypropane-1
-yl) -3-n-octadecylcarbamoyloxypropane m7b 1.617g (2,89 mmol)
, a suspension of 170 mg of 10% palladium-carbon catalyst in 150 ml of methanol is catalytically reduced under a hydrogen stream for 1 hour.
By filtering the reaction solution and distilling off the solvent, the title compound Reference Example 130 2-(2-benzoyloxypropan-1-yl)-
Production of 1-(3-chloropropylsulfonylamino)-3-〇-octadecylcarbamoyloxypropane m9 By adding 495 μl (3.52 mmol) of triethylamine and performing the reaction and post-treatment in the same manner as in Reference Example 4.
．． 56g (Yield 80, 2% from wax and azide mass)
The title compound m9 was obtained.

N1'lR: δppm (CDC1.) 0.88
<t. J=6.4Hz. 3H).

1, 17-1.36 (m.30H), 1.39 (
d. J=6.2Hz.

38), 1.37-1.53 (m.2H), 1.
57-1.88 (m.

28), 1.90-2.11 (m.IH), 2.
17-2.36 (m.2H), 2.92-3.29
(m.6H), 3.65 (t.

J=6.2Hz. 2H), 3.97-4.35 (m
．． 2H).

4, 70-4.86 (br., LH), 5.20-
5.50 (m.2H), 7.39-7.64 (m+
3'H), 8.04 (d.

J=6.　8Hz. 2H).

(Left below) The previously obtained 2-(2-benzoyloxypropane-1)
-yl)-3-n-octadecylcarbamoyloxypropylamine m8 crude product dichloromethane 60ml
Add 330 μm (2.71 mmol) of 3-chloropropanesulfonyl chloride to a solution of Reference Example 131 1-(3-chloropropylsulfonylamino)-2-(
941 mg (1,40 mmol) of 2-(2-benzoyloxypropan-1-yl)-1-(3) produced in mL O(7) -Chloropropylsulfonylamino-5-n-octadedylcarbamoyloxypropane 1 in 50 ml of methanol was added with 0.539 ml (2.80 mmol) of 5.18 Mol/L sodium methoxide-methanol solution under ice cooling, and The reaction solution, which is stirred for 1 hour, is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate.The ethyl acetate layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off.The residue is extracted with n-hexane. -ethyl acetate (1:2
491 mg (yield 61.7%) of the title compound mlO is obtained by separating and purifying the mixture by silica gel column chromatography using the eluent.

NMR: Sppm (CDC1,) 0.88 (t
, J=6.4Hz, 3H).

1.12-1.36 (m, 33H), 1.36-1
．． 60 (m, 4h).

1.80-2.20 (m, 2H), 2.18-2.
37 (m, 21().

2.99-3.27 (m, 6H), 3.68 (t
, J-6,2Hz.

2H), 3.83-4.27 (m, 3H), 4.
67-4.96(br,,IH), 5.27-5.8
5 (br,,IH).

(Left below) Reference Example 132 1-(3-chloropropylsulfonylamino)-3-〇-octadecylcarbamoyloxy-2-(2-year-old xop-pan-1-yl)propane If [ml (7) Production chloride Add 106 μm (1.5 mmol) of dimethyl sulfoxide to a solution of 65.4 μm (0.75 mmol) of oxalyl in 50 ml of dichloromethane at -78°C and stir for 5 minutes.To the reaction mixture, add 1-(3-chloropropylsulfonylamino)- 2-(2-hydroxypropan-1-yl)
A solution of 10285 mg (0.5 mmol) of -3-n-octadecylcarbamoyloxypropane m in 2 ml of dichloromethane is added dropwise with vigorous stirring.

After reacting at -70°C for 15 minutes, triethylamine 8
After adding 36 μm (6 mmol) and gradually raising the reaction temperature to room temperature, the product was extracted with dichloromethane. The dichloromethane layer was washed successively with 2N hydrochloric acid, water, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 11 [ml] of a crude product of the title compound.

NMR: Sppm (CDCIm) 0.88 (t,
J=6.4Hz, 3H).

1.14-1.41 (m, 30H), 1.37-
1.61 (m, 2H).

2.12-2.77 (m, 5H), 2.18 (
s, 3H), 2.97-3.28 (m, 6H),
3.68 (t, J=6.2Hz, 2H).

3.86-4.25 (m, 2H), 4.65-4
．． 86 (br, IH).

5, 26-5.42 (br, , IH).

(Left below) Reference Example 133 1-(3-iodopropylsulfonylamino)-3-n
-Ctadecylcarbamoyloxy-2-(2-Ctadecylcarbamoyloxy-2-(2-Catadecylcarbamoyl)propane 1ml1c7) Production ■l
111 The crude product obtained in Reference Example 132 is used as is as a raw material.

The yield from compound mlO is 66%.

Example 66 3-n-year-old ctadezylcarbamoyloxy-2-(2-
Oxopropan-1-yl)-1-(3-quinoliniopropylsulfonylamino)propane Production of iodite 1 ridge 1 [ml l-(3-'70propylsulfonylamino)-3-
Using 1 ml of 〇-octadecylcarbamoyloxy-2-(2-year-old xopropan-1-yl)propane, the reaction was carried out in the same manner as in Reference Example 5, and the post-treatment was performed. Table 8 shows the amount charged and the physical properties of the product. Shown below.

3-n-year-old ctadezylcarbamoyloxy-2-(2-
The reaction was carried out in the same manner as in Example 25, using ml of (xopropan-1-yl)-1-(3-iodopropylsulfonylamino)propane I, and the post-treatment was carried out. Shown in the table.

Reference example 134 5-n-hexadecyloxymethyl-2-phenyl-1
, Preparation of 3-dioxane and ethyl acid extraction. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.

The obtained residue was recrystallized from pentane-methanol to obtain 16.203 g (yield 97%) of the title compound.

Reference Example 135 Production of 2-bromomethyl-5-n-hexadecyloxypropanol benzoic acid ester n3 7.769 g
(40 mmol) of 5-hydroxymethyl-2-phenyl-1,3-dioxane n1 of anhydrous benzene 150 ml
2.08 g (52 mmol) of 60% oily sodium hydride was added to the solution and heated at 50°C for 1 hour, then a solution of 17.28 g (54 mmol) of n-hexadecyl methanesulfonate in 50ffi of anhydrous benzene was added and heated for 7 hours. After cooling the refluxing reaction solution, water was added and vinegar 5-n-hexadecyloxymethyl-2-phenyl-1,3-dioxane 214.703 g (35.2 mmol), N-
Promofusuccinimide 6.90g (38.4 mmol)
and 700 mg of barium sulfate and 200 ml of dichloromethane
The reaction solution was heated under reflux for 1 hour. The reaction solution was poured into water-cooled saturated sodium bicarbonate water, and the dichloromethane layer was heated to reflux for 1 hour.
After sequentially washing with % sodium thiosulfate water and saturated brine, drying over anhydrous magnesium sulfate, and distilling off the solvent.

The residue was separated by short-path silica gel column chromatography using n-hexane-ethyl acetate (9:1) as the eluent to obtain 13.845 g (yield 7).
9.3%) of the title compound n3 is obtained.

Reference Example 136 2-Cyanomethyl-5-n-hexadecyloxypropanol Manufacture of benzoic acid esterosis The layer was washed four times with water, then with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. This gives 12.42 g of a crude product of the title compound.

NMRr 8 ppm (CDCIm) 0.88
(t, J=6.4Hz, 38).

1.15-1.43 (m, 26H), 1.45-1
．． 70 (m, 2B).

2.39-2.67 (m, 3H), 3.45 (t
, J=4.8Hz.

2H), 3.50-3.67 (m, 2H), 4.
26-4.52 (m.

2H), 7.40-7.65 (m, 3H), 8.
05 (dd.

J=6.4 & 1.6Hz, 21).

Reference Example 137 Production of 2-cyanomethyl-5-n-hexadecyloxypropanol Vnl 2-bromomethyl-5-n-hexadecyloxypropanol Benzoic acid ester n313.845g (27
, 9 mmol) in 150 ml of dimethyl sulfoxide (1.439 g of 95% sodium cyanide (27,
9 mmol) was added and reacted at 90°C for 1 hour. While cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Ethyl acetate 2
-cyanmethyl-5-n-hexadecyloxypropanol Benzoic fli-cs5-l n3' 12.42g
methanol 60ml and tetrahydrofuran 100ml
Add 2N aqueous sodium hydroxide solution 15,5 to the solution of
Add m1 (30.7 mmol) and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate.
The solvent is distilled off. *The residue was diluted with n-hexane-ethyl acetate (4
:1) was separated and purified by silica gel column chromatography as an elution solvent to obtain 6.430 g (yield 67.8
%) of the title compound L1.

NMR: &ppm (CDCIg>0.88 (
t, J=6.4Hz, 3H).

1.15-1.43 (m, 26H), 1.45-1
．． 70 (m, 2H).

1.96-2.27 (m, 2H), 2.45-2.
69 (m, 2H).

3.45 (t, J=6.6Hz, 2H), 3.59
(d.

J: 4.8Hz, 2H), 3.67-3.88 (
m, 2H).

(The following is a blank space) Reference example 138 2-cyanmethyl-5-n-hexadecyloxypropanol methanesulfonic acid ester y! Production of 2-cyanomethyl-5-n-hexadecyloxypropanol Vnl 3.40 g (10 mmol), methanesulfonyl chloride 1.08 ml (14 mmol),
2.39 ml (17 mmol) of IJ ethylamine was reacted in 60 ml of dichloromethane in the same manner as in Reference Example 50.
Work-up gives the crude title compound V nla.

NMR: δppm (CDC1,) 0.88 (t
, J=6.4Hz, 3H).

1.15-1.43 (a+, 26H), 1.45-
1.64 (m, 2H).

2.33-2.57 (m, IH), 2.50-2.
62 (m, 2H).

3.06 (s, 3H), 3.43 (t, J=6.
6Hz, 2H).

3.43-3.59 (m, 2H), 4.19-4.
42 (m, 2H).

Reference Example 139 Manufacture of 1-azido-2-cyanomethyl-5-n-hexadecyloxypropane V nibReference Example 140 2-cyanomethyl-5-n-hexadecyloxypropylamine Obtained from the manufacturer of nl 2-cyanmethyl-5-n-hexadecyloxydibrobanol methanesulfonic acid ester V
Reference Example 5: nla crude product and 4.9 g (100 mmol) of lithium azide were mixed in 30 ml of dimethylformamide.
The reaction and post-treatment were carried out in the same manner as in 2. 3.504 mice (yield: 9
6.1%) of the title compound Enib is obtained as an oil.

NMR: δppm (CDCIg) 0.88
(t, J=6.4Hz, 3H).

1.15-1.43 (m, 26H), 1.45-
1.64 (m, 2H).

2.10-2.30 (m, IH), 2.50 (
d, J=6.81 (z.

2B>, 3.37-3.59 (m, 6H).

1-azido-2-cyanomethyl-5-n-hexadecyloxypropane, 3. OOg (8,23mM
) A suspension of 300 mg of 10% palladium-carbon catalyst in 100 ml of methanol is post-reacted in the same manner as in Reference Example 129 to obtain the title compound L1 as a crude product.

NMR: δppa+ (CDCIn) 0.88 (
t, J=6.4Hz, 3H).

1.15-1.43 (m, 28H), 1.45-1
．． 64 (m, 2H).

1.88-2.11 (m, IH), 2.53 (d
, J=6.4Hz.

2H), 2.70-2.93 (m, 2H), 3.
31-3.50 (m, 41).

(Left below blank) Reference Example 141 1-(3-chloropropylsulfonylamino)-2-cyanmethyl-5-n-hexadecyloxypropane 11
1nl Production Reference Example 142 2-cyanomethyl-5-n-hexadecyloxy-1,
-(3-iodopropylsulfonylamino)propane 1
Preparation El/n1 11nl Using the crude product of 2-cyanomethyl-5-n-hexadecyloxypropylamine 1 row obtained earlier, react in the same manner as in Reference Example 4 and perform post-treatment. Preparation The amounts and physical properties of the products are shown in Table 7.

1-(3-chloropropylsulfonylamino)-2-diazumethel-5-n-hexadecyloxypropane, l
Table 8 shows the amount charged and the physical properties of the product.

Example 67 2-cyanomethyl-5-n-hexadecyloxy-1-
Production Example 68 of (5-1-limethylammoniopropylsulfonylamino)propane iodite Inl 2-cyanmethyl-5-n-hexadecyloxy-L-
Production of (3-quinoliniopropylsulfonylamino)propane iodite In2 1 [nL 2-cyanomethyl-5-n-hexadecyloxy-1-
(5-iodopropylsulfonylamino)propane-U
Using Ni, the reaction was carried out in the same manner as in Example 8, and the post-treatment was carried out. Table 9 shows the amount charged and the physical properties of the product.

2-cyanomethyl-3-hexadecyloxy-1-(5
-iodofurobirsulfonylamino)propane I[n
Table 10 shows the amount charged and the physical properties of the product.

Reference example 143 5-n-year old tadecylcarbamoyloxy-2-phenyl-1,3-dioxane n4 Reference example 144 2-bromomethyl-5-n-octadecylcarlevamoyloxy-propanol Production of benzoic acid ester n5 5- Hydroxymethyl-2-phenyl-1,3-'; oxane nl 7.769g (40 mmol), octadecyl isocyanate 21.991ml (64 mmol) and dimethylaminopyridine lOQmg pyridine l
Reaction and post-treatment were carried out in the same manner as in Reference Example 122 in QOml.
By recrystallizing the obtained residue with ethanol 1
5.861 g (yield: 81.0%) of the title compound was obtained.

IR: νmax (CHCl, > 3440.170
5 am-' (blank below) 5-n-year-old ctadezylcarbamoyloxy-2-phenyl-1,3-dioxane n42.55g (5,22
mol), N-bromosuccinimide 938 mg (
5.22 mmol) and 100 mg of barium sulfate were reacted and post-treated in the same manner as in Reference Example 135 in 50 ml of dichloromethane to obtain 51.86 g of the title compound (yield 62.6%).
).

NMR'S ppffi (CDCIs) 0.
88 (t, J=6.4Hz, 3H).

1.17-1.41 (m, 30H), 1.36
−1.57 (m, 2H).

2.46-2.68 (m, LH), 3.16 (
q, J = 6.2Hz.

2) 1), 3.57 (d, J: 5.6Hz, 2H
), 4.26 (d.

J=6.4Hz, 2H), 4.44 (d, J=6
．． 0Hz, 2H).

4.59-4.77 (br, IH), 7.40-
7.60 (m, 3H).

8.03 (d, J=7.0Hz, 2H).

Reference Example 145 Production of 2-cyanomethyl-5-n-octadecylcarbamoyloxypropanol n5' In 130 ml, reaction and post-treatment were carried out in the same manner as in Example 136, and 1.49 g (yield 95.5%) of the title compound was obtained. obtain.

NMR r Sppm (CDC1.) 0.88
(t.J=6.4Hz.3H).

1, 17-1.41 (m.30H), 1.36
-1.57 (m.2H).

2,61 (s.3H), 3.17 (q.J=6
．． 2Hz. 2H).

4, 16-4.53 (m.4H), 4.65-4
．． 81 (m.IH).

7, 41-7.67 (m.3H), 8.05 (
d.

J=7.　0Hz. 2H).

(Left below) 1.76 g (3.10 mmol) of 2-bromomethyl-3-n-octadecylcarbarimoyloxypropanol n5 and 185 mg (3.26 mmol) of 95% sodium cyanide were added to dimethylsulfoxy Reference Example 146 2- Preparation of cyanmethyl-3-n-octadecylcarbamoyloxypropanol Vn2 J=6.4Hz. 2H
), 3.65 (d.J=4.8Hz.2H).

4, 22 (d, J=5.4Hz.2H), 4.7
0-4.87 (br., IH).

Reference Example 147 2-cyanomethyl-3-n-octadecylcarbamoyloxypropanol Methanesulfonic acid ester Edanbutton production 2-cyanomethyl-3-n-octadecylcarbamoyloxypropanol Benzoic acid ester n5' 1.4
9 g (2.96 mmol) and 1.66 ml (3.32 mmol) of a 2N aqueous sodium hydroxide solution were reacted and post-treated in the same manner as in Reference Example 137 in a mixture of 15 rnl of methanol and 15 ml of tetrahydrofuran to obtain the title compound V n2. 966 mg (yield 76, 8%) are obtained.

NMR Z Sppm (CDC1.>0.88
(t.J-6.4Hz, 3H).

1, 17-1.40 (m.30H), 1.37-1
．． 57 (m.2H).

2, 11-2.32 (m.IH), 2.47 (d
．． J=7.2Hz.

2H), 2.56-2, 77 (br.IH), 3
．． 18 (q.

2-cyanomethyl-3-n-octadecylcarbamoyloxypropanol Vn2 940mg (2.29
mM), methanesulfonyl chloride 231 μm (2
．． 98mM), triethylamine 483μm (3.
44mM) in 10ml of dichloromethane in the same manner as in Reference Example 52, post-treatment was performed, and the title compound V n2
A crude product of a is obtained.

NMR2 l; ppm (CDCIs) 0.
88 (t, J=6.4)1z, 3H).

1.16-1.38 (m, 30H), 1.40
-1.58 (m, 1)1).

2.45-2.63 (m, 3H), 3.80
(s, 3H), 3.16 (q, J=6.4Hz,
2) 1), 4.09-4.45 (m, 4H)4.
73-4.87 (br,, LH) Reference Example 148 1-and-2-cyanomethyl-5-n-octadeflucarbamoyloxypropane) is obtained.

NMR: Sppm (CDC1.) 0.88
(t.J=6.4Hz.3H).

1, 16-1.40 (m.30) 1), 1.40
-1.58 (m.2H).

2, 20-2.40 (m.IH), 2.51
(d.J=6.6Hz.

2H), 3.18 (q.J=6.4Hz.2H)
, 3.40-3.66 (m.2H), 4.00
-4.23 (m.2H), 4.60-4.84 (
br. , IH).

Reference Example 149 Crude of 2-cyanomethyl-3-n-octadecylcarbamoyloxypropanol methanesulfonic acid ester V n2a obtained from the manufacturer of 2-cyanomethyl-3-n-octadecylcarbamoyloxypropylamine Product and notium azide1. 121 g (22.
9mM) in 15ml of dimethylformamide in the same manner as in Reference Example 53, post-treatment was performed, and the target compound V
n2b 854mg (yield 85.6% 1-azido-
2-cyanomethyl-3-n-octadecylcarbamoyloxypropane 1, 84 mM) over 10% palladium-carbon catalyst 801 m
catalytic reduction in 40 ml of methanol in the same manner as in Reference Example 129, followed by post-treatment to obtain the title compound as a crude product.

NMR: l; ppm (CDCIs) 0.8
8 (t.J=6.4Hz.3H).

1, 16-1.40 (m.30H), 1. '40-
1.58 (m.2H).

1, 96-2.97 (m.7H), 3. OQ
-3.29 (m.2H).

3, 96-4.27 (m.2H), 4.60-4.
90 (br., LH) Reference Example 150 1-(3-chloropropylsulfonylamino)-2-ene anomethyl-3-n-octadecylcarbamoyloxypropane 2-cyanomethyl-3-n-octadecylcarbamoyloxybropane obtained previously Using the crude product of bilamin IVn2, the reaction was carried out in the same manner as in Reference Example 4, and the post-treatment was carried out. Table 7 shows the amount charged and the physical properties of the product.

Reference Example 151 2-cyanomethyl-3-n-old ctadezylcarbamoyloxy-1-(3-iodopropylsulfonylamino)
Production of propane I[n2 ■n2 I[[n2 1[[n2 1-(3-Chloropropylsulfonylamino-2-ene is reacted with anomether-3-n-octadecylcarbamoyloxy and post-treated. The physical properties of the product are shown in Table 8.

Example 69 Preparation of 2-cyanomethyl-3-n-octadedylcarbatomoyloxy-honylamino)propane iodite Same as Example 25 using yloxy-1-(3-iodopropylsulfonylamino)propane IIn2 React with and perform post-processing. Table 10 shows the amount charged and the physical properties of the product.

Reference example 152 2-(2-benzoyloxypropan-1-yl)-
3-n-hexadecylthiopropanol Production of methanesulfonic acid ester m12a 1
(2-benzoyloxypropan-1-yl)-3-n
-hexadecylthiopropanol m121, 268
g (2.65mM>, methanesulfonyl chloride 27oB 1 (3.45mM), triethylamine 5
60μm (3.98mM) in 30ml dichloromethane
The reaction and post-treatment were carried out in the same manner as in Reference Example 52 to obtain the title compound m12a as a crude product.

NMR: Sppm (CDCIs) 0.88
(t.J=6.4Hz.3H).

1, 15-1.37 (m.26H), 1.39 (
d. J=6.4Hz.

3Hz), 1.41-1.62 (m.2H), 1
．． 68-1.86 (m.IH), 1.88-2.21
(m, 28), 3.02 (s.

3H), 4.24-4.43 (m.2H), 5.
19-5.42 (m.

LH), 7.38-7.63 (m.3H), 8.
03 (d.

J=7.　2Hz. 2H).

Reference example 153 1-azido-2- (2-benzoyloxypropane-
Production of 1-yl)-3-n-hexadecylthiopropanol Methanesulfonic acid ester m12a and 1.297 g (26.5 mM) of lithium azide were reacted in the same manner as in Reference Example 53 in 50 ml of dimethylformamide, followed by post-treatment. title compound m12b 1. 291g
(yield 96.6%).

NMR: Sppm (CDCIs) 0.88
(t.c6.4Hz.3H).

1, 16-1.37 (+n.26H), 1.38
(d.J-6.0Hz.

3H), 1.44-1.62 (m.2H), 1.
63-1.78 (m.LH>, 1.80-2.03
(m.2H), 2.38-2.50 (m.2)1),
2.49-2.72 (m.2H), 3.41-3
．． 62 (m.2H), 5.17-5.37 (m.I
H), 7.39-7.62 (m.3H), 8.03
(d.J=7.2Hz.2H).

(Left below) The previously obtained 2-(2-benzoyloxypropane-1)
-yl) -3-n-hexadecylthioxypropane Reference Example 154 1-Amino-2-(2-benzoyloxypropane-1
-yl)-3-n-hexadecylthiopropane m13 Reference Example 155 2-(2-benzoyloxypropan-1-yl)-
1-(3-chloropropylsulfonylamino)-3-n
-Production of hexadecylthiopropane 1-Azide-2-
(2-benzoyloxypropan-1-yl) -3-
n-hexadecylthiopropane ridge 2b 1.291 g
(2,56mM>10% palladium-carbon catalyst 13
Reference Example 129 in 100ml of methanol using 0mg
After catalytic reduction in the same manner as above, the crude product of the title compound is obtained by post-treatment.

NMR: Sppm (CDC1,) 0.88 (
t, J=6.4Hz, 3H).

1.12-2.00 (m, 36)1), 2.34-
2.91 (m, 6H).

5.19-5.38 (m, 11(), 7.39-7
．． 62 (m, 3H).

8.03 (d, J=7.2Hz, 2H).

The previously obtained crude product of 1-amino-2-(benzoyloxypropan-1-yl)-3-n-hexadecylthiopropane, triethylamine 540 μm (3,8
4mM), 3-chloropropanesulfonyl chloride 37
0 μH (3.07 mM) in 30 ml of dichloromethane in the same manner as in Reference Example 4, followed by post-treatment to obtain 141.295 g (yield: 81.6%) of the title compound.

NMR: S ppm (CDC1, > 0.88
(t, , T=6.4Hz, 3H).

1.14-1.45 (m, 29H), 1.41-
1.61 (m, 2H).

1.63-1.81 (m, IH), 1.82-
2.01 (m, 2H).

2.15-2.37 (m, 2H), 2.37-2
．． 77 (m, 4H).

3.09-3.34 (m, 4H), 3.65 (t
, J=6.4Hz.

2H), 4.65-5.08 (br,, LH),
5.10-5.46 (m, LH), 7.39-7
．． 62 (m, 31), 8.03 (d.

J=7.2Hz, 28).

(Left below) Reference Example 156 1-<3-chloropropylsulfonylamino)-2-(
Preparation H of 2-hydroxypropan-1-yl)-3-n-hexadecylthiopropane 11115 1,24 g (2,0 mmol) of 2-(benzoyloxypropan-1-yl)-1-(3-chloro 5.18Mo in a solution of propylsulfonylamino-5-n-hexadecylthio-propane ml4 in 50ml methanol
l/L sodium methoxide methanol solution 770μ
m (2 mmol) was added, and reaction and post-treatment were carried out in the same manner as in Reference Example 131 to obtain 15562 mg (yield 54.5%) of the title compound m.

NMR: S ppm (CDCIs) 0188
(t, J: 6.4Hz, 3)1).

1.17-1.42 (m, 29H), 1.43-1
．． 77 (m, 5H).

1.91-2.18 (m, IH), 2.20-2.
37 (m, 2H).

2.42-2.65 (m, 4H), 3.02-3.
38 (m, 4H).

3.69 (t, J=6.0Hz, 2H), 3.80
-4.13 (m.

LH), 5.10-5.45 (broad, 11)
.

(Left below) Reference Example 157 1-(3-'70-propylsulfonylamino)-3-
n-hexadecylthio-2-(2-year-old xobroban-1
-yl〉Manufacture of propane seal R Trifluoroacetic anhydride dichloromethane 20 ml Rusulfoxide 190 μm Stir for 6 minutes 6 Add dimethyl (2.66 mmol) to a solution of 190 μm (1.33 mmol) to the reaction mixture at -78°C and add 5 liters -(3-chloropropylsulfonylamino)-2-(2-hydroxypropane-
1-yl)-3-n-hexadecylthiopropane, m1
5428 mg (0.83 mmol) dichloromethane 2
ml solution dropwise with vigorous stirring. 1 at -70℃
After reacting for 5 minutes, add 3.50 ml of triethylamine (
24.9 mmol) and reacted in the same manner as in Reference Example 132.
After work-up, 2213 mg (yield: 41.6%) of the title compound is obtained.

NMRr S ppm (CDC1*) 0.88
(t, 6.4Hz, 3H).

1.10-1.43 (m, 26H), 1.46-1
．． 66 (m, 2H).

2.22-2.44 (m, 3H), 2.44-2.
59 (m, 4H).

2.65 (d, J=6.0Hz, 2)1), 3.0
9-3.29 (m.

4H), 3.68 (t, J=6.4Hz, 2)1)
, 4.80 (t.

J=6.4Hz, LH>.

(Left below) Reference Example 158 3-n-hexadecylthio-1-(5-iodopropylsulfonylamino)-2-(2-oxopropane-1-
11 m2 of l-(3-chloropropylsulfonylamino)-3-n
-hexadecylthio-2-(2-oxopropane-1-
Table 8 shows the amount charged and the physical properties of the product.

Example 70 Preparation of 3-n-hexadecylthio-2-(2-year-old xopropan-1-yl)-1-(3-trimethylammoniopropylsulfonylamino)propane iodite 1-1-yl)propane I [m2 Table 9 shows the amount charged and the physical properties of the product.

(Left below) 1[m2 3-n-hexadecylthio-1-(5-iodopropylsulfonylamino)-2-(2-oxopropane Example 71 1-hexadecylthio-2-(5-methyl-28-1,
Preparation of 2,4-triacyly-2-yl)-3-(3-trimethylammoniopropylsulfonylamino)propane iodite 1 shown in Table 9.

The above starting materials are those of Reference Example 77.79.80, except that 3-methyl-2H-1, 2.4-triazole is used instead of 5-methyltetrazole in Reference Example 77.
It can be produced by reacting in the same manner as 81.3.4 and 5.

Example 72 2-(3-methyl-2H-1,2,4-triazole-
2-yl)-1-year-old ctadezylcarbamoyloxy-5
-(3-quinoliniopropylsulfonylamino)propane Production of iodite 1-1-hexadecylthio-5-
(3-iodopropylsulfonylamino)-2-(3-
Using methyl-28-1,2,4-1-riazol-2-yl)propane I[o2, the reaction was allowed to proceed in the same manner as in Example 8, and the post-treatment was carried out. (3-iodopropylsulfonylamino)-2-(
3-Methyl-2H-l, 2.4-)
Using 2-yl)-1-octadecylcarbamoyloxypropane IIo2, the reaction was carried out in the same manner as in Example 25, and the post-treatment was carried out.
Shown in Table 0.

, L starting material is 3-methyl-2H-l, 2.4-instead of 5-methyltetrazole in Reference Example 77.
Reference Example 77.79.80 except for using triazole
．． It can be produced by reacting in the same manner as 82.3.4 and 5.

3-(3-iodopropylsulfonylamino)-2-(
3-Methyl-2H-l, 2.4-triazol-2-yl)-1-octadecylcarbarimoyloxypropane. React in the same manner and post-process. Table 10 shows the amount charged and the physical properties of the product.

The above starting materials are as follows: -Reference Examples 77, 79, 80, except that 3-methyl-2H-1,2,4-triazole is used in place of 5-methyltetrazole in Reference Example 77.
, 82, 3, 4 and 5.

Example 73 2-(3-methyl-IH-1.2.4-triazole-
1-yl)-1-year-old ctadezylcarbamoyloxy-3
-Production of (3-quinoliniopropylsulfonylamino)propane iodite Io3 Using hydroxypropane Io3, the reaction is carried out in the same manner as in Example 25, followed by post-treatment. Table 10 shows the amount charged and the physical properties of the product.

The above starting materials are Reference Examples 77, 79, 80, except that 3-methyl-2H-1,2,4-triazole is used instead of 5-methyltetrazole in Reference Example 77.
It can be produced by reacting in the same manner as 82, 3, 4 and 5.

(Left below) 3-(3-iodopropylsulfonylamino)-2-(
Effects of the Invention The compound of the present invention is a PAF analog and acts as a P-AF receptor antagonist. 0 In addition to suppressing platelet aggregation caused by PAF, the compounds of the present invention may also inhibit symptoms or diseases in which PAF is thought to be involved, such as entodochin shock, asthma, inflammation, acute tissue graft rejection, hypotension, gastric ulcer, or It can be a useful treatment for nephritis. It can also be a useful antitumor agent. Below, test examples of in vitro platelet aggregation inhibitory effects are shown for representative compounds.

[Test materials and test methods] Male rabbit (NIBS-J Ken, weight 2.2-2.5 kg)
, Rabbiton Ranch) and bendoparbital sodium (
Somnopentyl: Pitmab Moore, approx. 25
mg/kg, intra-ear vein injection), a cannula connected to a three-way stopcock was introduced into the carotid artery, and a plastic syringe containing 0.8 ml of 3.8χ sodium citrate was used to give 7.2 ml of blood, a total volume of 8 ml each. Whole blood was collected continuously. The blood was placed in a plastic test tube, mixed by gentle inversion, and then centrifuged at 2008 g for 10 minutes at 22°C.
plasma) was collected. 22 more remaining blood
℃, 3000 rpm (approx. 1900×g) for 10 minutes, and platelet poor plasma [PPP (Platelet p
oor plasma)] was obtained.

PRP platelet count is measured with a fuerter counter and 5
The mixture was diluted with PPP to a concentration of 0 to 55 x 10'/μm and subjected to aggregation measurement.

Platelet aggregation reaction was performed using the Born method [Born G, V.

Ro, Nature + - (Nature), Out, 927-9
29 (1962)], Ablibometer (Mod
el ALITORAM-61, Rika Denki Kogyo). That is, the platelet count is 50-55XLO'
PPP 230μm adjusted to /μm was placed in a measurement cuvette, set in a flocculation needle, stirred at 37℃ for 1 minute <120Orpm), prewarmed, and then mixed with a test compound solution (dimethyl sulfoxide solution 1μm and physiological saline). 9μ
m), and 2 minutes later, 20 nM (final concentration) of platelet activating factor (PAF, C,) as an aggregation-inducing substance was added at 10
In addition to μm, the change in permeability caused by aggregation was recorded over time.

The aggregation rate of platelets is calculated by setting the permeability of PRP and PPP to 10 oz and 10 oz, respectively.
The maximum permeability of P was taken as the maximum aggregation rate.

The aggregation inhibition rate (X) was calculated from the ratio of the maximum aggregation rate of the test compound addition group to the maximum aggregation rate of the control group (carrier addition group).

The test results are shown below. The test results showed that platelet aggregation was 50%
Concentration of test compound required to inhibit X, ICa. (μ
M).

(Margin below) *Compound numbers correspond to those in Examples.

PGE r was used as a comparative compound because
, is known to have a strong inhibitory effect on PAF-induced platelet aggregation, and a new compound was synthesized with this level of effect as a target. As a result, the compound of the present invention was able to considerably approach the platelet aggregation inhibitory effect level of pGE +.

The antitumor activity of the compound of the present invention can be demonstrated by, for example, Meth A (
Reduction in tumor weight and size regression in Ba1b/c mice transplanted with mouse fibroblastosarcoma and M) I-1
C3) 1/HeN7 transplanted with 34 (7 mice ascites liver cancer)
The survival effect was confirmed in DS mice transplanted with Ehrlich Ascites and Ehrlich Ascites carcinoma.

Compound (I) of the present invention can be administered orally or parenterally to humans or animals. For example, compound (I
) can be administered by intravenous, intramuscular, or subcutaneous injection after being dissolved or suspended in a suitable injection solvent (e.g., distilled water for injection, ethanol, glycerin, propylene glycol, olive oil, peanut oil, etc.). . When used as an injection, Compound (I) can be sealed in an ampoule as a solution or suspension, but it can also be stored in an ampoule or vial as a crystal, powder, microcrystal, freeze-dried product, etc. It is preferable to adjust the time before use, and a stabilizer may be added in advance.
) are pharmaceutical agents such as diluents (e.g., starch, sucrose, lactose, calcium carbonate, limestone, etc.), lubricants (e.g., stearic acid, sodium benzoate, boric acid, silica, polyethylene glycol, etc.) With the addition of ingredients, it can be formed into a powder, tablet, granule, capsule, troche, dry syrup, etc. and administered orally.

When Compound (I) is used to treat conditions such as endotoxic shock, asthma, inflammation, acute tissue graft rejection, hypotension, gastric ulcer, nephritis, or tumor, the daily dose for adults is usually 1 mg or more.
Administer 5g 1 to 3 times a day. However, the dose may be increased or decreased as appropriate depending on the patient's age, medical condition, medical history, etc.

Claims (1)

[Claims] 1. Formula: ▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R_1 is alkyl or alkylcarbamoyl; R_2 is lower alkyloxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxy carbonylamino, lower alkyl ureido,
lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl or heterocyclic group or heterocyclyloxy; R_2' represents hydrogen or R_2
together to form -O(CH_2)m- (wherein m represents an integer from 1 to 5); R_3, R_4 and R_5 each independently represent hydrogen or lower alkyl, or R_3, Two or three of R_4 and R_5 together with adjacent N form a cyclic ammonio; R_5 is hydrogen or lower alkyl carbonyl; X^- is a counter ion; Y is oxygen or sulfur; and n is 1 to each representing an integer of 10]. 2. The compound according to claim 1, wherein R_1 is C_1_2-C_2_0 alkyl; and n is an integer from 1 to 5. 3. The compound according to claim 1, wherein R_1 is C_1_2-C_2_0 alkylcarbamoyl; and n is an integer of 1 to 5. 4. The compound according to claim 2 or 3, wherein R_2' is hydrogen; R_5 is hydrogen; and X^- is a halogen anion. 5. R_2 is lower alkyloxy; and the cyclic ammonio is thiazolio or quinolinio.
4. Compound according to 3 or 4. Claim 1, wherein R_2 is lower alkyloxymethyl; and the cyclic ammonio is thiazolio or thiazolio.
, 2, 3 or 4. 7, a nitrogen-containing 5- to 6-membered heterocyclic group in which R_2 may contain oxygen or sulfur and may have a substituent;
and cyclic ammonio is thiazolio or quinolinio. 8. The compound according to claim 1, 2, 3 or 4, wherein R_2 is lower alkylcarbamoyloxy; and the cyclic ammonio is thiazolio or quinolinio. 9, R_2 is lower alkyloxymethyl; and R_3
, R_4 and R_5 are each lower alkyl.