WO2002088105A1

WO2002088105A1 - Process for producing oxirane compound

Info

Publication number: WO2002088105A1
Application number: PCT/JP2002/003986
Authority: WO
Inventors: Manabu Sasyou; Toshihiko Naito
Original assignee: Eisai Co., Ltd.
Priority date: 2001-04-27
Filing date: 2002-04-22
Publication date: 2002-11-07
Also published as: JPWO2002088105A1

Abstract

An industrially more advantageous process for producing an oxirane derivative. The process, by which a compound (8) represented by the general formula (8) (wherein PG1 represents a hydroxyl-protecting group), a salt thereof, or a hydrate of either is produced, is characterized by eliminating the leaving groups of a compound (6) represented by the general formula (6) (wherein X represents halogeno; Y represents C¿2-11? acyl; and PG?1¿ is as defined above) and/or a compound (7) represented by the general formula (7) (wherein the symbols are as defined above). (6) (7) (8)

Description

Specification

Method for producing oxysilane compounds

The present invention relates to a lipid A (Lipid A) analog (lipid A) useful for prevention and treatment of endotoxin exposure including infectious disease (sepsis), septicemia (septicemia), endotoxemia and various forms of septic shock. The present invention relates to a novel method for producing an oxysilane compound which is important as a side chain synthesis intermediate of E5564). Background art

E5564, a lipid A. analog disclosed in U.S. Patent Nos. 5,750,664 and 5,935,938, is a compound represented by the following structural formula:

It is highly effective in preventing and treating gram-negative bacteremia with a high lethality caused by the lipopolysaccharide (LPS) component of the outer membrane of gram-negative bacteria, especially endotoxin shock.

Lipid A is thought to play a central role in the toxicity exhibited by this bacterial lipopolysaccharide molecule.It has a structure in which diphosphorylated disaccharides are acylated by long-chain fatty acids. I have.

E5564 is a compound that has been developed as an analog to suppress the toxicity of lipid A. As shown in the above formula, E5564 has four side chains from diphosphorylated disaccharide. It has a rugged structure.

Of these four side chains, the fourth side chain from the right (hereinafter referred to as the “fourth side chain”), a 3-methoxydecanol derivative, is a side chain having a characteristic structure. As a result of diligent studies, the present inventors have found an industrially advantageous method for producing a 3-methoxydeoxyl derivative from (S)-(2-benzyloxystyl) oxylan and have filed a patent application ( Japanese Patent Application No. 200 1-1 23 95 1).

For example, Frick et al. Disclose a method for preparing (S)-(2-benzyloxyshethyl) oxylan from aspartic acid in three steps (Synthesis, p621, 1992). Although this method has a short number of steps, it has problems in the yield and purity of the target compound. Disclosure of the invention

An object of the present invention is to provide an excellent method for synthesizing (S)-(2-benzyloxyshethyl) oxysilane, which solves the above problems.

Another object of the present invention is to provide a method for producing highly pure (S)-(2-benzyloxystyl) oxylan which has an excellent total yield and does not require purification using a column, in addition to the above objects. An object of the present invention is to provide an industrially very useful method.

As a result of intensive studies, the present inventors have found that the novel production method satisfies these conditions and is industrially very useful. That is, the present inventors have found the following <1> to <11>. ―

<1> A compound represented by the general formula (6), wherein X represents a halogen atom, Y represents a C2-111 acyl group, and PG ¹ represents a hydroxyl-protecting group. Or leaving a leaving group of the compound (7) represented by the general formula (7) wherein each symbol represents the same group as defined above, wherein the general formula (8) [ Wherein the symbol represents the same group as defined above.] A method for producing a compound (8) or a salt thereof or a hydrate thereof:

OY

γ Τ „(7)

<2> A compound represented by the general formula (5) wherein R ³ and R ⁴ each represent a Cl 6 alkyl group which may be the same or different, and PG ¹ represents a hydroxyl-protecting group. (5) is reacted with a compound represented by the formula Y—X (wherein X represents a halogen atom, and Y represents a C 2-11 acyl group), and a compound represented by the general formula (6): Each symbol has the same definition as described above.] Compound (6) and Z represented by general formula (7)

[Wherein each symbol has the same definition as described above], and the leaving group of these compounds (6) and / or (7) is then eliminated. A method for producing a compound (8) represented by the general formula (8) wherein the symbols have the same definitions as described above, or a salt thereof, or a hydrate thereof:

x_

Y0 1 (6)

<3> The compound (4) represented by the general formula (4) [wherein PG ¹ represents a protecting group for a hydroxyl group] is a compound represented by the general formula (5) , R ³ and R ⁴ each represent a C 1 _6 alkyl group which may be the same or different, and PG ¹ has the same definition as described above.)

The compound (5) is reacted with a compound represented by the formula Y—X wherein X represents a halogen atom and Y represents a C 2-11 acyl group. And each symbol has the same definition as described above.] A compound (6) and / or a general formula (7) [Wherein each symbol has the same definition as above], and then the leaving group of these compounds (6) and Z or compound (7) is eliminated. A method for producing a compound (8) or a salt thereof or a hydrate thereof represented by the following general formula (8): wherein the symbols have the same definitions as described above:

OY

(7)

OPG

4> A compound represented by the general formula (3) wherein R ¹ and R ² each represent a C 16 alkyl group which may be the same or different, and PG ¹ represents a hydroxyl-protecting group. (3) is treated with an acid to give a compound (4) represented by the general formula (4), wherein PG ¹ has the same definition as described above; and then the two hydroxyl groups of the compound (4) Wherein R ³ and R ⁴ each represent a C 16 alkyl group which may be the same or different, and PG ¹ has the same definition as described above. Compound (5)

The compound (5) is reacted with a compound represented by the formula Y—X wherein X represents a halogen atom and Y represents a C 2-11 acyl group. And each symbol has the same definition as described above.] A compound (6) and / or a general formula (7)

[Wherein each symbol has the same definition as above], and the leaving group of these compounds (6) and (h) or compound (7) is then eliminated. A method for producing a compound (8) represented by the general formula (8) wherein the symbols have the same definitions as described above, or a salt thereof, or a hydrate thereof: Ji.

OR 4

(Five)

YO, ^ ^ c 1 (6)

OY

X, / \ ^ \ ha nha 1

( ⁸ ).

<5> A protecting group is introduced into the compound (2) represented by the general formula (2), wherein R ¹ and R ² each represent a C 1 _6 alkyl group which may be the same or different, and Wherein R ¹ and R ² have the same definition as described above, and PG ¹ represents a hydroxyl-protecting group.

Treating the compound (3) with an acid to give a compound (4) represented by the general formula (4) wherein PG ¹ has the same definition as described above;

Then shows two hydroxyl groups by introducing protective groups in formula (5) [wherein, R ³ and R ⁴ are the same or different may be C 1 one alkyl group of the compound (4), PG ¹ Has the same definition as described above.)

The compound (5) is reacted with a compound represented by the formula Y—X wherein X represents a halogen atom and Y represents a C 2-11 acyl group. And each symbol has the same definition as described above.] (6) and a compound represented by the general formula (7)

[Wherein each symbol has the same definition as described above], and the leaving group of these compounds (6) and / or (7) is then eliminated. Represented by the general formula (8) wherein the symbols have the same definitions as above. Ji Method for producing compound (8) or a salt thereof or a hydrate thereof

Two

R

0

0% (2)

R

(3)

OH

χ_

YO 1 (6)

ΟΥ

X 1 ( ⁷ )

<6> A protecting group is introduced into the compound (1) represented by the general formula (1) to form a compound represented by the general formula (2) wherein R ¹ and R ² may be the same or different and each is a C 16 alkyl group. And the compound (2) represented by

A compound represented by the general formula (3) wherein a protecting group is introduced into the compound (2), wherein R ¹ and R ² have the same definition as described above, and PG ¹ represents a hydroxyl-protecting group. Treating the compound (3) with an acid to obtain a compound (4) represented by the general formula (4) wherein PG ¹ has the same definition as described above;

Then shows two hydroxyl groups by introducing protective groups in formula (5) [wherein, R ³ and R ⁴ are the same or different may be C 1 _ 6 alkyl group of the compound (4), PG ¹ Has the same definition as described above.)

In the compound (5), a compound represented by the formula Y—X wherein X is a halogen atom, and Y is a C 2-11 acyl A compound represented by the general formula (6), wherein each symbol has the same definition as above, and a compound (6) and Z or a compound represented by the general formula ( 7)

[Wherein each symbol has the same definition as described above], and then the leaving group of these compounds (6) and / or compound (7) is eliminated. A method for producing a compound (8) represented by the general formula (8) wherein the symbols have the same definitions as described above, or a salt thereof, or a hydrate thereof:

OH

To HO (1)

OH

(Four)

OPG

OR

R

0 (5)

X 1 ( ⁷ )

<7> The method according to any one of <1> to <6>, wherein X is a bromine atom.

<8> The method according to any one of <1> to <7>, wherein Υ is an acetyl group.

<9> The method according to any one of <1> to <8>, wherein PG ^{1 is a} benzyl group.

<10> R < ³ > and R < ⁴ > are methyl groups. the method of.

<1 1> R ¹ and R ² walks in Echiru group 4> ~ <1 0 The method of mounting the serial to any of>. Embodiment of the Invention

Hereinafter, the terms used in the present specification will be described in detail.

In the present specification, a C 1-6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, a methyl group, an ethyl group, an n-propyl group, i -Propinole, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, neopentyl, 1-methylol Butyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, i-hexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl Group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2- Examples include methylpropyl group, 1-ethyl-1-methylpropyl group, 1_ethyl-2-methylpropyl group, and the like, preferably, methyl group, ethyl group, n-propyl group, i-propynole group, and n-butyl. Group, i-butyl group, sec-butynole group, t-butynole group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group and i-hexyl group, more preferably methyl group, ethyl group, n-propyl group and i-hexyl group. Propyl, n-butyl, i-butyl, sec-butyl, t_butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, neopentyl, 1-methylbutyl Group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1, 2-dimethylpropyl group, more preferably methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, and Preferred are a methyl group, an ethyl group, an n-propyl group and an i-propyl group.

The C 2-11 acyl group means a C 2-11 aliphatic acyl group, a C 7-11 aromatic acyl group, and a C 1-10 alkyl group, a C 2-10 alkenyl group or Above C A 2- to 10-alkyl group having a carbonyl group bonded to the terminal thereof; and a C6-10 aryl group having a terminal carbonyl group or the above C2-7 aliphatic acyl group at the terminal thereof. In addition, a group derived by removing one hydrogen atom and corresponding thereto is bonded, and specifically, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a vivaloyl group, and a hexanoyl group Octanoyl group, acryloyl group, methacryloyl group, methacrylonitrile group, benzoyl group, o-tonoleoyl group, m-tonoleoyl group, P-toluoyl group, cinnamoyl group, 1-naphthoyl group, 2-naphthoyl group, etc. The group of is mentioned. Preferable are acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, otatanyl, acryloyl, methacryloyl, crotoninole, benzoynole, and o-tonolenole. , M_ tonoleinoyl group, p-tonoleinoyl group, cinnamoyl group, 1-naphthoyl group, and 2-naphthoyl group, more preferably acetyl group, propionyl group, butyryl group, isoptyryl group, valeryl group, isonokrilleryl group, and vivaloyl. Group, hexanoyl group, otanoinoyl group, benzoyl group, 0-toluoyl group, m_tonoleoinole group, p-toluoyl group, cinnamoyl group, and more preferably acetyl group, propionyl group, butyryl group, isoptyryl group, benzoyl A cinnamoyl group, most preferably Asechiru group, propionic group, an Benzoiru group. '

Specific examples of the hydroxyl-protecting group include, but are not particularly limited to, any group that is generally known as a hydroxyl-protecting group in organic synthesis. Examples thereof include a trimethylsilyl group and a t-butyl group. A lower alkylsilyl group such as a dimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group and a 2-methoxyethoxymethyl group; for example, a tetrahydroviranyl group; for example, a benzyl group, a P-methoxybenzyl group, and 2,4; Aralkyl groups such as -dimethyloxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, and trityl group; for example, acyl groups such as formyl group and acetyl group; for example, t-butoxy force / repotinole group, Lower alkoxycarbonyl groups such as 2-odoethoxyka ^ boninole and 2,2,2-trichloroethoxycarbonyl; for example, 2-propenyloxy Kanorepo two Norre group, 2 - click every mouth - 2-propenyl Nino les oxy Kano levo Nino les group, 3 - main Tokishikanoreboni Honoré - 2-propenyl O alkoxycarbonyl group, 2-methyl - 2-propenyl Nino les butyloxycarbonyl Alkenyloxycanolebonyl groups, such as 2-penyloxycarbonyl, cinnamyloxycarbonyl, etc .; for example, benzyloxycanolepo-nore, p-methoxybenzinoleoxy / reponyl And aralkyloxycarbonyl groups such as 0-nitrobenzyloxycanolebonyl group and p-nitrobenzyloxycarbonyl group. Preferably, it is a benzyl group.

Elimination of these protecting groups can be carried out by a conventional method such as hydrolysis or reduction depending on the type of the protecting group used.

The halogen atom specifically refers to, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The leaving group may be any group that is generally known as a leaving group in organic synthesis, and is not particularly limited. Examples thereof include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; Substituted or unsubstituted acetoxy groups such as trifluoroacetoxy group; substitution of methanesulfonolenoxy group, trifluoromethanesulfoninoleoxy group, benzenesnolephoninolexy group, p-toluenesolephoninoleoxy group, etc. A sulfonyloxy group; a substituted phosphoryloxy group such as a diphenoxyphosphoryloxy group; and the like, preferably a bromine atom, an iodine atom, an acetoxy group, a methanesulfoninoleoxy group, a trif / reolomethansnolephoninoleoxy group. , Benzenesulfonyloxy, -toluenesulfonyloxy, etc. A Suruhoniruo alkoxy group, more preferably a bromine atom, an iodine atom, Asetokishi group, methanesulfonic sulfo two / Reokishi group, p - toluene sulfonyl Nino les group.

In the present invention, the type of the salt is not particularly limited, but specific examples thereof include, for example, hydrofluoric acid, hydrochloride, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate Addition salts of inorganic acids such as, hydrobromide and hydroiodide; organic carboxylic acids such as acetate, maleate, fumarate, oxalate, lactate, tartrate, trifluoroacetate Addition salts; methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, hydroxymethanesulfonate, hydroxyxetane snorefonate, benzenesnolefonate, tonoleensnolefonate, taurine salt, etc. Addition salts of organic sulfonic acids; trimethylamine salts, triethylamine salts, pyridin salts, proline salts, picoline salts, dicyclohexylamine salts, N, N '— Giben Addition salts of amines such as diethylenediamine salt, N-methyldalcamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt and phenylbenzylamine salt; sodium salt, Addition salts of alkali metals such as potassium salts; addition salts of alkaline earth metals such as magnesium salts and calcium salts; addition of amino acids such as arginine, lysine, serine, glycine, aspartate and glutamate Salts and the like can be mentioned. Preferred are pharmacologically acceptable salts.

The production method of the present invention can be carried out by the following method.

General manufacturing method

OY

OPG ¹

7

In the formula, each symbol represents the same group as defined above.

Step 1 (compounds 1 and 2) is a step of introducing a protecting group into the diol. To the triol compound of the formula (1), a dialkoxyalkyl such as dimethoxypropane, dimethoxypentane, dimethoxyheptane, ethoxypropane, diethoxypentane or diethoxyheptane, or a ketone such as acetone, getylketone or diisopropylketone is acidified. By reacting in the presence of a catalyst, a compound of formula (2) can be obtained. The acid catalyst is not particularly limited. For example, hydrochloric acid, hydrogen bromide, hydrogen fluoride, sulfuric acid, phosphoric acid, boron trifluoride getyl ether complex, p-toluenesulfonate, pyridinium p-toluenesulfonate, (1S ) _ (+) - 10-camphorsulfonic acid, and the like may be used triphenylmethyl salts such TrC10 _4. The solvent is not particularly limited as long as it does not participate in the reaction.For example, dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, getyl ether, t- Butyl methyl ether, toluene, chloroform, methylene chloride, or benzene chloride, or a mixed solvent thereof can be used. -Incubate at 20 ° C to 100 ° C for several hours to tens of hours.

Step 2 (compounds 2 to 3) is a step of introducing a protecting group into a hydroxyl group. The alcohol compound of formula (2) is reacted with a reagent such as benzyl chloride, methoxymethyl chloride, benzyloxymethyl chloride, or p-methoxybenzyloxymethyl chloride in the presence of a base, usually in the presence of a base. The compound represented by (3) can be obtained. Bases include n-butyllithium, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, carbon dioxide, carbon dioxide, potassium t-butoxide, lithium disopropylamide, lithium Hexamethyldisilazane, sodium hexamethyldisilazane, or the like can be used. The reaction can be performed at 0 to 100 ° C. in a non-protonic solvent such as tetrahydrofuran, getinoleatenole, t-butynolemethinoleatele, or dioxane, or a mixed solvent thereof. The reaction time is usually several hours.

Step 3 (compounds 3 to 4) is a step of deprotecting the protecting group of the diol. Can be carried out by a compound represented by the formula (3) are reacted in conditions PG ¹ is not deprotected. For example, in the case of an acetal-based protecting group, it can be deprotected with an acid such as hydrochloric acid. In this case, the reaction can be performed in a solvent such as methanol, ethanol, propanol, butanol, acetonitrile, toluene, or dimethylformamide, or a mixed solvent thereof. The reaction can be performed at 0 to 100 ° C for several hours to tens of hours.

Step 4 (compounds 4 to 5) is a step of converting 1,2-diol to a cyclic orthoester. The compound represented by the formula (4) is converted to trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthobutyrate, trimethyl orthovalerate, trimethyl orthobenzoate, trimethyl orthoacetate, triethyl orthopropionate in the presence of an acid catalyst. The compound represented by the formula (5) can be obtained by reacting with orthoesters such as triethyl orthobutyrate, triethyl orthovalerate, and triethyl orthobenzoate. The acid catalyst is not particularly limited. For example, hydrochloric acid, hydrogen bromide, hydrogen fluoride, sulfuric acid, phosphoric acid, boron trifluoride dimethyl ether complex Body, p- toluenesulfonic acid, Pirijiniumu p- toluenesulfonate Na one preparative, (1S) - (+) - 10- camphorsulfonic acid, and the like may be used triphenylmethyl salts such TrC10 _4. The solvent is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, diethylenoethenol, t-butynolemethynoleethenol, and tonolone. , Chlorophonolem, methylene chloride, or benzene chloride, or a mixed solvent thereof can be used. The reaction is usually performed at 0 ° C to 100 ° C for several tens of minutes to several hours.

Step 5 (compounds 5 to 6 and 7) is a step of opening the cyclic orthoester and introducing a leaving group. By reacting the compound represented by the formula (5) with an acyl halide represented by the general formula Y—X, wherein each symbol has the same meaning as described above, the compounds represented by the formulas (6) and ( The compound represented by 7) can be obtained. As the acyl halide, acetyl chloride, acetyl chloride, acetyl chloride, acetyl chloride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide, etc. may be used. it can. The solvent is not particularly limited as long as it does not participate in the reaction.For example, dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, getyl ether, t-butyl methine ether, toluene, chloroform, chloride, etc. Methylene, benzene chloride, or a mixed solvent thereof can be used. The reaction is usually performed at 0 ° C to 100 ° C for tens of minutes to several hours.

Step 6 (compounds 6 and 7 to 8) is a step of a ring-closing reaction of the oxysilane. By reacting the compounds represented by the formulas (6) and (7) with a base, the oxysilane compound represented by the formula (8) can be obtained. As the base, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, carbon dioxide lime, hydrogen carbonate lime, or the like can be used. The solvent is not particularly limited as long as it does not participate in the reaction. For example, methanol can be used. The reaction is usually performed at 0 ° C to 100 ° C for several tens of minutes to several hours.

Steps 4 to 6 can be applied to the next reaction without isolating each target compound. In the present application, X is preferably a bromine atom and the like, Y is preferably an acetyl group and the like, PG] is preferably a benzyl group and the like, R ³ and R ⁴ are preferably a methyl group and the like, R ¹ and R ² are preferably an ethyl group. Therefore, the method of the present invention can be implemented by the following scheme.

Method 1 1

2N-HCl MeOH

r.t.

In the formula, Ts is a p-toluenesulfonyl group, Bn is a benzyl group, TBAI is tetra-n-butylammonium hydroxide, PPTS is pyridyl-dimethyl P-toluenesulfonate, and Ac is acetyl Each means a group. '

As described above, the solvent that can be used in the present invention is not particularly limited as long as it does not inhibit the reaction, and may be any solvent that is generally used in organic synthesis. Examples of the solvent include methanol and ethanol. , Lower alcohols such as propanol and butanol, polyalcohols such as ethylene glycol and glycerin, ketones such as acetone, methinoolethylene ketone, ethynoleketone and cyclohexanone, getyl ether, isopropyl ether, tetrahydrofuran, and dioxy. Ethers such as sun, 2-methoxyethanol and 1,2-dimethoxetane, trinitols such as acetonitrile and propionitrile, and esters such as methyl acetate, ethyl acetate, isopropyl acetate, petitinole acetate, and ginolephthalate. S, dichloro methane, black hole Holm, carbon tetrachloride, 1, 2-Jikuroroetan, Torikuroroechi Ren, halogenated hydrocarbons such as tetrachloroethene port ethylene, benzene, toluene, Aromatic substances such as xylene, monochlorobenzene, nitrobenzene, indene, pyridine, quinoline, collidine, phenol, pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine, petroleum hydrocarbon, etc. , Ethanolamine, getylamine, triethylamine, pyrrolidine, piperidine, piperazine, monoleforin, aniline, dimethinorea diline, benzinoleamine, toluidine and other amines, formamide, N-methylpyrrolidone, N, N-dimethylimidazo Amides such as RON, N, N-dimethinoleacetamide, N, N-dimethylformamide, phosphate amides such as hexamethyl phosphate triamide, hexamethyl phosphite triamide, water, and others Can be exemplified one or two or more kinds of mixed solvents such as solvent use, the mixing ratio is not particularly limited.

As described above, the bases that can be used in the present invention are those that do not inhibit the reaction, and are not particularly limited as long as they are generally known as bases in organic synthesis. Specifically, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N, N-diisopropylethyl N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8-diazabicik mouth [5,4,0] pendene-7-ene (DBU), pyridine , 4-dimethylaminoviridine, picoline, lutidine, quinoline, isoquinoline, sodium hydroxide, hydroxylated water, hydroxylated Lithium, heptyl lithium, sodium methylate, Kariumumechi acrylate, etc. Natoriumu or force Riumuarukora Ichito such Natoriumuechira one preparative and the like.

After completion of the above reaction, if desired, purification can be performed by a usual treatment method, for example, by column chromatography using silica gel or an adsorption resin, or by recrystallization from a suitable solvent. Example

The present invention will be described in detail and specifically with reference to the following Examples. However, the present invention is not limited to the embodiment.

Example 1. Method for producing (S)-(2-benzyloxyshethyl) oxylan

Example 1-1) (S) -2,2-Getyl-4- (2-hydroxyxethyl) -1,3-dioxolan ()

At room temperature, (S) -1,2,4-butanetriol: 30.0 g (0.277 mol) in dimethylformamide (150 ml) solution, 3,3-diethoxypentane: 49.8 g (0.311 mol), _p -Toluenesulfonic acid monohydrate: 400 mg was added, and the mixture was stirred. Triethylamine: 5 ml was added, the solvent was distilled off, a saturated saline solution containing sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (300 ml). The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. . After filtration, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 41.8 g (bp 80 to 84 ° C / 0.20 mmHg; 0.240 mol, 86.7%) of the title compound.

-丽_{R (CDC1 3) δ: 0.90} (3H, t, J = 7.6Hz), 0.91 (3H, t, J = 7.6Hz), 1.63 (2H, q, J = 7.6Hz), 1.66 (2H, q , J = 7.6Hz), 1.80-1.86 (2H, m), 2.35 (1H, bs), 3.55 (1H, t, J = 8.2Hz), 3.78-3.84 (2H, m), 4.10 (1H, dd, J = 8.2, 6.2Hz), 4.22-4.30 (1H, m). Example 1-2) (S) _4- (2_benzyloxyshetyl) -2,2-getyl-1,3-dioxolane ( 3)

In a nitrogen stream, ice-cooled sodium hydride: 7.5 g (0.188 mol: 60% dispersion in mineral oil was washed three times with Tonolene (50 ml)) in tetrahydrofuran (200 ml) was added to (S) -2,2. -Jetyl-4- (2-hydroxyxetyl) -1,3-dioxolane: A solution of 25.0 g (0.143 mol) of tetrahydrofuran (50 ml) was added dropwise, and the mixture was heated at 70 ° C for 30 minutes. After cooling to room temperature, benzyl bromide: a solution of 25.5 g (0.149 mol) in tetrahydrofuran (50 ml), tetra-n-butylammonium iodide: 5.3 g (0.014 mol) And heated again at 70 ° C for 2 hours. Under ice-cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 ml). The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and n-hexane (250 ml) was added to the residue. After filtration of the insolubles, the solvent was distilled off to obtain 40.8 g (quant.) Of the title compound.

'H-NMR (CDC1 ₃ ) δ 0.90 (6 t, t, J 二 7.6Ηζ), 1.61 (2Η, q, J = 7.6Hz), 1.63 (2H, q, J = 7.6Hz), 1.80-1.89 ( 1H, m), 1.90-1.99 (1H, m), 3.53 (1H, t, J = 8.2Hz), 3.55-3.62 (2H, m), 4.07 (1H, dd, J = 8.2, 6.2), 4.17- 4.25 (1H, m), 4.50 (2H, s), 7.24-7.36 (5H, m). Examples 1-3) (S) -4- (Benzyloxy) butane-1,2-diol (

At room temperature, (N) -hydrochloric acid was added to a solution of 40.0 g (0.151 mol) of methanol (280 ml) in (280 ml) of (S) -4- (2-benzyloxethyl) -2,2-diethyl-1,3-dioxolane: 120 ml (0.240 mol) was added and stirred. After the methanol was distilled off, the aqueous layer was washed with heptane: 80 ml. Salt was added to the aqueous layer and extracted with ethyl acetate (200 mix 3). The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and 27.6 g of the title compound (0.141 mol, quant, from about 7 mg) was obtained.

_{'H-NMR (CDC1 3)} δ: 1.69-1.78 (1H, m), 1.79-1.88 (1H, m), 3.50 (1H, dd, J: 11.0, 5.5Hz), 3.63 (1H, dd, J = ll.0, 4.1Hz), 3.65-3.74 (2H, m), 3.89-3.95 (1H, m), 7.26-7.38 (5H, m) .Example 1-4) (S)-(2-benzylo Kishetil) Oxylan ()

At room temperature, pyridinium p-toluenesulfonate: 320 mg (1.27 g) was added to a solution of (S) -4- (benzyloxy) butane-1.2-diol: 25.0 g (0.127 mol) in methylene chloride (200 ml). Bandar ol), trimethyl orthoacetate: 19.5 ml (0.152 mol) was added, and the mixture was stirred for 30 minutes. The solvent was distilled off and dried with a vacuum pump for 3 minutes. At room temperature, 10.7 ml (0.143 mol) of acetyl bromide was added to a solution of the residue in methylene chloride (200 ml), and after stirring for 40 minutes, the solvent was distilled off. At room temperature, 23.0 g (0.166 mol) of potassium carbonate was added to a solution of the residue in methanol (200 ml), the mixture was stirred for 2.5 hours, and then concentrated. Ethyl acetate (200 ml) and water were added to the residue for extraction. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 20.7 g (bp-93 ° C / 0.15 mmHg; 0.116 mol, 91.5%) of the title compound.

_{'Η - NMR (CDC1 3)} δ: 1.74-1.83 (1Η, m), 1.88-1.97 (1H, m), 2.53 (1H, dd, J = 4.8, 2.4Hz), 2.79 (1H, t, J = 4.8Hz), 3.05-3.10 (1H, m), 3.60-3.66 (2H, m), 4.54 (2H, s), 7.26-7.37 (5H, m).

Reference example

(S)-(2-Benzyloxshetyl) oxylan () obtained in this manner is a lipid A analog useful for the prevention and treatment of dallam-negative bacteremia, especially endotoxin shock. Useful as an intermediate for producing E5564 represented by the structural formula.

Specifically, (S)-(2-benzyloxystyl) oxysilane () is converted to the following (3R) -3-methoxy-1-decanol (4) or (3R) -3-methoxydecanyl methanesulfur Fornate (5) , Used by guiding. Reference Example 1. Method for producing (3R) -3- 3-methoxydecanyl methanesulfonate

Reference Example 1-1) (3R) -1-benzyloxydecane-3_ol (6)

Hexylmagnesium bromide in a solution of copper (I) iodide: 2.22 g (ll. 1 mmol) in tetrafuran-furan (25 ml) cooled to 30 ° C under a nitrogen stream: 11.10 ml (22.4)

2.0M getyl ether solution), and the mixture was stirred for 30 minutes, and then a solution of (S)-(2-benzyloxyshethyl) oxysilane: 1.97 g (ll.l mmol) in tetrahydrofuran (5 ml) was added. After stirring for 1 hour, the mixture was brought to room temperature and further stirred for 1 hour. An aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml). The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to obtain 2.74 g (10.4 mmol, 93.8%) of the title compound.

_{! H- NMR (CDC1 3) δ} 0.88 (3Η, t, J = 7.0Hz), 1.28 (10H, bs), 1 · 36 - 1.52 (2H, m), 1.72-1.78 (2H, m), 2.87 ( 1H, bs), 3.62-3: 68 (1H, m), 3.70- 3.76 (1H, m),

3.77-3.83 (1H, m), 4.51 (2H, s), 7.26-7.37 (5H, m). Reference Example 1-2) (3R) -1_benzyloxy-3-methoxydecane (7) (7)

At room temperature, (3R) _1-benzyloxydecane-3-ol: A solution of 1.80 g (6.8 mmol) in tetrahydrofuran (2 ml) was mixed with potassium hydroxide: 895 mg (13.6 s ol), and lodomethane: 0.55 ml ( 8.8 mmol) and stirred for 4 days. Water was added to the reaction solution, extracted with n-hexane, and the extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane, The residue was purified by ethyl acetate to give 1.52 g (5.5 t, 80.2%) of the title compound. — Marauder R (CDC1 ₃ ) δ: 0.88 (3Η, t, J "2 7.0Hz), 1.27 (10H, bs), 1.40-1.52 (2H, m), 1.72-1.80 (2H, m), 3.32 (3H , s), 3.27-3.36 (1H, m), 3.50-3.62 (2H, .m), 4.50 (2H, s), 7.26-- 7.37 (5H, m) .Reference example 1-3) (3R) -3 -Methoxy-1-decanol (4)

At room temperature, (3R) -1-benzyloxy-3-methoxydecane: 1.30 g (4.7 mmol) in methanol (20 ml) was added with 20% palladium hydroxide (water to 50%): 260 mg, and added water. (Normal pressure). After the reaction solution was filtered through celite, the solvent was distilled off to give 880 mg (4.7 mmol, quant.) Of the title compound. Reference example 1-4) (3R)-3 -Methoxydecanyl methanesulfonate (5)

OMe

^ / ^ A ^ _0Ms (5) Ice-cooled (3R) -3- 3-methoxy-1-decanol: 1.90 g (10.1 acetyl) of tetrahydrofuran (20 ml) in solution of triethylamine: 1.60 ml (11.5 glutanol) ), And then 0.80 ml (10.3 tmol) of methanesulfonyl chloride was added, followed by stirring for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml). The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography ( _n- hexane, ethyl acetate) to obtain 2.68 g (10.1 mmol, 99.7%) of the title compound.

^ -NMRiCDC ^) δ: 0.88 (3Η, t, J = 7.2Hz), 1.29 (10H, bs), 1.40-1.48 (1H, m), 1.51-1.59 (1H, m), 1.78-1.87 (1H, m), 1.90-1.99 (1H, m), 3.01 (3H, s), 3.29-3.36 (1H, m), 3.33 (3H, s), 4.28-4.39 (2H, m).

(3R) -3-Methoxy-1-decanol (4) and (3R) -3-methoxydecanyl methanesulfonate (5) thus obtained can be used for the production of E5564 by the following method. Can be. This E5564 can be produced, for example, by a method represented by the following scheme, as disclosed in US Pat. Nos. 5,750,664, 5,935,938, and JP-T-11-506793.

twenty one

Replacement form (Rule 26) The compound represented by the formula used in the reaction of 6. in the method of 6.

21/1

Replacement form (Rule 26)

E5564 can be similarly produced by using the following formula synthesized in the present application instead of

CH ₃ Q

twenty two.

Claims

The scope of the claims

1. General formula (6): wherein, X is a halogen atom, Y is C 2_ l 1 a Ashiru group, PG ¹ denotes a protecting group for hydroxyl group] are represented by the compound (6) and Bruno or general Wherein the leaving group of the compound (7) represented by the formula (7) [wherein each symbol represents the same group as defined above], is represented by the following general formula (8): The symbols represent the same groups as defined above.] A method for producing compound (8) or a salt thereof or a hydrate thereof:

2. A compound represented by the general formula (5) wherein R ³ and R ⁴ each represent a C 16 alkyl group which may be the same or different, and PG ^] represents a hydroxyl-protecting group. 5) is reacted with a compound represented by the formula Y—X (wherein X represents a halogen atom and Y represents a C 2-11 acyl group), and a compound represented by the general formula (6) Wherein the symbols have the same definition as described above), and compounds (6) and Z or a compound (7) represented by the general formula (7) wherein each symbol has the same definition as described above;

Then, the compound represented by the general formula (8), wherein the symbols have the same definitions as described above, wherein the leaving group of the compound (6) and / or the compound (7) is eliminated. (8) or a method for producing the salt or hydrate thereof:

YO. A i (6)

twenty three

( ⁸ ).

3. A protecting group is introduced into two hydroxyl groups of the compound (4) represented by the general formula (4) [wherein, PG ¹ represents a protecting group for a hydroxyl group], and the general formula (5) R ³ and R ⁴ each represent a C 1-6 alkyl group which may be the same or different, and PG ¹ has the same definition as described above.)

The compound (5) is reacted with a compound represented by the formula Y—X wherein X represents a halogen atom and Y represents a C 2-11 acyl group. And each symbol has the same definition as described above.) Compound (6) and / or general formula (7)

[Wherein each symbol has the same definition as above], and the leaving group of these compounds (6) and (h) or compound (7) is then eliminated. A method for producing a compound (8) represented by the general formula (8) wherein the symbols have the same definitions as described above, or a salt thereof, or a hydrate thereof:

OH

HO (4)

OPG 1

χ_

YO 1 (6)

4. A compound represented by the general formula (3) wherein R ¹ and R ² each represent a C 16 alkyl group which may be the same or different, and PG ¹ represents a hydroxyl-protecting group. 3) is treated with an acid to form a general formula (4) wherein PG ¹ has the same definition as above.

twenty four And a protecting group is introduced into two hydroxyl groups of the compound (4) to obtain a compound represented by the general formula (5): wherein R ³ and R ⁴ may be the same or different. Represents a 1-6 alkyl group, and PG ¹ has the same definition as above.)

OH

(Four)

OPG ¹

5. General formula (2) wherein a protecting group is introduced into the compound (2) represented by the general formula (2) wherein R ¹ and R ² each represent a C 1-6 alkyl group which may be the same or different. Wherein R ¹ and R ² have the same definition as described above, and PG ¹ represents a hydroxyl-protecting group.

twenty five Treating the compound (3) with an acid to give a compound (4) represented by the general formula (4) wherein PG ¹ has the same definition as described above;

Then, protecting groups are introduced into two hydroxyl groups of the compound (4) to obtain a compound represented by the general formula (5) wherein R ³ and R ⁴ each represent a C 1 -6 alkyl group which may be the same or different, and PG ¹ Having the same definition as described above].

The compound (5) is reacted with a compound represented by the formula Y_X (wherein X represents a halogen atom and Υ represents a C 2-11 acyl group), and a compound represented by the following general formula (6): The symbols have the same definitions as described above.] (6) and Ζ or the general formula (7)

YO (6)

26

6. A protecting group is introduced into the compound (1) represented by the general formula (1) to form a compound represented by the general formula (2) wherein R ¹ and R ² are each a C 1-6 alkyl group which may be the same or different. The compound (2) represented by

The compound (5) is reacted with a compound represented by the formula Y—X wherein X represents a halogen atom and Y represents a C 2-11 acyl group. Wherein each symbol has the same definition as described above.] (6) and Z or the general formula (7)

OH

HO ^^ oH (1)

0H

H0

OPG 1 ¹ ( ⁴ )

27

7. The method according to any one of claims 1 to 6, wherein X is a bromine atom.

8. The method according to any one of claims 1 to 7, wherein Y is an acetyl group.

9. PG ¹ Gabe Njiru method of any one of claims 1-8 is a group.

0 R ³ and R ⁴ are the method of any one of claims 2-9 is a methyl group

The method according to any one of claims 4 to 10, wherein 11 R ¹ and R ² are an ethyl group.

28