CN101238140A - Method for producing lipid a analogue - Google Patents

Abstract

The present invention provides a process for producing alpha-D-glucopyranose, 3-O-decyl-2-deoxy-6-O- [ 2-deoxy-3-O- [ (3R) -3-methoxydecyl ] -6-O-methyl-2- [ [ (11Z) -1-oxo-11-octadecenyl ] amino ] -4-O-phosphono-beta-D-glucopyranosyl) -2- [ (1, 3-dioxotetradecyl) amino ] -, 1- (dihydrogenphosphate) tetrasodium salt and a synthetic intermediate thereof, which are excellent in safety, operability and reproducibility, and are useful as a raw material for producing a medicament. The present invention provides a method for producing a compound represented by the formula (I), wherein a compound represented by the formula (VIII) is reacted with a palladium catalyst in the presence of a nucleophile, and then treated with a sodium source.

Description

Method for producing lipid A analogs

technical field

The present invention relates to a method for producing a lipid A analog E5564 (also known as B1287, name of Eritoran) represented by formula (I) for use as a medicine.

[chemical 1]

Background technique

For E5564 represented by formula (I) (also known as B1287, the name of Eritoran), the lethality rate caused by lipopolysaccharide (LPS: Lipopolysaccharide) components or endotoxins present in the outer membrane of Gram-negative bacteria is known. It has excellent effects in the prevention and treatment of high Gram-negative bacteremia, especially endotoxic shock. In addition, E5564 has been confirmed to have an excellent anti-endotoxin effect on humans (Non-Patent Document 1), and it is also known to have antagonism against TLR4 (Toll-like receptor 4), which is one of the receptors that recognize bacterial cell components Effect (see Patent Document 1, Non-Patent Document 2). Based on these actions, it is reported that E5564 is particularly effective as a prophylactic or therapeutic agent for improving the prognosis of sepsis, endotoxemia, coronary artery bypass surgery (CABG: prognosis of coronary-arterybypass graft surgeies), etc. (See, for example, Patent Documents 2, 3, 4).

Patent Document 2 describes the free form of E5564 represented by formula (I), and Patent Document 3 describes E5564 (B1287) represented by formula (I). In addition, synthesis methods of E5564 are disclosed in Patent Documents 5, 6 and 7.

According to the synthesis methods disclosed in Patent Documents 5, 6 and 7, E5564 is prepared by introducing two acyl-type side chains after the combination of two carbohydrates (saccharide), but it is necessary to change the functional group for the introduction of side chains. Multiple processes, and moreover, in multiple processes, dichloromethane must be used. In Patent Documents 6 and 7, other synthesis methods in which two sugars are combined after introducing one acyl-type side chain in advance are disclosed, but the yield of the remaining second acyl-type side chain is very low, In addition, the use of dichloromethane cannot be avoided. In addition, Patent Document 3 describes a method of producing a lipid A analog represented by formula (I) by introducing two acyl-type side chains in advance and then combining two sugars. For example, in Step 3 (p123-124) of Example 5 of Patent Document 3, the compound of formula (VIII) of the present invention is described. However, according to the method described in step 3, in order to obtain the compound of formula (VIII), it is necessary to use dichloromethane as a solvent, and in the presence of explosive tetrazole, after introducing a phosphorous acid group, at a temperature of -78 ° C, a high price m-chloroperbenzoic acid as oxidizing agent and the product was purified by column chromatography. In addition, in Step 4 (p124-125), a method for producing the compound of formula (II) and its tetrasodium salt (B1287) of the present invention is disclosed. According to this production method, it is necessary to transport tetrakis(triphenylphosphine)palladium into a reaction vessel filled with nitrogen gas into a spherical package. In addition, as a synthesis example of saccharides constituting the β-D glucopyranosyl moiety of the lipid A analog of the present invention, for example, in Example 1 Step 3 (p100-101), it is disclosed that the formula ( X) A process for the manufacture of compounds of formula (III), but with extremely low yields.

Patent Document 1: WO2004/071465

Patent Document 2: WO96/39411

Patent Document 3: WO2004/074303

Patent Document 4: US20050153929

Patent Document 5: US5750664

Patent Document 6: US5935938

Patent Document 7: US6417172

Non-Patent Document 1: Lynn et al., J.Pharmacol.Exp.Ther.308(1):175-181, 2004)

Non-Patent Document 2: Mullarkey et al., J.Pharmacol.Exp.Ther.304(3):1093-1102, 2003)

Contents of the invention

The problem to be solved by the invention

E5564 has shown good effects as a preventive or therapeutic agent for sepsis, endotoxemia, recovery period improvement of coronary artery bypass surgery (CABG: prognosis of coronary-arterybypass graft surgeries), etc. Some manufacturing methods have problems in the number of steps, raw material cost, safety during the manufacturing process, operability, reproducibility, etc. from the viewpoint of commercial production as a pharmaceutical raw material. In addition, according to the existing production method, in the synthesis process of E5564, for example, dichloromethane must be used as a reaction solvent, but dichloromethane is classified according to the UN Hazard Class because of its influence on the human body. Classified as 6.1 [Toxic Substances], Classified as Level 2 [Solvents that need to be controlled in drug residues] according to the Quality Standard Q3C [Standards on Impurities: Residual Solvents] of the International Council for Harmonization of Technical Requirements for Drug Registration (ICH) . In addition, in Japan, upper limit values are set as environmental standards for air pollution and water pollution.

After pre-introducing two acyl-type side chains, the preparation method described in Patent Document 3 in which two sugars are combined is excellent in reducing the total number of steps, especially in improving the process after the sugars are combined, but it is difficult to use toxic reagents. There are problems in the use of a large amount, the use of explosive reagents, operability in the manufacturing process, reproducibility, etc. In addition, the use of dichloromethane cannot be avoided.

Therefore, a production method of E5564 that is excellent in environment, safety, operability, and reproducibility is required.

method used to solve the problem

The present inventors etc. have carried out meticulous research, and found that the new manufacturing method of E5564 represented by formula (I) and its synthetic intermediate are good to the environment, and the new manufacturing method of safety, operability, reproducibility is excellent, thus completed the following of the invention.

<1> A method for producing a compound represented by formula (I), wherein the compound represented by formula (VIII) is reacted with a palladium catalyst in the presence of a nucleophile, followed by treatment with a sodium source.

[Chem 2]

<2> A method for producing a compound represented by formula (I), wherein the compound represented by formula (VII) is mixed with diallyl N in the presence of pyridine-trifluoroacetic acid in a first aromatic hydrocarbon solvent , N-diisopropyl phosphoramidate and oxidizing agent react successively to obtain the compound represented by formula (VIII), then in the presence of nucleophilic reagent, after making the compound represented by formula (VIII) react with palladium catalyst, use sodium source deal with.

[Chem 3]

<3> A method for producing a compound represented by formula (I), wherein the 1-propenyl group of the compound represented by formula (VI) is selectively deprotected to obtain a compound represented by formula (VII), and then, in the first In an aromatic hydrocarbon solvent, in the presence of pyridine-trifluoroacetic acid, the compound represented by the formula (VII) is reacted with diallyl N, N-diisopropyl phosphoramidate and an oxidizing agent in sequence to obtain the compound represented by the formula (VIII). Then, in the presence of a nucleophile, the compound represented by the formula (VIII) is reacted with a palladium catalyst, and treated with a sodium source.

[chemical 4]

[chemical 5]

<4> A method of producing a compound represented by formula (I), wherein, in the first solvent containing a hydrocarbon solvent and/or the second aromatic hydrocarbon solvent, in the presence of an organic sulfonic acid, the compound of formula (IV) ) is reacted with a compound represented by formula (V) to obtain a compound represented by formula (VI), and then, the 1-propenyl group of the compound represented by formula (VI) is selectively deprotected to obtain the compound represented by formula (VII) Compound, then, in the 1st aromatic hydrocarbon solvent, in the presence of pyridine-trifluoroacetic acid, the compound represented by formula (VII) is reacted successively with diallyl N, N-diisopropyl phosphoramidate and oxidizing agent , to obtain the compound represented by the formula (VIII), and then react the compound represented by the formula (VIII) with a palladium catalyst in the presence of a nucleophile, and then treat it with a sodium source.

[chemical 6]

[chemical 7]

<5> In any one of the above <1> to <4>, the first aromatic hydrocarbon solvent is a toluene solvent.

<6> In the above <4> or <5>, the organic sulfonic acid is methanesulfonic acid or ethanesulfonic acid.

<7> In any one of the above <4> to <6>, the first solvent is a toluene-heptane mixed solvent.

<8> In any one of the above <4> to <7>, the compound represented by the formula (IV) is prepared by making the compound represented by the formula (III) in a mixed solvent of acetate solvent and water in the presence of potassium carbonate The compound represented is obtained by reacting 1 to 10 equivalents of trichloroacetonitrile with respect to 1 equivalent of the compound represented by the formula (III).

[chemical 8]

<9> In any one of the above <4> to <8>, the compound represented by formula (IV) is represented by formula (III) by selectively deprotecting the 1-propenyl group of the compound represented by formula (X). compound, then in the mixed solvent of acetate solvent and water, in the presence of potassium carbonate, make the compound represented by formula (III) and the compound represented by formula (III) be 1 to 10 equivalents of three Chloroacetonitrile obtained by reaction.

[chemical 9]

<10> In any one of the above-mentioned <4> to <9>, the compound represented by the formula (IV) is obtained by reacting the compound represented by the formula (IX) with diallyl N in the presence of pyridine-trifluoroacetic acid, N-diisopropyl phosphoramidate and oxidizing agent react successively to obtain the compound represented by formula (X), then, the 1-propenyl group of the compound represented by formula (X) is selectively deprotected to obtain the compound represented by formula (III) Compound, then, in the mixed solvent of acetate solvent and water, in the presence of potassium carbonate, make the compound represented by formula (III) and the compound represented by formula (III) be 1～10 equivalents of three Chloroacetonitrile obtained by reaction.

[chemical 10]

<11> In any one of the above <8> to <10>, the acetate-based solvent is methyl acetate.

<12> In any one of the above <8> to <11>, the content of water in the mixed solvent is 1 to 10% (volume/capacity ratio).

<13> In any one of the above <1> to <12>, the nucleophile is a cyclic organic acid ester or a cyclic ketone.

<14> In any one of the above <1> to <13>, the nucleophile is Meldrum's Acid or dimedone.

<15> In any one of the above <1> to <14>, the palladium catalyst is tetrakis(triphenylphosphine)palladium.

<16> In the above <15>, tetrakis(triphenylphosphine)palladium is generated in the system from palladium acetate and triphenylphosphine.

<A1> A method for producing a compound represented by formula (I), wherein the compound represented by formula (VIII) is reacted with a palladium catalyst in the presence of a nucleophile, followed by treatment with a sodium source.

[chemical 11]

<A2> A method for producing a compound represented by formula (I), wherein, in a toluene solvent, in the presence of pyridine-trifluoroacetic acid, the compound represented by formula (VII) and diallyl N, N-di Isopropyl phosphoramidate and an oxidizing agent react sequentially to obtain a compound represented by formula (VIII), and then react the compound represented by formula (VIII) with a palladium catalyst in the presence of a nucleophile, and then treat it with a sodium source.

[chemical 12]

<A3> A method for producing a compound represented by formula (I), wherein the 1-propenyl group of the compound represented by formula (VI) is selectively deprotected to obtain a compound represented by formula (VII), and then, in toluene solvent In, in the presence of pyridine-trifluoroacetic acid, the compound represented by the formula (VII) is reacted with diallyl N, N-diisopropyl phosphoramidate and an oxidizing agent in sequence to obtain the compound represented by the formula (VIII), and then In the presence of a nucleophile, the compound represented by the formula (VIII) is reacted with a palladium catalyst, followed by treatment with a sodium source.

[chemical 13]

[chemical 14]

<A4> A method for producing a compound represented by formula (I), wherein, in a mixed solvent of toluene-heptane, in the presence of methanesulfonic acid, the compound represented by formula (IV) and the compound represented by formula (V) reaction of the compound to obtain the compound represented by formula (VI), then, the 1-propenyl group of the compound represented by formula (VI) is selectively deprotected to obtain the compound represented by formula (VII), and then, in toluene solvent, in In the presence of pyridine-trifluoroacetic acid, the compound represented by formula (VII) is reacted successively with diallyl N, N-diisopropyl phosphoramidate and an oxidizing agent to obtain the compound represented by formula (VIII), and then in nucleophilic In the presence of the reagent, the compound represented by the formula (VIII) is reacted with the palladium catalyst, followed by treatment with a sodium source.

[chemical 15]

[chemical 16]

<A5> In the above <A4>, the compound represented by the formula (IV) is prepared by mixing the compound represented by the formula (III) and the compound represented by the formula (III) with respect to 1 equivalent The formula (III) represents that the compound is obtained by reacting 1 to 10 equivalents of trichloroacetonitrile.

[chemical 17]

<A6> In the above <A4>, the compound represented by the formula (IV) is obtained by selectively deprotecting the 1-propenyl group of the compound represented by the formula (X), to obtain the compound represented by the formula (III), and then the compound represented by the acetate It is obtained by reacting the compound represented by the formula (III) with 1 to 10 equivalents of trichloroacetonitrile relative to 1 equivalent of the compound represented by the formula (III) in the presence of potassium carbonate in a mixed solvent of a solvent and water.

[chemical 18]

<A7> In the above <A4>, the compound represented by the formula (IV) is obtained by mixing the compound represented by the formula (IX) with diallyl N,N-diisopropyl phosphoramidate in the presence of pyridine-trifluoroacetic acid. Ester and oxidizing agent react successively to obtain the compound represented by formula (X), then the 1-propenyl group of the compound represented by formula (X) is selectively deprotected to obtain the compound represented by formula (III), and then in acetate solvent and It is obtained by reacting the compound represented by the formula (III) with 1 to 10 equivalents of trichloroacetonitrile relative to 1 equivalent of the compound represented by the formula (III) in the presence of potassium carbonate in a mixed solvent of water.

[chemical 19]

<A8> In any one of <A5> to <A7> above, the acetate-based solvent is methyl acetate.

<A9> In any one of the above <A5> to <A8>, the content of water in the mixed solvent is 1 to 10% (volume/capacity ratio).

<A10> In any one of the above <A1> to <A9>, the nucleophile is a cyclic organic acid ester or a cyclic ketone.

<A11> In any one of the above-mentioned <A1> to <A10>, the nucleophile is merbellic acid or dimedone.

<A12> In any one of the above <A1> to <A11>, the palladium catalyst is tetrakis(triphenylphosphine)palladium.

<A13> In the above <A12>, tetrakis(triphenylphosphine)palladium is produced in the system from palladium acetate and triphenylphosphine.

Invention effect

According to the present invention, the compound (E5564) of the formula (I) that acts on the lipopolysaccharide (LPS: lipopolysaccharide) component present in the outer membrane of Gram-negative bacteria or Gram-negative bacteremia with high lethality caused by endotoxin, especially lipid A, which plays a major role in endotoxin shock, produces antagonism and shows excellent anti-endotoxin effect. TLR4 (Toll-like receptor 4), one of the body, shows antagonism, so as the recovery period of sepsis (sepsis), endotoxemia (endotoxemia), coronary artery bypass graft surgery (CABG: prognosis of coronary-artery bypass graft prophylactic or therapeutic agents such as surgeries) are particularly useful.

Detailed ways

In this specification, the following apostrophes are used.

DDP: diallyl N, N-diisopropyl phosphoramidate;

Py: pyridine;

TFA: trifluoroacetic acid.

Hereinafter, the production method of the compound of formula (I) of the present invention will be described in detail.

The compound of formula (I) can be produced by the following production method.

Manufacturing method

[chemical 20]

[chem 21]

[chem 22]

The first step of the production method is to introduce a phosphorous acid group into the compound of the formula (IX), and then undergo an oxidation reaction to form the compound of the formula (X). The solvent used in this step is not particularly limited, and is preferably an inert solvent that does not easily react with the raw material, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, and dimethoxyethane. , Halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane, hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene, acetates such as ethyl acetate and methyl acetate N, N-dimethylformamide, N-methyl-2-piperidone, amides such as hexamethylphosphoramide, sulfoxides such as dimethyl sulfoxide and their mixed solvents, among them, aromatic Hydrogen hydrocarbon solvents, such as toluene are particularly preferred.

This step can be reacted under mild conditions by performing the reaction in the presence of pyridine and trifluoroacetic acid. Pyridine and trifluoroacetic acid used in this step can be used in equal amounts or in excess relative to the compound of formula (IX). In consideration of smooth reaction, purification treatment, etc., they are preferably 1.0-3.0 equivalents and 1.0-3.0 equivalents, respectively, Among them, 1.0 to 2.0 equivalents and 1.0 to 2.0 equivalents are more preferable, respectively.

This step is composed of a total of two steps of introducing a phosphorous acid group and an oxidation step. The diallyl N, N-diisopropyl phosphoramidate used in the step of introducing a phosphorous acid group is relative to the formula (IX) The compounds can be used in equal amounts or in excess, preferably 1.0 to 2.0 equivalents. The reaction time of the phosphorous acid group introducing step is 0.5 to 4 hours, preferably 1 to 2 hours. The reaction temperature is -78°C to room temperature, preferably -40°C to 0°C. Examples of the oxidizing agent used in the oxidation step include hydrogen peroxide, m-chloroperbenzoic acid, and potassium persulfate preparations, among which hydrogen peroxide is most preferred. Hydrogen peroxide can be used in an equal amount or in excess relative to the compound of formula (IX), preferably 1.0 to 3.0 equivalents. The reaction time of the oxidation step is 0.5 to 6 hours, preferably 1 to 4 hours. The reaction temperature is preferably -50 to 0°C.

The second step of this production method is a step of producing a compound of formula (III) by selectively deprotecting the 1-propenyl group by acid hydrolysis of the compound of formula (X). The solvent used in this step is not particularly limited, and is preferably an inert solvent that does not easily react with the raw material, and examples thereof include alcohols such as methanol, ethanol, isopropanol, and tert-butanol, tetrahydrofuran, diethyl ether, and diisopropyl ether. , dioxane, dimethoxyethane, diethoxyethane, diglyme and other ethers, chloroform, carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbons, Hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene, nitriles such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2- Amides such as piperidone and hexamethylphosphoramide, and sulfoxides such as dimethyl sulfoxide, among them, nitriles such as acetonitrile are preferable.

Acids used in this step include common organic acids and inorganic acids. Examples of organic acids include monocarboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid, and benzoic acid; dicarboxylic acids such as oxalic acid; methanesulfonic acid; Organic sulfonic acids such as acid, toluenesulfonic acid, and trifluoromethanesulfonic acid. Examples of inorganic acids include phosphoric acid, hydrochloric acid, sulfuric acid, and nitric acid, preferably inorganic acids such as hydrochloric acid and sulfuric acid.

The acid used in this step can be used in a catalytic amount or in excess relative to the compound of formula (X), and in consideration of smooth reaction, purification, etc., it is preferably 0.01 to 1.5 equivalents, and more preferably 0.1 to 1.0 equivalents. .

The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. The reaction temperature is from 0°C to reflux, preferably from 10°C to 60°C.

In addition, by crystallizing the obtained compound of formula (III) under appropriate conditions, effects such as improvement in purity can be obtained.

The third step of the production method is a step of introducing a trichloroacetylimidate group as a leaving group into the compound of the formula (III) in the presence of a base to produce the compound of the formula (IV). The trichloroacetonitrile used in this step can be used in the same amount or in excess relative to the compound of formula (III). In consideration of smooth reaction, purification, etc., it is preferably 1.0 to 10.0 equivalents, and more preferably 2.0 to 10.0 equivalents. 5.0 equiv.

Solvents used in this step include, for example, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, and dimethoxyethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Halogenated hydrocarbons such as ethyl acetate and methyl acetate, acetates such as ethyl acetate and methyl acetate, water, their mixed solvents, etc. Among them, a mixed solvent of acetates such as methyl acetate and ethyl acetate and water is preferred, and reproducibility can be achieved. React well.

The mixing ratio of the acetate used as a solvent and water is preferably 1 to 10% (volume/volume ratio) in terms of water, and more preferably 2 to 5%.

The alkali used in this step includes, for example, carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, bicarbonates such as sodium bicarbonate, alkali metals such as sodium methoxide and potassium tert-butoxide, among which potassium carbonate is preferred. etc. carbonates.

The base used in the present invention can be used in an equal amount or in excess relative to the compound of formula (III). In consideration of smooth reaction, purification treatment, etc., it is preferably 0.5 to 3.0 equivalents, and more preferably 1.0 to 1.3 equivalents. .

The reaction time is 0.5 to 24 hours, preferably 1 to 5 hours. The reaction temperature is preferably carried out at -20°C to room temperature, more preferably -5 to 10°C.

The fourth step of this production method is a step of preparing a compound of formula (VI) by bonding the compound of formula (IV) and compound of formula (V) to a sugar group. The glycosylation reaction can be carried out in the presence of an acid catalyst. Examples of the acid catalyst used in this step include organic acids and Lewis acids, preferably organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, and particularly preferably methanesulfonic acid. acid, ethanesulfonic acid.

The solvent (first solvent) used in this step is preferably an inert solvent that does not easily react with the raw material, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, and dimethoxyethane. , chloroform, carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbons, hexane and heptane and other hydrocarbons, benzene and toluene and other aromatic hydrocarbons (the second aromatic hydrocarbon solvent), acetonitrile, etc. Nitrile solvents or their mixtures. Among them, solvents of hydrocarbons such as hexane and heptane, and aromatic hydrocarbons such as benzene and toluene (second aromatic hydrocarbon solvent) are preferable, and among them, a mixed solvent of heptane and toluene is preferable. The reaction temperature can range from 0°C to reflux, preferably from 10°C to 30°C. The reaction time may be 1 hour to 7 days, preferably 8 hours to 3 days.

The fifth step of the present invention is a step of producing a compound of formula (VII) by selectively deprotecting the 1-propenyl group by acid hydrolysis from the compound of formula (VI). The solvent used in this step is not particularly limited, but is preferably an inert solvent that does not easily react with the raw material, and examples thereof include alcohols such as methanol, ethanol, isopropanol, and tert-butanol, tetrahydrofuran, diethyl ether, and diisopropyl ether. , dioxane, dimethoxyethane, diethoxyethane, diglyme and other ethers, chloroform, carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbons, Hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene, nitriles such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2- Among amides such as piperidone and hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile are preferred.

Acids used in this step include common organic acids and inorganic acids. Examples of organic acids include monocarboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid, and benzoic acid; dicarboxylic acids such as oxalic acid; methanesulfonic acid; Organic sulfonic acids such as acid, toluenesulfonic acid, and trifluoromethanesulfonic acid. Examples of inorganic acids include phosphoric acid, hydrochloric acid, sulfuric acid, and nitric acid, preferably inorganic acids such as hydrochloric acid and sulfuric acid.

The acid used in this step can be used in a catalytic amount or in excess relative to the compound of formula (VI). In consideration of smooth reaction, purification treatment, etc., it is preferably 0.01 to 1.5 equivalents, and more preferably 0.1 to 0.5 equivalents. .

The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. The reaction temperature is from 0°C to reflux, preferably from 10°C to 60°C.

In addition, in this step, by performing the reaction and treatment under reduced pressure, effects such as increase in yield, improvement in operability, and reduction in by-products can be obtained.

The sixth step of the production method is a step of introducing phosphorous acid into the compound of formula (VII), followed by an oxidation reaction to form a compound of formula (VIII). The solvent used in this step is not particularly limited, and is preferably an inert solvent that does not easily react with the raw material, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, and dimethoxyethane. , chloroform, carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbons, hexane, heptane and other hydrocarbons, benzene, toluene and other aromatic hydrocarbons (the first aromatic hydrocarbon solvent), ethyl acetate esters, acetates such as methyl acetate, amides such as N,N-dimethylformamide, N-methyl-2-piperidone, and hexamethylphosphoramide, sulfoxides such as dimethyl sulfoxide, and their Among them, aromatic hydrocarbon solvents (first aromatic hydrocarbon solvents) are preferred, and toluene, for example, is particularly preferred.

This step can be reacted under mild conditions by performing the reaction in the presence of pyridine and trifluoroacetic acid. Pyridine and trifluoroacetic acid used in this step can be used in equal amounts or in excess relative to the compound of formula (VII). In consideration of smooth reaction, purification, etc., they are preferably 1.0-3.0 equivalents and 1.0-3.0 equivalents respectively, Among them, 1.0 to 2.0 equivalents and 1.0 to 2.0 equivalents are more preferable, respectively.

This step is made up of a total of 2 steps: the step of introducing a phosphorous acid group and the oxidation step. The diallyl N, N-diisopropyl phosphoramidate used in the step of introducing a phosphorous acid group is relative to the compound of formula (VII). , can be used in equal amounts or in excess, preferably 1.5 to 3.0 equivalents. The reaction time of the phosphorous acid group introducing step is 0.5 to 24 hours, preferably 0.5 to 4 hours. The reaction temperature is -78°C to room temperature, preferably -40°C to 0°C. Examples of the oxidizing agent used in the oxidation step include hydrogen peroxide, m-chloroperbenzoic acid, and potassium persulfate preparations, among which hydrogen peroxide is most preferred. The reaction time of the oxidation step is 0.5 to 6 hours, preferably 1 to 3 hours. The reaction temperature is preferably -50 to 0°C.

The seventh step of this production method is a step of producing the compound of formula (II) by deprotecting the 2-propenyl group of the compound of formula (VIII). The removal of the 2-propenyl group can be carried out by a method described in the literature, for example, hydrolysis using an acid or base, deallylation using a metal catalyst such as a palladium catalyst, or the like. Among them, for example, a deallylation reaction using a metal catalyst such as a palladium catalyst is preferable, and a zero-valent palladium catalyst such as tetrakis(triphenylphosphine)palladium is particularly preferable. Zero-valent palladium catalysts such as tetrakis (triphenylphosphine) palladium can also use commercially available reagents. From the stability of the reagents, the method of generating in the system is preferred, for example, preferably divalent palladium reagent and triphenylphosphine Composition of other ligands. Examples of the divalent palladium reagent used in this step include palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) chloride, and the like. For example, when palladium acetate is used as the divalent palladium reagent, palladium acetate can be used in a catalytic amount relative to the compound of formula (VIII), and it is preferably 0.01 to 0.50 equivalents in consideration of smooth reaction, purification, etc. More preferably, it is 0.05-0.25 equivalent. Triphenylphosphine can be used in an amount of 1.5 to 10 equivalents, more preferably 3.0 to 5.0 equivalents, based on the compound of formula (VIII). The nucleophilic reagent used in this reaction is preferably a compound having a methylene structure in the molecule, for example, chain organic acid esters such as ethyl cyanoacetate, melonic acid (isopropylidene malonate, etc.) ), or cyclic ketones such as dimedone (5,5-dimethyl-1,3-cyclohexanedione), among them, from the viewpoint of reducing by-products, preferred They are cyclic organic acid esters such as plumbellic acid, and cyclic ketones such as dimedone.

The nucleophile used in this step is used in an equal amount or in excess relative to palladium acetate, preferably 10 to 100 equivalents, more preferably about 20 to 30 equivalents. The reaction time is 1 to 12 hours, preferably 2 to 6 hours. The reaction temperature is a temperature of 10 to 50°C, preferably 20 to 40°C.

The solvent used in this step is not particularly limited, and is preferably an inert solvent that does not easily react with the raw material, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, and dimethoxyethane, Solvents of halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane, hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene, or mixtures thereof, tetrahydrofuran is particularly preferred.

In the removal process of the residual palladium caused by the palladium catalyst used in this process, there is no particular limitation, and it is preferable to use sulfur-containing compounds such as trimercaptotriazine, sodium dimethyldithiocarbamate, Diayion (registered trademark, an ion exchange resin ) CR20 and other resin-immobilized adsorbents, and column chromatography such as silica gel columns, among which sulfur-containing compounds such as trimercaptotriazine and sodium dimethyldithiocarbamate are preferred.

The eighth step of this production method is a step of producing the compound of formula (I) by adding sodium ions to the compound of formula (II).

Although it does not specifically limit as a sodium source of the sodium ion used in this process, Sodium hydroxide and potassium hydroxide are mentioned, Among these, sodium hydroxide is preferable.

The solvent used in this step is not particularly limited, and is preferably an inert solvent that does not easily react with the raw material, and examples thereof include alcohols such as methanol, ethanol, isopropanol, and tert-butanol, tetrahydrofuran, diethyl ether, and diisopropyl ether. , ethers such as dioxane and dimethoxyethane, ketones such as acetone and butanone, nitriles such as acetonitrile, water or their mixed solvents, etc. Among them, methanol, ethanol, isopropanol and t-butanol are preferred and other alcohols.

The compound of the formula (I) of the present invention is effective against Gram-negative bacteremia with high lethality caused by lipopolysaccharide (LPS: lipopolysaccharide) components or endotoxins present in the outer membrane of Gram-negative bacteria, especially Lipid A, which plays a major role in endotoxin shock, produces antagonism and shows excellent anti-endotoxin effect. In addition, it shows antagonism to TLR4 (Toll-like receptor 4), one of the receptors that recognize bacterial cell components, so It is particularly effective as a preventive or therapeutic agent for sepsis, endotoxemia, recovery period improvement of coronary artery bypass surgery (CABG: prognosis of coronary-artery bypass graft surgeries), and the like.

Example

Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited to these Examples.

The identification of the compound of the present invention was carried out by comparing the retention time by HPLC method with a compound synthesized according to the production method described in WO2004/074303 (Patent Document 3) as a control. The quantification of the compound was calculated from the intensity obtained by the UV detector by the HPLC method using a detection line prepared using a compound synthesized according to the production method described in WO2004/074303 (Patent Document 3) as a control.

The stationary phase that can be used in the HPLC method is not particularly limited, but reversed-phase columns such as C18 (ODS), C4, C8, C22, and C30 are preferred. The mobile phase is not particularly limited, preferably solvents such as acetonitrile, methanol, water or their mixed solvents, and acids such as perchloric acid, trifluoroacetic acid, acetic acid, phosphoric acid and their salts, triethylamine, di Amines such as ethylamine for good peak separation. In addition, by using a constant temperature column oven to keep the column temperature stable, it is possible to improve the reproducibility of peak separation and retention time.

Example 1

α-D-glucopyranose, (1Z)-1-propenyl 2-deoxy-3-O-[(3R)-3-methano Oxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-, 4- (di-2-propenyl phosphate)

[chem 23]

In a 2L four-neck flask, dissolve α-D-glucopyranose, (1Z)-1-propenyl 2-deoxy-3-O-[(3R)-3-methoxydecane in 933 mL of toluene Base]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-[CAS accession number: 748165-17-5] After 235g, at room temperature 129 mL of diallyl N,N-diisopropyl phosphoramidate, 39.4 mL of pyridine, and 36.3 mL of trifluoroacetic acid were added dropwise in sequence. 1.5 hours after the completion of the dropping, the reaction solution was cooled to -20°C, and a dilute acetonitrile solution (933 mL) containing 47.5 mL of hydrogen peroxide was added dropwise over 37 minutes. After completion of the dropping, the temperature was raised to 10° C. over 40 minutes. After 3 hours, 940 mL of 5% aqueous sodium bisulfite solution was added to stop the reaction, and the temperature was raised to room temperature. It was extracted with ethyl acetate, and the resulting solution was used as a solution of the title compound as it was in the following reaction.

Example 2

α-D-glucopyranose, 2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl Base-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-, 4-(di-2-propenylphosphoric acid ester)

[chem 24]

The α-D-glucopyranose obtained in Example 1, (1Z)-1-propenyl 2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O -Methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-, 4-(di.-2-propenyl phosphate) solution was washed with 699mL 1N hydrochloric acid water, added 27.9mL 5N hydrochloric acid water, stirred at room temperature for 5 hours. After neutralizing with 699 mL of 5% sodium bicarbonate water, the liquid was separated with ethyl acetate, and the organic layer was washed with 699 mL of 5% saline. After adding 69.9 g of anhydrous magnesium sulfate and drying, it was filtered, and the filtrate was concentrated under reduced pressure. 466 mL of acetone was added to the residue, followed by concentration under reduced pressure again. This acetone treatment was repeated to obtain 289.1 g of a crude product of the title compound (92.1% content, 266.3 g content) yield 97%.

1065 mL of acetonitrile was added to 289.1 g of the obtained crude product, and after stirring at 20° C. for 5 minutes, it was cooled to 0° C. over 4 hours, and stirred for an additional 4 hours. The precipitated crystals were filtered and dried overnight at room temperature under reduced pressure to obtain 228.6 g of the title compound.

Example 3

α-D-glucopyranose, 2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl Base-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-, 4-(di-2-propenylphosphoric acid Esters) 1-(2,2,2-Trichloroacetylimidate)

[chem 25]

In a 2L four-neck flask, add 280g α-D-glucopyranose, 2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2 -[[(11Z)-1-oxo-11-octadecenyl]amino]-, 4-(di-2-propenyl phosphate), 46.8g potassium carbonate, 560mL methyl acetate, 170mL trichloroacetonitrile , 8.4 mL of water, stirred at 0° C. for 2 hours under a nitrogen atmosphere. The reaction solution was filtered through celite, and concentrated under reduced pressure at 40°C. Next, 560 mL of heptane was used to azeotrope three times to obtain 432 g of the title compound (content: 63.9%, containing 171.4 mL of heptane). Yield 87.5%.

Example 4

α-D-glucopyranose, (1Z)-1-propenyl 6-O-[4-O-[di(2-propenyloxy) Phosphinyl]-2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2-[[(11Z) -1-oxo-11-octadecenyl]amino]-β-D-glucopyranosyl]-3-O-decyl-2-deoxy -2-[(1,3-dioxotetradecyl)amino]-,4-(di-2-propenyl carbonate)

[chem 26]

In a 2L four-neck flask, add 410.8g α-D-glucopyranose, 2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl -2-[[(11Z)-1-oxo-11-octadecenyl]amino]-,4-(di-2-propenyl phosphate) 1-(2,2,2-trichloroacetylide Amino acid ester) heptane solution (content 50.4%), 249.7mL heptane, 105.9g α-D-glucopyranose, (1Z)-1-propenyl 3-O-decyl-2-deoxy- 2-[(1,3-dioxotetradecyl)amino]-,4(2-propenyl carbonate)[CAS accession number: 185955-29-7], 140mL toluene, 2.89mL methanesulfonic acid, Stir at 25°C for 15 hours under nitrogen atmosphere. Add 2000mL of ethyl acetate and 1000mL of water to the reaction solution for extraction, and after liquid separation, the organic layer is washed successively with 1000mL of 5% aqueous sodium bicarbonate and 1000mL of 10% brine. After concentration under reduced pressure (warm bath 45-50° C.), 800 mL of methanol was added to the residue, followed by concentration, and the same operation was repeated to obtain a crude product of the title compound.

1920 mL of methanol was added to the obtained crude product, the insoluble matter was filtered out with celite, and the insoluble matter and celite were washed with methanol. After adding 1400mL of methanol to the solution, it was cooled to 17°C, and 375mL of water was added dropwise. Then, it was cooled to -20° C., stirred for 45 minutes, and then filtered. The filtrate was washed with 400 mL of 90% aqueous methanol previously cooled to 0° C., and then directly dried with a Buchner funnel under reduced pressure to obtain 427.2 g of wet product.

Add 427.2g of wet product into a 10L four-necked bottle, and add 2400mL of methanol to dissolve it. After cooling to 10°C, 180 mL of water was added dropwise. After completion of the dropping, it was cooled to 0° C., stirred for 50 minutes, and then filtered. The filtrate was washed with 400 mL of 90% aqueous methanol previously cooled to 0°C, and then dried under reduced pressure at 35°C to obtain 199.5 g of the title compound (content: 92.2%). Yield 92.6%.

Example 5

α-D-glucopyranose, 6-O-[4-O-[bis(2-propenyloxy)phosphinyl]-2-deoxy -3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-deca Octenyl]amino]-β-D-glucopyranosyl]-3-O-decyl-2-deoxy-2-[(1,3-dioxo Tetradecyl)amino]-, 4-(di-2-propenyl carbonate)

[chem 27]

In a 10L four-necked bottle, add 199.0g (content 92.2%) α-D-glucopyranose, (1Z)-1-propenyl 6-O-[4-O-[bis(2-propenyloxy )phosphinyl]-2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11 -octadecenyl]amino]-β-D-glucopyranosyl]-3-O-decyl-2-deoxy-2-[(1,3-dioxotetradecyl)amino] -, 4-(2-propenyl carbonate), 1990mL acetonitrile, 34.6mL 1N hydrochloric acid water, stirred at 30°C for 2 hours at a vacuum of 130hPa. Slowly increase the decompression degree and the jacket temperature, and finally concentrate the acetonitrile to about 3/4 of the volume under the vacuum degree of 106 hPa. Add 995mL of 10% saline and 1493mL of ethyl acetate to the concentrated solution for extraction. Then the organic layer was washed successively with 995mL 5% sodium bicarbonate water and 995mL 10% saline. After drying the organic layer with 60 g of anhydrous magnesium sulfate, it filtered. The filtrate was concentrated, and 640 mL of toluene was added to the residue for dissolution to obtain a toluene solution of 778.1 g of the title compound (corresponding to a content of 155.6 g). Yield 87.2%.

Example 6

α-D-glucopyranose, 6-O-[4-O-[bis(2-propenyloxy)phosphinyl]-2-deoxy -3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-deca Octenyl]amino]-β-D-glucopyranosyl]-3-O-decyl-2-deoxy-2-[(1,3-dioxo Tetradecyl)amino]-, 1-(di-2-propenyl phosphate) 4-(2-propenyl carbonate)

[chem 28]

550.6g (equivalent to a content of 110g) α-D-glucopyranose, 6-O-[4-O-[bis(2-propenyloxy)phosphinyl]-2-deoxy-3-O- [(3R)-3-Methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-β-D-pyran Glucosyl]-3-O-decyl-2-deoxy-2-[(1,3-dioxotetradecyl)amino]-,4-(di-2-propenyl carbonate) The toluene solution was concentrated under reduced pressure at 50°C. A solution obtained by adding 440 mL of toluene to the residue was concentrated under reduced pressure at a bath temperature of 45-50°C. 440 mL of toluene was added, and then replaced with nitrogen to prepare 537.6 g (content: 109.13 g) of toluene solution. After the solution was concentrated under reduced pressure, 665 mL of dry toluene was added and replaced with nitrogen. 11.91 mL of trifluoroacetic acid was added, and after stirring for 15 hours, 12.50 mL of pyridine was added. After cooling to -20°C, 37.15 mL of diallyl N,N-diisopropyl phosphoramidate was added dropwise. 30 minutes after the end of the dropping, it was cooled to -30°C, and 15.17 mL of 30% hydrogen peroxide was added dropwise. Six minutes after the end of the dropping, the thermostat was set to -20°C. After 1 hour and 10 minutes, 655 mL of 5% aqueous sodium thiosulfate was added to stop the reaction. Add 655mL of ethyl acetate for extraction, wash the organic layer successively with 655mL of 0.5N hydrochloric acid water, 655mL of 10% salt water, 655mL of 5% sodium bicarbonate water, and 655mL of 10% of salt water, add 43.7g of anhydrous magnesium sulfate to dry, filter . The filtrate was concentrated under reduced pressure to obtain 159.0 g of the title compound (content: 101.6 g). Yield 83.5%.

Example 7

α-D-glucopyranose, 3-O-decyl-2-deoxy-6-O-(2-deoxy-3-O-[(3R) -3-Methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amine Base]-4-O-phosphono-β-D-glucopyranosyl)-2-[(1,3-dioxotetradecyl)amine base]-, 1-(dihydrogen phosphate), tetrasodium salt

[chem 29]

Into a 3L four-necked flask were added 70.49 g of melon acid, 2.93 g of palladium acetate, and 51.3 g of triphenylphosphine. After replacing with nitrogen, add 1321mL tetrahydrofuran, add α-D-glucopyranose, 6-O-[4-O-[bis(2-propenyloxy)phosphinyl]-2-deoxy-3-O -[(3R)-3-Methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-β-D-pyridine Glucopyranosyl]-3-O-decyl-2-deoxy-2-[(1,3-dioxotetradecyl)amino]-, 1-(di-2-propenyl phosphate) 4-(di-2-propenyl carbonate) 101.6g tetrahydrofuran solution (203mL), stirred at 32°C for 2 hours, then stirred at 30°C for 4 hours, added 250mL of methanol to the reaction solution, concentrated under reduced pressure , 466.7 g of residue were obtained. Add 4570mL of methanol thereto, heat to 40°C to dissolve, add 5.55g of trimercaptotriazine, and stir overnight at room temperature. The precipitated trimercaptotriazine-palladium complex was filtered and washed with methanol to obtain 4330 g of filtrate.

3908.2 mL of this methanol solution was concentrated under reduced pressure to obtain 440.9 g of a residue. 450 mL of acetone was added to the residue, concentrated under reduced pressure, and then 450 mL of acetone was added to concentrate. After the residue was refrigerated overnight, 1800 mL of acetone was added, heated to 40° C., and stirred for 1.5 hours. It was air-cooled, stirred at below 30° C. for 1.5 hours, and then filtered. After the filtrate was washed with 750 mL of acetone, the solid obtained was dried under reduced pressure at 35 to 40° C. to quantitatively obtain 104.48 g (content 74.2%) of the free phosphate of the title compound as a crude product.

The resulting crude phosphate-free product was treated with 0.1N aqueous sodium hydroxide solution to afford the title compound.

Claims (16)

1. A method for producing a compound represented by formula (I), wherein, in the presence of a nucleophile, reacting a compound represented by formula (VIII) with a palladium catalyst, and then treating it with a sodium source, thereby producing the compound represented by formula (I) compound, [chemical 1]

2. A method for producing a compound represented by formula (I), wherein, in the first aromatic hydrocarbon solvent, in the presence of pyridine-trifluoroacetic acid, the compound represented by formula (VII) is mixed with diallyl N, N- Diisopropyl phosphoramidate and oxidizing agent react sequentially to obtain the compound represented by formula (VIII), then in the presence of nucleophilic reagent, after reacting the compound represented by formula (VIII) and palladium catalyst, treat with sodium source, thereby manufacture the compound represented by formula (I), [Chem 2]

3. A method for producing a compound represented by formula (I), wherein the 1-propenyl group of the compound represented by formula (VI) is selectively deprotected to obtain a compound represented by formula (VII), and then, in the first aromatic hydrocarbon In a solvent, in the presence of pyridine-trifluoroacetic acid, the compound represented by formula (VII) is reacted with diallyl N, N-diisopropyl phosphoramidate and an oxidizing agent in sequence to obtain the compound represented by formula (VIII), Then, in the presence of a nucleophilic reagent, after making the compound represented by formula (VIII) react with a palladium catalyst, treat with a sodium source, thereby producing a compound represented by formula (I),

[chemical 4]

4. A method for producing a compound represented by formula (I), wherein, in a first solvent containing a hydrocarbon solvent and/or a second aromatic hydrocarbon solvent, in the presence of an organic sulfonic acid, the compound represented by formula (IV) is The compound represented by the compound and the formula (V) is reacted to obtain the compound represented by the formula (VI), and then, the 1-propenyl of the compound represented by the formula (VI) is selectively deprotected to obtain the compound represented by the formula (VII), and then , in the first aromatic hydrocarbon solvent, in the presence of pyridine-trifluoroacetic acid, the compound represented by formula (VII) is reacted with diallyl N, N-diisopropyl phosphoramidate and oxidizing agent in sequence to obtain the formula The compound represented by (VIII), then, in the presence of a nucleophilic reagent, after making the compound represented by the formula (VIII) react with a palladium catalyst, and then treat with a sodium source, thereby producing the compound represented by the formula (I), [chemical 5]

[chemical 6]

5. The method according to any one of claims 1 to 4, wherein the first aromatic hydrocarbon solvent is a toluene solvent. 6. The method according to claim 4 or 5, wherein said organic sulfonic acid is methanesulfonic acid or ethanesulfonic acid. 7. The method according to any one of claims 4 to 6, wherein the first solvent is a toluene-heptane mixed solvent. 8. The method according to any one of claims 4 to 7, wherein the compound represented by the above formula (IV) is prepared by making the compound of the formula (III) in a mixed solvent of acetate solvent and water in the presence of potassium carbonate ) is obtained by reacting the compound represented by the formula (III) with 1 to 10 equivalents of trichloroacetonitrile relative to 1 equivalent of the compound represented by the formula (III), [chemical 7]

9. The method according to any one of claims 4-8, wherein the compound represented by the above formula (IV) is obtained by selectively deprotecting the 1-propenyl group of the compound represented by the formula (X) to obtain the compound represented by the formula (III) Then, in the mixed solvent of acetate solvent and water, in the presence of potassium carbonate, make the compound represented by formula (III) and the compound represented by formula (III) be 1 to 10 equivalents relative to 1 equivalent obtained by the reaction of trichloroacetonitrile, [chemical 8]

10. The method according to any one of claims 4 to 9, wherein the compound represented by the above formula (IV) is obtained by reacting the compound represented by the formula (IX) with diallyl N in the presence of pyridine-trifluoroacetic acid. , N-diisopropylphosphoramidate and oxidizing agent are reacted successively to obtain the compound represented by formula (X), and the 1-propenyl group of the compound represented by formula (X) is selectively deprotected to obtain the compound represented by formula (III) , then in a mixed solvent of acetate solvent and water, in the presence of potassium carbonate, the compound represented by the formula (III) and the trichloroacetonitrile represented by 1 to 10 equivalents of the compound represented by the formula (III) relative to 1 equivalent obtained by the reaction, [chemical 9]

11. The method according to any one of claims 8-10, wherein the acetate-based solvent is methyl acetate. 12. The method according to any one of claims 8 to 11, wherein the content of the water in the mixed solvent is 1 to 10% (volume/volume ratio). 13. The method according to any one of claims 1 to 12, wherein the nucleophile is a cyclic organic acid ester or a cyclic ketone. 14. The method according to any one of claims 1 to 13, wherein the nucleophile is mechric acid or dimedone. 15. The method according to any one of claims 1 to 14, wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium. 16. The method as claimed in claim 15, wherein tetrakis(triphenylphosphine)palladium is generated in the system from palladium acetate and triphenylphosphine.