KR100848977B1 - Process for producing 3-aminomethyltetrahydrofuran derivative - Google Patents

Abstract

An object of the present invention is to provide a method for producing a 3-aminomethyltetrahydrofuran derivative from a cheap industrial raw material with high efficiency.

Inexpensive preparation of 3-cyanotetrahydrofuran derivatives in high yield from malic acid derivatives which are readily available industrially and reduction of cyano groups of 3-cyanotetrahydrofuran derivatives to produce 3-aminomethyltetrahydrofuran derivatives do.

Description

Production method of 3-aminomethyltetrahydrofuran derivative {PROCESS FOR PRODUCING 3-AMINOMETHYLTETRAHYDROFURAN DERIVATIVE}

The present invention relates to a method for producing a 3-aminomethyltetrahydrofuran derivative. In more detail, it is related with the manufacturing method of the 3-aminomethyl tetrahydrofuran derivative which reduces a 3-cyano tetrahydrofuran derivative. The 3-aminomethyltetrahydrofuran derivative is useful as an intermediate such as a pharmaceutical pesticide.

The (tetrahydro-3-furanyl) methylamine derivative having the structure represented by the following formula (1) exhibits very high insecticidal activity and is also low toxicity and has very excellent performance as an active ingredient of pesticides (see Patent Document 1). However, the manufacturing method of the 3-aminomethyl tetrahydrofuran derivative which becomes the raw material is hardly known, and only two methods described below are known. This is due to the fact that the tetrahydrofuran compound having a substituent at the 2-position can be derived relatively easily from the substitution reaction of the furan ring, whereas the synthesis of the tetrahydrofuran compound having a substituent at the 3-position is very difficult.

(Wherein R ¹⁰ , R ¹¹ and R ¹² represent a hydrogen atom or a lower alkyl group.)

As one of the manufacturing methods of a 3-aminomethyl tetrahydrofuran derivative, the method of reducing amination in the presence of hydrogen in aqueous ammonia using tetrahydrofuran 3-carboxyaldehyde as a raw material is known (refer patent document 2). However, in this method, in order to obtain tetrahydrofuran-3-carboxyaldehyde which is a raw material, for example, after cyclizing expensive 2-butene-1,4-diol and further using an expensive rhodium catalyst, hydroform It is not an industrially advantageous method to use an extremely expensive raw material, for example, to be densified.

As another production method, for example, 3-hydroxymethyltetrahydrofuran is used as a raw material, and guided to 3- (tetrahydrofuryl) methylhalide or 3- (tetrahydrofuryl) methylsulfonate, Patent Document 1 describes a method of reacting with potassium phthalimide to hydrolyze or hydrazine decomposition. However, also in this method, 2-hydroxymethyl-1,4-butanediol, which is a raw material of 3-hydroxymethyltetrahydrofuran, is expensive, and a large amount of by-products derived from phthalimide are produced or a high risk of hydrazine is used. It is not an industrially advantageous method.

Moreover, regarding the method of hydrogenating a 3-cyano tetrahydrofuran derivative, there are few synthesis examples itself which can obtain a 3-cyano tetrahydrofuran derivative efficiently, Therefore, of the 3-aminomethyl tetrahydrofuran derivative which uses this as a raw material, Examples of preparation methods are not known. The method for obtaining amines by reducing cyano groups is generally known, but the preferred method varies greatly depending on the substrate. The reduction reaction of the cyano compound having a tetrahydrofuran ring is not known at all about the 3-cyano tetrahydrofuran derivative or its isomer 2-cyanotetrahydrofuran derivative, and therefore the preferred method is not known at all.

In addition, as a manufacturing method of 3-cyano tetrahydrofuran derivative, the method of irradiating tetrahydrofuran and chlorocyanate in the presence of sodium hydrogencarbonate (refer patent document 3), ethylene oxide and acrylonitrile in presence of a catalyst Only two examples of the method of reacting (refer to Patent Document 4) are known, and the former has a low yield and selectivity, and the latter has a high selectivity but no description of the yield, so that neither method is effective for the 3-cyanotetrahydrofuran derivative. It is not a manufacturing method. The method for producing the 3-cyanotetrahydrofuran derivative from the 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative which is the method of the present invention is not known.

Moreover, the method of manufacturing 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative from the 3-hydroxy tetrahydrofuran derivative which is the method of this invention is also unknown.

(Patent Document 1) Japanese Unexamined Patent Publication No. 1995-179448

(Patent Document 2) Japanese Unexamined Patent Publication No. 1997-110848

(Patent Document 3) German Patent Publication No. 1234227

(Patent Document 4) Japanese Unexamined Patent Publication No. 2000-264884

<Start of invention>

<Problems to Solve Invention>

Therefore, an industrially advantageous method for producing a 3-aminomethyltetrahydrofuran derivative has not been found yet, and a method for efficiently producing the derivative from an inexpensive raw material is urgently desired. An object of the present invention is to provide a method for producing a 3-aminomethyltetrahydrofuran derivative from an inexpensive industrial raw material with high efficiency.

<Means for solving the problem>

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to achieve the said subject, the present inventors discovered the method of manufacturing 3-aminomethyl tetrahydrofuran derivative by reducing the cyano group of 3-cyano tetrahydrofuran derivative, and also 3-cyano tetra The present invention has been completed by finding a method for producing hydrofuran derivatives at low yield from a commercially available malic acid derivative at high yield.

That is, the first of the present invention is general formula (1)

3-Csia represented by (In formula, R <^1> , R <^2> , R <^3> , R <^4> , R <^5> , R <^6> , R <^7> may be same or different, and represent a hydrogen atom or a C1-C4 hydrocarbon group. General formula (2) characterized by reducing the cyano group of the notetrahydrofuran derivative

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ Is the same or different, and represents a hydrogen atom or a C1-C4 hydrocarbon group.) It is a manufacturing method of the 3-aminomethyl tetrahydrofuran derivative represented by these.

Second of the present invention is general formula (3)

(In formula, R <^1> , R <^2> , R <^3> , R <^4> , R <^5> , R <^6> , R <^7> may be same or different, and represent a hydrogen atom or a C1-C4 hydrocarbon group. X is a halogen atom or a hydrocarbon 1 Reacting an organic or inorganic cyano compound with a 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative represented by -6 alkylsulfonate group or an aryl sulfonate group having 6 to 12 carbon atoms. It is a manufacturing method of the 3-cyano tetrahydrofuran derivative represented by general formula (1) characterized by the above-mentioned.

3rd of this invention uses 3-cyano tetrahydrofuran derivative obtained by the 2nd manufacturing method of this invention, The manufacture of 3-aminomethyl tetrahydrofuran derivative by the 1st manufacturing method of this invention. Way.

4th of this invention is general formula (3a) manufactured from a malic acid derivative by 3 steps.

It is a manufacturing method of the 3-aminomethyl tetrahydrofuran derivative by the 3rd manufacturing method of this invention using 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative represented by the following.

<Effect of the invention>

According to the present invention, the 3-aminomethyltetrahydrofuran derivative can be produced industrially advantageously from an inexpensive raw material as compared to the conventional method.

<Best form for carrying out invention>

Hereinafter, the manufacturing method of the 3-aminomethyl tetrahydrofuran derivative of this invention is demonstrated concretely.

3-cyanotetrahydrofuran derivative of the method of this invention is represented by General formula (1).

In General formula (1), R <^1> , R <^2> , R <^3> , R <^4> , R <^5> , R <^6> , R <^7> may be same or different from each other, and represents a hydrogen atom or a C1-C4 hydrocarbon group, respectively. . As a C1-C4 hydrocarbon group, More specifically, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, 2-butyl group, isobutyl group, t-butyl group etc. are mentioned, for example. Can be mentioned. As such 3-cyano tetrahydrofuran derivative, specifically 3-cyano tetrahydrofuran, For example, 4-ethyl-3-cyano tetrahydrofuran, 3-methyl- 3-cyano tetra And 3-cyanotetrahydrofuran substituted with a hydrocarbon group such as hydrofuran.

Although the manufacturing method of the 3-cyano tetrahydrofuran derivative used for the method of this invention is not limited, it is suitable by the method of cyanoating the 3-halogenation or 3-alkyl or arylsulfonated tetrahydrofuran derivative mentioned later. Can be manufactured.

In this invention, the cyano group of the 3-cyano tetrahydrofuran derivative represented by General formula (1) is reduced, and the 3-aminomethyl tetrahydrofuran derivative represented by General formula (2) is manufactured.

In the formula ^{(2), R 1, R} 2, R 3, R 4, R 5, R 6, R 7 of the general formula ^{(1) R 1, R 2} , R 3, R 4, a R ^5, R ⁶ and R ⁷ are the same. Specific examples of such 3-aminomethyltetrahydrofuran derivatives include 3-aminomethyltetrahydrofuran and, for example, 4-ethyl-3-aminomethyltetrahydrofuran and 3-methyl-3-aminomethyltetra. And 3-cyanotetrahydrofuran substituted with a hydrocarbon group such as hydrofuran. The 3-aminomethyltetrahydrofuran derivative obtained by the method of the present invention corresponds to the 3-cyanotetrahydrofuran derivative used, and R ¹ , R ² , R ³ , R ⁴ , R ^5, R ^6, R ⁷ substituents and each of the obtained methyl 3-amino-tetrahydrofuran derivatives, R ^1, R ^2, of the ^{R 3, R 4, R 5} , R 6, each substituent of R ⁷ is the same. For example, when 3-cyanotetrahydrofuran is used, 3-aminomethyltetrahydrofuran is 3-methyl-3-amino when 3-methyl-3-cyanotetrahydrofuran is used, for example. Methyltetrahydrofuran is obtained.

As a method of reducing the cyano group of the 3-cyano tetrahydrofuran derivative of this invention, the method of reducing with metal hydride, the method of reducing with hydrogen in presence of a hydrogenation catalyst, etc. are mentioned, for example. .

Specific examples of the metal hydride in the case of reduction by metal hydride include aluminum hydride compounds such as lithium aluminum hydride, lithium hydride trimethoxyaluminum, aluminum hydride, and diisobutylaluminum hydride, for example. And boron hydride compounds such as diborane, lithium borohydride, and sodium borohydride. As the usage-amount in the case of reducing by metal hydride, it is the range of 2-10 mol, Preferably it is 3-6 mol with respect to 1 mol of 3-cyano tetrahydrofuran derivatives normally used.

The hydrogenation catalyst in the case of reducing with hydrogen in the presence of a hydrogenation catalyst may be any compound as long as it catalyzes the reaction for reducing the cyano group of the 3-cyanotetrahydrofuran derivative of the present invention with an aminomethyl group by molecular hydrogen. Usually, at least 1 sort (s) of metal or metal compound chosen from group 7-13 of a periodic table is used suitably. More specifically, metals or metal compounds, such as manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, aluminum, are mentioned. These metals or metal compounds may or may not be dissolved in the reaction solution. Specific examples of these hydrogenation catalysts include metal bodies such as rhodium metal powder and palladium metal powder, for example, Raney metal compounds such as Raney nickel, Raney copper, Raney cobalt, and the like. Stabilized metal compounds such as stabilized nickel, for example, metals such as rhenium, ruthenium, rhodium, palladium, and the like supported on inorganic carriers such as carbon black, activated carbon, alumina, silica gel, diatomaceous earth, zeolite, magnesia, etc. Metal supported catalysts, for example, metal oxides such as ruthenium oxide, palladium oxide, rhenium oxide, copper oxide, for example, metal composite oxides such as copper oxide-chromium oxide, copper oxide-zinc oxide-aluminum oxide, and the like Examples thereof include complex compounds of Group 8 to 10 metals of the periodic table such as RuClH (CO) (PPh ₃ ) ₃ , RuCl ₂ (PPh ₃ ) ₃ , and PdCl ₂ (PPh ₃ ) ₂ . These catalysts may be used alone or in combination of two or more. As a usage-amount of a hydrogenation catalyst, when the catalyst to be used melt | dissolves in a reaction liquid, it is the range of 0.1 weight%-10 weight% normally with respect to 3-cyano tetrahydrofuran derivative, Preferably it is the range of 1 weight%-5 weight%, When the catalyst used does not melt | dissolve in a reaction liquid, it is the range of 0.1 weight%-500 weight% normally, Preferably it is 1 weight%-200 weight% with respect to 3-cyano tetrahydrofuran derivative.

Among these reduction methods, a method of reducing with hydrogen in the presence of a hydrogenation catalyst is preferable. The hydrogenation catalyst is preferably a metal or metal compound of Group 9 or 10 of the periodic table, more preferably a metal or metal compound of cobalt or nickel, and most preferably a metal or metal compound of cobalt.

In the method of reducing the 3-cyanotetrahydrofuran derivative of this invention, although it can be performed without using a solvent, it is usually implemented in presence of a solvent. As a solvent in the case of using, a suitable solvent differs according to the reduction method of a cyano group.

When reducing by metal hydride, C5-C20 aliphatic or alicyclic hydrocarbons, such as n-hexane, n-pentane, or cyclohexane, for example, benzene, toluene, ethylbenzene, etc. Aliphatic or aromatic halides having 1 to 20 carbon atoms, such as chloroform, chlorobenzene and dichlorobenzene, for example, diethyl ether, diphenyl ether and tetrahydrofuran; C2-C20 ethers, such as ethylene glycol dimethyl ether, are used suitably. Moreover, you may use these solvents in mixture of 2 or more types. Of these solvents, the use of ethers is particularly preferred.

As a solvent when reducing with hydrogen in the presence of a hydrogenation catalyst, C1-C20 alcohols, such as methanol, ethanol, butanol, for example, n-hexane, n-pentane, or cyclohexane C5-C20 aliphatic or cycloaliphatic hydrocarbons, for example, C6-C20 aromatic hydrocarbons, such as benzene, toluene, and ethylbenzene, For example, diethyl ether, diphenyl ether, tetrahydro C2-C20 ethers, such as furan and ethylene glycol dimethyl ether, are used suitably. Moreover, you may use these solvents in mixture of 2 or more types. Of these solvents, the use of water, alcohols, ethers is preferred, and the use of water is more preferred.

The amount of the solvent when used is not the same depending on the reaction conditions, but is usually 0.01 to 200 parts by weight, preferably 0.02 to 50 parts by weight, more preferably 0.05 to 1 part by weight of 3-cyanotetrahydrofuran derivative. It is the range of 2 weight part.

In the method for reducing the 3-cyanotetrahydrofuran derivative of the present invention, when the cyano group is reduced by hydrogen in the presence of a hydrogenation catalyst, it is preferable to perform a reduction reaction in the presence of ammonia. In this invention, although ammonia is ammonia water, liquid ammonia, or ammonia gas, it is more preferable that ammonia is ammonia water. The amount of ammonia in the case of use is not particularly limited, but is usually in the range of 0.01 to 50 moles of ammonia, preferably in the range of 0.1 to 20 moles of ammonia, more preferably 0.3 ammonia per 1 mole of 3-cyanotetrahydrofuran derivative. It is the range of -5 mol.

In the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention, a method of reducing by hydrogen in the presence of ammonia and in the presence of a metal or a metal compound of Group 9 or 10 of the periodic table as a catalyst is particularly preferable. Do. In this case, the catalyst is more preferably a metal or metal compound of nickel or cobalt, and more preferably ammonia water. Moreover, when reacting in presence of ammonia water, it is preferable to carry out in presence of 0.05-2 weight part of ammonia water with respect to 1 weight part of 3-cyano tetrahydrofuran derivatives.

In the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention, it is preferable that all of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen atoms.

The temperature and time at the time of reaction are not the same depending on the kind of 3-cyano tetrahydrofuran derivative used and a reduction method. When reducing with a metal hydride, the reaction temperature is usually in the range of -10 to 150 ° C, preferably in the range of 0 to 120 ° C, and more preferably in the range of 10 to 100 ° C. When reducing with hydrogen in the presence of a hydrogenation catalyst, reaction temperature is the range of 0-250 degreeC normally, Preferably it is the range of 50-200 degreeC, More preferably, it is the range of 80-150 degreeC. The reaction time is usually within 100 hours, preferably in the range of 0.01 to 50 hours.

Although the pressure at the time of reaction can be implemented by any of pressure reduction, normal pressure, or pressurization, a preferable aspect changes with the reduction method to be performed. In the case of the method of reducing by metal hydride, it is preferably performed at normal pressure. In the case of the method of reducing with hydrogen in the presence of a hydrogenation catalyst, it is preferably carried out under hydrogen pressurization. The hydrogen pressure in the case of pressurization is usually in the range of 0.01 to 25 MPa gauge pressure, preferably in the range of 0.1 to 20 MPa gauge pressure, and more preferably in the range of 1 to 10 MPa gauge pressure.

It does not specifically limit as a reaction method of the reduction of a cyano group, Any of a batch type, a semibatch type, or a continuous flow type may be sufficient.

When reducing with hydrogen in the presence of a hydrogenation catalyst, the catalyst used after completion | finish of reaction can be collect | recovered by the metal collection method used normally. For example, when the catalyst is dissolved in the reaction solution, the catalyst can be recovered by contacting with a metal adsorbent such as an ion exchange resin, or extracted with a solvent. When the catalyst is not dissolved in the reaction solution, for example, filtration Or by solid-liquid separation such as centrifugation. These recovery catalysts can be used repeatedly as a hydrogenation catalyst. In that case, the catalyst may be reused after performing the regeneration operation of the catalyst whose deactivation or activity is reduced, or a new catalyst may be added and used.

The 3-aminomethyltetrahydrofuran derivative produced by the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention can be isolated according to a commonly used separation method such as distillation, for example.

Next, the manufacturing method of this invention of 3-cyano tetrahydrofuran derivative is demonstrated below. 3-cyanotetrahydrofuran derivative represented by the general formula (1) by reacting a 3-halogenated or 3-alkyl or aryl sulfonated tetrahydrofuran derivative represented by the general formula (3) with an organic or inorganic cyano compound To prepare.

In the formula ^{(3), R 1, R} 2, R 3, R 4, R 5, R 6, R 7 of the general formula ^{(1) R 1, R 2} , R 3, R 4, a R ^5, R ⁶ and R ⁷ are the same. X represents a halogen atom or an alkylsulfonate group having 1 to 6 carbon atoms or an arylsulfonate group having 6 to 12 carbon atoms. Specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Specific examples of the alkylsulfonate group having 1 to 6 carbon atoms include, for example, a methylsulfonate group and an ethylsulfonate group. C1-C6 halogen-substituted alkylsulfo, such as a C1-C6 hydrocarbon alkylsulfonate group, for example, a trifluoromethylsulfonate group, a 1, 1, 1- trifluoroethylsulfonate group, etc. Nate group etc. are mentioned. Moreover, as a C6-C12 aryl sulfonate group, For example, C6-C12 hydrocarbon aryl sulfonate groups, such as a benzene sulfonate group and p-toluene sulfonate group, For example, p-trifluoro C6-C12 halogen-group substituted arylsulfonate groups, such as a rommethylbenzene sulfonate group, etc. are mentioned. As a 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative, More specifically, 3-halogenated tetrahydrofuran, such as 3-chlorotetrahydrofuran and 3-bromotetrahydrofuran, For example, 3-halogenated tetrahydrofuran substituted by hydrocarbon groups, such as 4-ethyl- 3-chlorotetrahydrofuran and 3-methyl- 3-iode tetrahydrofuran, for example, 3- (p-toluenesulfonate 3-alkyl or arylsulfonated tetrahydrofuran such as) -tetrahydrofuran and 3-trifluoromethanesulfonate tetrahydrofuran, for example, hydrocarbons such as 4-ethyl-3-benzenesulfonate tetrahydrofuran Group-substituted 3-alkyl or arylsulfonated tetrahydrofuran is mentioned.

Although the manufacturing method of the 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative used for the method of this invention is not limited, It can manufacture suitably by the method of using the malic acid derivative mentioned later as a starting material. .

In the method of the present invention, the organic or inorganic cyano compound to be used is a 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative of a 3-position halogen group or an alkyl or arylsulfonate group to a cyano group. Organic or inorganic cyano compounds. Specific examples of such organic cyano compounds include hydrogen cyanide adducts of ketones or aldehydes having 1 to 20 carbon atoms such as glycolonitrile and acetonecyanhydrin, for example, tetramethylammonium cyanide and cyanide tree. Organic ammonium cyanide salts, such as ethyl ammonium, etc. are mentioned. Examples of the inorganic cyano compound include hydrogen cyanide, alkali metal cyanide such as ammonium cyanide, for example, lithium cyanide, sodium cyanide and potassium cyanide, for example, alkaline earth metal cyanide such as magnesium cyanide, for example And transition metal cyanohydrates of Groups 3 to 12 of the periodic table such as manganese cyanide, copper cyanide and ruthenium cyanide. Among these organic or inorganic cyano compounds, a hydrogen cyanide adduct of a ketone or aldehyde having 1 to 20 carbon atoms and an alkali metal cyanoate are preferable, and an alkali metal cyanoate is more preferable.

The amount of the organic or inorganic cyan compound to be used is usually in the range of 0.1 to 10 moles, preferably in the range of 0.8 to 3 moles with respect to 1 mole of 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative.

In the method for cyanolating the compound of the general formula (3) of the present invention, a compound for promoting the cyanoation reaction may be added to the reaction mixture. As a compound which accelerates a cyanoation reaction, ammonium halide salts, such as tetraethylammonium chloride, tetraethylammonium bromide, triethylammonium chloride, and cetylpyridinium chloride, for example, tetraphenylphosphonium chloride and tetraphenylphosph Halogenated phosphonium salts, such as ponium bromide, For example, cyclic ether compounds, such as 15-crown-5-ether and 18-crown-6-ether, For example, Halogenated phosphazenium salts, such as phosphazenium chloride, For example, halogenated alkali metals or alkaline earth metals such as sodium chloride, lithium chloride, potassium bromide, magnesium chloride, sodium iodide and potassium iodide, for example, 1,8-diazabicyclo [5.4.0] undeca-7- And amines such as 1,4-diazabicyclo [2.2.2] octane. The usage-amount of these compounds at the time of use is 0.001-100 mol normally with respect to 1 mol of organic or inorganic cyano compounds, Preferably it is the range of 0.01-50 mol.

In the method of cyanoating the compound represented by General formula (3) of this invention, although it can carry out even in absence of a solvent, it is usually implemented in presence of a solvent. As a specific example of the solvent at the time of using, In addition to water, C1-C20 monovalent or polyhydric alcohols, such as methanol, ethanol, butanol, ethylene glycol, for example, n-hexane, n-pentane Or aliphatic or cycloaliphatic hydrocarbons having 5 to 20 carbon atoms such as cyclohexane, for example, aromatic hydrocarbons having 6 to 20 carbon atoms such as benzene, toluene and ethylbenzene, for example, chloroform, chlorobenzene and dichlorobenzene C2-C20 ethers, such as C1-C20 aliphatic or aromatic halides, for example, diethyl ether, diphenyl ether, tetrahydrofuran, and ethylene glycol dimethyl ether, for example, N, N C2-C20 aliphatic or aromatic amides, such as -dimethylformamide and N, N-dimethylacetamide, for example, C2-C20 aliphatic, such as 1, 3- dimethyl- 2-imidazolidinone, or Aromatic imidazolidi Aliphatic or aromatic pyrrolidones having 4 to 20 carbon atoms such as N-methylpyrrolidone, for example, ethyl acetate, aliphatic or aromatic esters having 2 to 20 carbon atoms, for example, Aliphatic or aromatic ketones having 3 to 20 carbon atoms such as acetone and methyl ethyl ketone, for example, aliphatic or aromatic nitriles having 2 to 20 carbon atoms such as acetonitrile and benzonitrile, for example, dimethyl sulfoxide Aliphatic or aromatic sulfoxide of -20, For example, C2-C20 aliphatic or aromatic sulfones, such as sulfolane, etc. are mentioned.

Among these solvents, the use of a solvent having a dielectric constant of 20 F · m ⁻¹ or more is preferable. The dielectric constant in this invention is dielectric constant in 20-30 degreeC. Preferred solvents of the present invention, there is the dielectric constant in the entire 20F · m ^-1 or greater within the temperature range, if at some temperature range from 20F · m ^-1 or more is included in the preferred solvents of the present invention. The permittivity of the solvent is described, for example, in the solvent handbook (Shozo Asahara et al., Kodansa, 1976) or the Basic Edition of the Chemical Handbook, 5th Edition (II) (Japanese Chemical Society, Maruzen, 2004). The value can be used. According to the literature, the dielectric constant is described as a relative dielectric constant, but the same meaning. Specific examples of the solvent having a dielectric constant of 20 F · m ⁻¹ or more include methanol, ethanol, propanol, ethylene glycol, acetone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1, 3 Although -dimethyl-2-imidazolidinone, dimethyl sulfoxide, N-methylpyrrolidone, etc. can be mentioned, It is not limited to this. The use of an aprotic solvent among solvents having a dielectric constant of 20 F · m ⁻¹ or more is more preferable. Moreover, the use of aliphatic or aromatic amides, aliphatic or aromatic imidazolidinones, aliphatic or aromatic sulfoxides having a dielectric constant of 20 F · m ⁻¹ or more among these solvents is most preferred.

You may use these solvent in mixture of 2 or more type. The amount of the solvent when used is not the same depending on the reaction conditions, but is usually 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight based on 1 part by weight of 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative. Part, More preferably, it is the range of 2-100 weight part.

In the method for cyanoating the compound represented by the general formula (3) of the present invention, it is particularly preferable to react in the presence of a solvent having a dielectric constant of 20 F · m ⁻¹ or higher while using an alkali metal cyanoide as the cyano compound. . In this case, it is more preferable that the solvent having a dielectric constant of 20 F · m ⁻¹ or more is aprotic.

In the method of cyanoating the compound represented by General formula (3) of this invention, it is preferable that all of R <^1> , R <^2> , R <^3> , R <^4> , R <^5> , R <^6> , and R <^7> are hydrogen atoms. Moreover, it is preferable that X is a halogen atom, and it is more preferable that it is a chlorine atom.

The reaction temperature in the method of cyanolating the compound represented by General formula (3) of this invention is the range of 0 degreeC-250 degreeC normally, Preferably it is the range of 20-200 degreeC, More preferably, it is 50- It is the range of 180 degreeC. The reaction time is usually within 100 hours, preferably in the range of 0.01 to 50 hours. The pressure at the time of reaction can be implemented by any of reduced pressure, normal pressure, or pressurization. It does not specifically limit as reaction method of this invention, Any of a batch type, a semibatch type, or a continuous flow type may be sufficient.

The compound which accelerates | stimulates the reaction in the case of using after completion | finish of reaction can also be collect | recovered, and may be used repeatedly for the next reaction.

The 3-cyanotetrahydrofuran derivative produced in the method of the present invention can be isolated according to a commonly used separation method such as distillation or extraction, for example.

In the present invention, using a 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative represented by the general formula (3a) produced from the malic acid derivative by the following three steps of the first step to the third step, It is preferable to manufacture 3-cyanotetrahydrofuran derivative by the method of this invention, and to manufacture 3-aminomethyl tetrahydrofuran derivative then.

[Step 1] General Formula (4)

-COOR of malic acid derivative represented by ^{(wherein, R 1, R 2, R} 3, R 8, R 9 may be the same or different and represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms) group and ⁸ - Reduction of ⁹ groups of COOR, general formula (5)

In the formula, R ¹ , R ² and R ³ may be the same or different and represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms.

[Second Step] The triols represented by the general formula (5) obtained by the first step were subjected to intramolecular dehydration reaction in the presence of an acid catalyst, thereby providing a general formula (6).

(In formula, R <^1> , R <^2> , R <^3> may be same or different, and may represent a hydrogen atom or a C1-C4 hydrocarbon group.) The 3-hydroxy tetrahydrofuran derivative corresponding to the used triols represented by Manufacture.

[Third Step] The 3-hydroxytetrahydrofuran derivative represented by the general formula (6) obtained by the second step is reacted with a halogenating agent or an alkyl or arylsulfonylating agent, and the hydroxyl group is halogenated or alkyl or arylsulfonate. To general formula (3a)

(In formula, R <^1> , R <^2> , R <^3> may be same or different and represents a hydrogen atom or a C1-C4 hydrocarbon. X is a halogen atom or a C1-C6 alkylsulfonate group or C6-C12 To an arylsulfonate group.). A 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative is represented.

The manufacturing method of the compound represented by general formula (3a) below is demonstrated in detail.

In the preferable method of this invention, the malic acid derivative represented by General formula (4) is used as a raw material.

In the formula (4), R ^1, R ^2, R ³ is and R ^1, R ^2, R ³ in the formula (1) It is the same meaning. R ⁸ and R ⁹ each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms. As such a malic acid derivative, more specifically, a 2-acid and / or 3-position of a hydrocarbon, such as citramal acid (2-methyl malic acid), 3-ethyl malic acid, 3, 3- dimethyl malic acid, is included, for example. Malic acid substituted with the group, for example, malic acid monoester or diester such as monoisopropyl malic acid, dimethyl malic acid, diethyl malic acid, for example, dimethyl citramal acid, monobutyl citrate, dimethyl 3-ethyl malic acid, and the like. And monoesters or diesters of malic acid in which the 2- and / or 3-positions of are substituted with hydrocarbon groups. Although these malic acid derivatives have asymmetric carbons, the malic acid derivatives used in the present invention may be either optically active or racemates. Of these malic acid derivatives, the use of malic acid, malic acid monoesters or malic acid diesters is preferred, and the use of malic acid is more preferred.

In the first step of a preferred method of the present invention, by reducing the general formula (4) -COOR ⁸ group of the malic acid derivative and represented by -COOR ⁹ groups to produce a tree olryu represented by the general formula (5).

In the formula (5), R ^1, R ^2, R ³ is the same meaning as R ^1, R ^2, R ³ in the formula (1). More specifically, such triols include 1,2,4-butane triol and, for example, 2-methyl-1,2,4-butane triol and 3-butyl-1,2,4- And 1,2,4-butane triol in which 2-position and / or 3-position, such as butanetriol, are substituted with a hydrocarbon group. The triols obtained in the first step of the present invention correspond to the used malic acid derivatives, and the hydrogen and hydrocarbon groups at 2-position and 3-position of the used malic acid derivative and the hydrogen and hydrocarbon groups at 2-position and 3-position of the obtained triol are the same. Do. For example, when using malic acid or malic acid mono or diester as a malic acid derivative, 1,2,4-butane triol is 2-methyl- when citramalic acid (2-methyl malic acid) is used, for example. When 1, 2, 4- butane triol uses 3-ethyl malate, for example, 3-ethyl 1, 2, 4- butane triol is obtained.

In the first step of the preferred method of the invention, the formula (4) As a method for reducing a group -COOR ⁸ group, and -COOR ⁹ of the malic acid derivatives such method, metal hydride for example, the electrolytic reduction is represented by And a method of reducing by hydrogen in the presence of a hydrogenation catalyst.

Specifically as a method of electrolytic reduction, the method of electrolytic reduction using a lead electrode in sulfuric acid aqueous solution is mentioned, for example.

Specific examples of the metal hydride in the case of reduction by the metal hydride include aluminum hydride compounds such as lithium aluminum hydride, lithium hydride trimethoxyaluminum, aluminum hydride and diisobutylaluminum hydride, for example, And boron hydride compounds such as diborane, lithium borohydride, and sodium borohydride. As the usage-amount in the case of reducing by metal hydride, it is 2-10 mol with respect to 1 mol of malic acid derivatives normally, Preferably it is the range of 3-6 mol.

The hydrogenation catalyst in the case of reducing by hydrogen in the presence of a hydrogenation catalyst may be any compound as long as it catalyzes the reaction of reducing the carboxyl group or ester group of the malic acid derivative of the present invention to a hydroxyl group by molecular hydrogen. At least one metal or metal compound selected from Group 13 is suitably used. The specific example of a hydrogenation catalyst and its usage-amount can illustrate the same thing as the hydrogenation catalyst and the usage-amount illustrated at the method of reducing the cyano group of the 3-cyanotetrahydrofuran derivative represented by General formula (1).

Among these reduction methods, a method of reducing with hydrogen in the presence of a hydrogenation catalyst is preferable. As the hydrogenation catalyst, a metal or metal compound of ruthenium, rhodium, palladium, copper or rhenium is preferable, a metal or metal compound of ruthenium or rhodium is more preferable, and a metal or metal compound of ruthenium is most preferred.

In the 1st process in the preferable method of this invention, although it can carry out without using a solvent, it is usually performed in presence of a solvent. As a solvent in the case of use, any solvent may be used as long as the reduction reaction is not inhibited.

As a solvent used in the case of the method by electrolytic reduction, C1-C20 alcohol, such as water, for example, methanol, ethanol, butanol, is used suitably. Moreover, you may use these solvents in mixture of 2 or more types.

When reducing by metal hydride, C5-C20 aliphatic or alicyclic hydrocarbons, such as n-hexane, n-pentane, or cyclohexane, for example, benzene, toluene, ethylbenzene, etc. C6-C20 aromatic hydrocarbons, for example, C1-C20 aliphatic or aromatic halides such as chloroform, chlorobenzene, dichlorobenzene, for example, diethyl ether, diphenyl ether, tetrahydrofuran, C2-C20 ethers, such as ethylene glycol dimethyl ether, are used suitably. Moreover, you may use these solvents in mixture of 2 or more types. The use of ethers among these solvents is preferred.

As a solvent in the case of reducing by hydrogen in the presence of a hydrogenation catalyst, C1-C20 alcohols, such as methanol, ethanol, butanol, for example, n-hexane, n-pentane, cyclohexane C5-C20 aliphatic or cycloaliphatic hydrocarbons, for example, C6-C20 aromatic hydrocarbons, such as benzene, toluene, and ethylbenzene, For example, diethyl ether, diphenyl ether, tetrahydro C2-C20 ethers, such as furan and ethylene glycol dimethyl ether, are used suitably. Moreover, you may use these solvents in mixture of 2 or more types. Among these solvents, the use of water, alcohols, ethers is preferred, and the use of water or alcohols having 1 to 4 carbon atoms is more preferred.

Although the quantity of the solvent at the time of using is not the same according to reaction conditions, it is normally 0.1-500 weight part with respect to 1 weight part of malic acid derivatives, Preferably it is the range of 1-200 weight part.

The temperature and time during the reaction are not the same depending on the type of the malic acid derivative used and the reduction method. However, normally, reaction temperature is the range of -10-250 degreeC, Preferably it is the range of 10-200 degreeC. The reaction time is usually 150 hours or less, preferably in the range of 0.01 to 100 hours.

Although the pressure at the time of reaction can be implemented by any of pressure reduction, normal pressure, or pressurization, a preferable aspect changes with the reduction method to be performed. In the case of the method of reducing by electrolytic reduction or metal hydride, it is preferably carried out at normal pressure. In the case of the method of reducing with hydrogen in the presence of a hydrogenation catalyst, it is preferably carried out under hydrogen pressurization. The hydrogen pressure at the time of pressurization is the range of 0.01-30 Mpa gauge pressure normally, Preferably it is the range of 0.1-25 Mpa gauge pressure.

It does not specifically limit as a reaction method of the 1st process of the preferable method of this invention, Any of a batch type, a semibatch type, or a continuous flow type may be sufficient.

When reducing with hydrogen in the presence of a hydrogenation catalyst in the 1st process of the preferable method of this invention, the catalyst used after completion | finish of reaction can be collect | recovered by the metal collection method used normally. For example, when the catalyst is dissolved in the reaction solution, the catalyst can be recovered by contacting with a metal adsorbent such as an ion exchange resin, or extracted with a solvent. When the catalyst is not dissolved in the reaction solution, for example, filtration Or by solid-liquid separation such as centrifugation. These recovery catalysts can be used repeatedly as a hydrogenation catalyst of the 1st process of this invention. In that case, it can also be reused after performing the regeneration operation of the catalyst whose deactivation or activity fell. If the remaining catalyst does not affect the subsequent step of recovering the triols and / or the second step of the preferred method of the present invention, the reaction solution may be used as it is in the next step without recovering the catalyst.

The triols produced in the first step of the preferred method of the present invention may be isolated in accordance with a commonly used separation method such as distillation, and then provided to the next second step, and only the solvent when used is distilled. After removal, the mixture may be used as the mixture in the next step or may be used in the next step in a state of being a reaction mixture containing a solvent.

In the second step of the preferred method of the present invention, the triols obtained by the first step are subjected to intramolecular dehydration reaction in the presence of an acid catalyst to prepare 3-hydroxytetrahydrofuran derivative represented by the general formula (6). .

In the formula (6), R ^1, R ^2, R ³ has the same meaning as R ^1, R ^2, R ³ in the formula (1). As such a 3-hydroxy tetrahydrofuran derivative, including 3-hydroxy tetrahydrofuran, for example, 4-ethyl- 3-hydroxy tetrahydrofuran, 3-methyl- 3-hydroxy tetrahydrofuran, etc. And 3-hydroxytetrahydrofuran in which the 3-position and / or 4-position of is substituted with a hydrocarbon group. The 3-hydroxytetrahydrofuran derivative obtained in the second step corresponds to the triols used, and the 2-position and 3-position hydrogen atoms or hydrocarbon groups of the used triols, and the 3-position of the 3-hydroxytetrahydrofuran derivative obtained and The hydrogen atom or hydrocarbon group at the 4 position is the same. For example, when 1,2,4-butane triol is used as the triol, when 3-hydroxytetrahydrofuran uses, for example, 2-methyl-1,2,4-butane triol 3-Methyl-3-hydroxytetrahydrofuran is obtained.

As the acid catalyst in the second step of the preferred method of the present invention, either bronsted acid or Lewis acid may be used, or may be soluble or insoluble in the reaction mixture. The acid catalyst may be any of an organic acid, an inorganic acid or a solid acid, and more specifically, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, boric acid, nitric acid, sulfuric acid, phosphoric acid, and chloric acid, for example, formic acid, Organic carboxylic acids such as acetic acid, propionic acid, chloroacetic acid, glycolic acid, benzoic acid and phthalic acid, for example, organic sulfonic acids such as methylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, For example, organic phosphates, such as diethyl phosphate and phenyl phosphate, for example, metal halides such as aluminum chloride, zinc iodide, titanium chloride, for example, trifluoromethane sulfonate, trifluoromethane Trifluoromethanesulfonic acid metal salts, such as samarium sulfonate, For example, acidic ion exchange resins, such as a sulfonic-acid type ion exchange resin, For example, silica magnesia, silica alumina, a yarn Composite oxides composed of two or more metal oxides such as cat titania, titania zirconia, alumina and boria, for example, natural clay minerals such as acid clay, montmorillonite and kaolin, for example, diatomaceous earth, silica gel, and cells Supported acids in which phosphoric acid or sulfuric acid is supported on a carrier such as lite, alumina or zirconia, for example, acidic natural or synthetic zeolites such as Y-type zeolite, mordenite and ZSM-5, for example niobic acid and oxidation Examples of the monometallic oxides such as zinc, alumina and titanium oxide, for example, solid superacids in which antimony fluoride and boron trifluoride are supported on a carrier such as silica alumina, silica zirconia, graphite or the like can be exemplified. The amount of acid catalyst to be used is usually in the range of 0.0001 to 10 mol%, preferably 0.001 to 5 mol% for soluble acids relative to triols as raw materials of the second step, and usually 0.001 to 50 for insoluble acids. % By weight, preferably in the range of 0.1 to 20% by weight.

In the 2nd process of the preferable method of this invention, you may carry out in presence of a solvent. As a solvent in the case of use, any solvent may be used as long as the intramolecular dehydration reaction of triols is not inhibited. As a specific example of such a solvent, C5-C20 aliphatic or alicyclic hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 aliphatic among what was illustrated as a solvent which can be used in a 1st process Or aromatic halides and C2-C20 ethers are used suitably. Moreover, you may use these solvents in mixture of 2 or more types. Although the quantity of the solvent at the time of using is not the same according to reaction conditions, it is 0.1-500 weight part with respect to 1 weight part of triols normally, Preferably it is the range of 1-200 weight part.

In the 2nd process of the preferable method of this invention, it is preferable to react, removing the water produced | generated by intramolecular dehydration reaction out of a reaction system. Although there is no restriction | limiting in particular as a method of removing the produced water out of a reaction system, For example, the method of distilling out the water produced by carrying out a reaction under reduced pressure, for example, azeotropes with water, such as toluene, etc. The method of making it react in presence of the solvent to make and remove out of a reaction system as an azeotropic mixture, the method of having a dehydrating agent in a reaction liquid, etc. are mentioned as an example of a preferable method.

The reaction temperature of the 2nd process of the preferable method of this invention is the range of 10-250 degreeC normally, Preferably it is the range of 30-200 degreeC. The reaction time is usually within 100 hours, preferably in the range of 0.01 to 50 hours.

Although the pressure at the time of reaction can be implemented by any of reduced pressure, normal pressure, or pressurization, when making it react, distilling water off, it is preferable to carry out under reduced pressure.

The reaction method of the present invention is not particularly limited and may be any of batch, semi-batch or continuous flow type.

The catalyst used after the completion of the reaction may be recovered and used repeatedly for the next reaction, for example, may be neutralized with a base such as sodium hydroxide, and in the case of a solid acid, may be separated by a solid-liquid separation method that is usually used, You may proceed to the next purification process as it is, without neutralizing or separating.

In the case where the 3-hydroxytetrahydrofuran derivative produced in the second step of the preferred method of the present invention is isolated in accordance with a commonly used separation method such as distillation and then provided in the following third step. It may be provided to the next process in the state which is a reaction mixture.

In the third step of the preferred method of the present invention, the 3-hydroxytetrahydrofuran derivative obtained in the second step is reacted with a halogenating agent or an alkyl or arylsulfonylating agent, and the hydroxyl group is halogenated or alkyl or arylsulfonated. To prepare a 3-halogenated or 3-alkyl or arylsulfonate tetrahydrofuran derivative represented by the general formula (3a).

In general formula (3a), R <^1> , R <^2> , R <^3> And X have the same meaning as R ¹ , R ² , R ³ and X in General Formula (3). As for the 3-halogenated or 3-alkyl or arylsulfonate tetrahydrofuran derivative represented by general formula (3a), all of R <^4> , R <^5> , R <^6> and R <^7> are the compounds represented by the above-mentioned general formula (3). It is a compound which is a hydrogen atom. The 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative obtained in the third step of the preferred method of the present invention corresponds to the 3-hydroxytetrahydrofuran derivative used, and used 3-hydroxytetrahydrofuran derivative. The 3- and 4-position hydrogen atoms or hydrocarbon groups of the same and the 3- and 4-position hydrogen atoms or hydrocarbon groups of the 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative obtained are the same. For example, when 3-hydroxytetrahydrofuran is used as the 3-hydroxytetrahydrofuran derivative, 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran is, for example, 3-methyl-3. When -hydroxytetrahydrofuran is used, 3-halogenated or 3-alkyl or arylsulfonated 3-methyltetrahydrofuran is obtained.

The halogenating agent in the third step of the preferred method of the present invention may be any compound as long as it is a compound capable of efficiently converting a hydroxy group of a 3-hydroxytetrahydrofuran derivative into a halogen group. Examples of such halogenating agents include, For example, halogenated alcohol compounds in Experimental Chemistry Lecture 20 (Japanese Chemical Society, Marzen, 1956) or New Experimental Chemistry Lecture 14 (I) (Japanese Chemical Society, Marzen, 1977) The halogenating agent used for the synthesis | combination of a compound is mentioned. More specifically, for example, fluorinating agents such as HF / pyridine solution, 1,1,2,2-tetrafluoroethyldiethylamine, trifluorodiphenylphosphorane, for example, phosgene and thionyl chloride Chlorinating agents such as zinc chloride / hydrochloric acid, t-butyl hypochlorite, N-chlorinated amine, for example, bromination agents such as hydrobromic acid, t-butyl hypobromite, thionyl bromide, for example hydroiodic acid and the like. Iodinating agent, and the like. The use of chlorinating agents in these halogenating agents is preferred, and the use of phosgene or thionyl chloride in chlorinating agents is preferred. The usage-amount of the halogenating agent to be used is 0.1-10 mol normally with respect to 1 mol of 3-hydroxy tetrahydrofuran derivatives, Preferably it is 0.8-3 mol.

As the alkyl or arylsulfonylating agent of the third step of the preferred method of the present invention, any compound may be used as long as it is a compound capable of efficiently converting the hydroxy group of the 3-hydroxytetrahydrofuran derivative to an alkyl or arylsulfonate group. As such an alkyl or arylsulfonylating agent, More specifically, C1-C6, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, an ethanesulfonic acid, trifluoromethanesulfonic acid, are mentioned, for example. Halides of alkyl or aryl sulfonic acids such as alkyl sulfonic acids or aryl sulfonic acids having 6 to 12 carbon atoms, for example, tosyl chloride (p-toluene sulfonate), such as ammonium trifluoromethanesulfonic acid, Ammonium salt of the said alkyl or aryl sulfonic acids, such as benzene sulfonate tetraethylammonium, For example, Alkali metal salt of the said alkyl or aryl sulfonic acids, such as sodium p-toluene sulfonate, For example, p-toluene sulfonic acid anhydride, etc. And anhydrides of the above alkyl or aryl sulfonic acids, for example, ester compounds of the above alkyl or aryl sulfonic acids such as ethyl methanesulfonic acid. Of these alkyl or arylsulfonylating agents, the use of halides and anhydrides of the alkyl or arylsulfonic acids is preferred, and the use of halides of the alkyl or arylsulfonic acids is more preferred. The amount of the alkyl or arylsulfonylating agent to be used is usually in the range of 0.1 to 10 moles, preferably 0.8 to 3 moles, per 1 mole of 3-hydroxytetrahydrofuran derivative.

The 3-hydroxytetrahydrofuran derivative of the present invention is reacted with a halogenating agent or an alkyl or arylsulfonylating agent, and a halogenated or alkyl or arylsulfonate is used to form a 3-halogenated or 3-alkyl group represented by the general formula (3a). In the method of manufacturing an alkyl or arylsulfonate tetrahydrofuran derivative, the method of halogenating with a halogenating agent is preferable, and the method of chlorination with a chlorinating agent is more preferable.

In the third step of the preferred method of the present invention, an appropriate catalyst and reaction promoter can be used to efficiently react the 3-hydroxytetrahydrofuran derivative with the halogenating agent or the alkyl or arylsulfonylating agent. The catalyst and reaction promoter in the case of use depend on the halogenating agent or alkyl or arylsulfonylating agent used. For example, when phosgene or thionyl chloride is used as the halogenating agent, for example, pyridine or triethyl Use of amines such as amines, such as amides such as N, N-dimethylformamide and N, N-dimethylacetamide, is preferable for promoting the reaction and improving the yield. Moreover, when using halides of alkyl or aryl sulfonic acids, such as tosyl chloride, use of amines, such as a pyridine and a triethylamine, is preferable, for example.

In the 3rd process of the preferable method of this invention, even if it exists in the absence of a solvent, it can carry out. As a solvent in the case of use, any solvent may be used as long as it does not inhibit the reaction of the 3-hydroxytetrahydrofuran derivative with the halogenating agent or the alkyl or arylsulfonylating agent. As a specific example of such a solvent, C5-C20 aliphatic or alicyclic hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 aliphatic among what was illustrated as a solvent which can be used in a 1st process Or in addition to aromatic halides and ethers having 2 to 20 carbon atoms, for example, aliphatic or aromatic amides having 2 to 20 carbon atoms such as N, N-dimethylformamide and N, N-dimethylacetamide, for example Aliphatic or aromatic esters having 2 to 20 carbon atoms such as ethyl acetate and butyl acetate, for example aliphatic or aromatic nitriles having 2 to 20 carbon atoms such as acetonitrile and benzonitrile, for example, dimethyl sulfoxide Aliphatic or aromatic sulfoxides having 2 to 20 carbon atoms are suitably used. Moreover, you may use these solvents in mixture of 2 or more types. Although the quantity of the solvent at the time of using is not the same according to reaction conditions, it is 0.1-500 weight part with respect to 1 weight part of 3-hydroxy tetrahydrofuran derivatives normally, Preferably it is the range of 1-200 weight part.

The reaction temperature of the 3rd process of the preferable method of this invention is the range of -80-150 degreeC normally, Preferably it is the range of -20-80 degreeC. The reaction time is usually within 200 hours, preferably in the range of 0.01 to 100 hours. The pressure at the time of reaction can be implemented by any of reduced pressure, normal pressure, or pressurization. It does not specifically limit as reaction method of this invention, Any of a batch type, a semibatch type, or a continuous flow type may be sufficient.

The catalyst or reaction promoter in the case of use after the reaction is completed may be recovered and used repeatedly for the next reaction, or may be separated by a separation method that is usually used.

The tri-halogenated or tri-alkyl or arylsulfonated tetrahydrofuran derivative produced in the third step of the present invention is isolated according to a commonly used separation method such as distillation or extraction, and then the following step Is provided.

Hereinafter, the present invention will be described in more detail with reference to Examples.

[Production example of 3-aminomethyltetrahydrofuran derivative]

Example 1

20.4 g (210 mmol) of 3-cyanotetrahydrofuran, 14.3 g of 25% aqueous ammonia (210 mmol as NH ₃ ), and 1.0 g of Raney nickel are placed in an autoclave. After nitrogen substitution, hydrogen pressure was 5 MPa gauge pressure, and it was made to react at 100 degreeC for 3 hours. After the reaction, the catalyst was filtered off and analyzed by gas chromatography. The conversion of raw material was 100%, and the yield of 3-aminomethyltetrahydrofuran as the target product was 89.8%. Moreover, as a main by-product, the amide body of the following structure by which the cyano group of 3-cyano tetrahydrofuran was hydrated was produced in the yield of 0.7%. The produced 3-aminomethyltetrahydrofuran was isolated as a transparent liquid by distillation under reduced pressure as an oil content of 67 degreeC / 2.0 kPa.

EXAMPLE 2-13

In Example 1, the same amount of 3-cyanotetrahydrofuran was used, except that the type and amount of the catalyst, the amount of 25% ammonia water, the hydrogen pressure, the reaction temperature, and the reaction time were changed as shown in Table 1. Reaction and post-treatment were performed similarly to Example 1. The results are shown in Table 1 together with the results of Example 1.

Table 1

Catalyst ^(*) 25% NH ₃ Water Pressure Temperature Time Raw Material Yield Amide Conversion Rate Yield Class Amount (g) (g) (MPa) (℃) (h) (%) (%) (%) Example 1 Example 2 Example 3 Example 4 Example 5  R-Ni 1.0 14.3 5 100 3 100.0 89.8 0.7 R-Ni 1.0 70.0 5 100 3 88.9 70.9 4.5 R-Ni 1.5 70.0 5 50 7 100.0 54.9 39.4 R-Ni 1.5 70.0 5 90 4 100.0 66.7 17.1 R-Ni 1.5 70.0 10 120 1 100.0 82.4 7.9 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13  R-Co 1.0 14.3 5 90 3 77.2 70.4 1.3 R-Co 1.0 14.3 5 100 3 99.4 95.2 2.0 R-Co 1.0 14.3 5 110 2 99.4 93.4 2.0 R-Co 1.5 70.0 4 50 4 28.7 21.0 3.7 R-Co 1.0 42.9 5 100 3 100.0 95.6 2.8 R-Co 1.0 4.3 5 100 3 99.5 91.4 1.4 R-Co 1.0 14.3 3 100 3 92.4 79.7 2.1 R-Co 1.0 14.3 10 100 3 99.4 93.8 1.4

(*) R-Ni: Raney nickel, R-Co: Raney cobalt

Example 14

In Example 1, reaction and post-treatment were performed like Example 1 except having used 14.3 g of water instead of ammonia water. The yield of 3-aminomethyltetrahydrofuran was 13.6%. As a by-product, 68.0% of secondary amines having the following structure other than 4.8% of the amide were produced.

Example 15

The reaction and post-treatment were carried out similarly to Example 1 except that ammonia water was not used in Example 1. The yield of 3-aminomethyltetrahydrofuran was 11.1%. As a by-product, 78.5% of secondary amines were produced.

[Production example of 3-cyanotetrahydrofuran derivative]

Example 16

26.6 g (250 mmol) of 3-chlorotetrahydrofuran, 18.4 g (375 mmol) of NaCN and 260 mL of N, N-dimethylformamide (hereinafter abbreviated as DMF) were placed in an autoclave. It heated up at 150 degreeC and made it react for 5 hours. The precipitated salt was filtered off after completion of the reaction, and the filtrate was analyzed by gas chromatography. The yield of 3-cyano tetrahydrofuran was 87.1%. Also, 2,5-dihydrofuran was produced by 10.1% as a main by-product. By distillation under reduced pressure, 21.1 g (217 mmol) of 3-cyanotetrahydrofuran were isolated as a transparent liquid as an oil of 123 占 폚 /10.8 kPa.

[Example 17-22]

In Example 16, reaction and post-treatment were performed like Example 16 except having changed the kind of solvent, reaction temperature, and reaction time as shown in Table 2. The results are shown in Table 2 together with the results of Example 16. Table 2 also records the permittivity of each solvent.

Table 2

Solvent Dielectric Constant ^(*) Temperature Time Conversion Rate Yield 2,5-DHF ^(#) (Fm- ¹ ) (° C) (h) (%) (%) Yield (%) Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 N, N-dimethylformamide 36.7 (25) 150 5 100 87.1 10.1 Dimethyl sulfoxide 48.9 (20) 130 4 100 89.6 8.8 1, 3-dimethyl-2-imidazolidinone 36.7 (25) 120 4 76.7 59.6 12.7 N Methylpyrrolidone 32.0 (25) 120 4 71.9 54.3 11.6 ethanol 23.8 (25) 140 7 58.6 22.8 15.3 sulfolane 43.3 (30) 140 7 86.3 55.6 10.3 N, N-dimethylacetamide 37.8 (25) 130 3 72.7 52.7 8.4 Solvent free-150 5 6.4 4.0 0.1

(*) Figures in parentheses indicate the measured temperature of permittivity

(#) 2,5-DHF: 2,5-dihydrofuran

Example 23

In Example 16, reaction and post-treatment were performed similarly to Example 16 except not using a solvent. The results are shown in Table 2.

Example 24

In Example 16 using DMF as a solvent, the reaction and the post-treatment were performed in the same manner as in Example 16 except that the reaction temperature was 170 ° C and the reaction time was 4 hours. The conversion rate was 100% and the yield of 3-cyanotetrahydrofuran was 74.6%.

Example 25

In Example 16 using DMF as the solvent, the reaction and the workup were carried out in the same manner as in Example 16 except that the solvent amount was 130 mL. The conversion rate was 100% and the yield of 3-cyanotetrahydrofuran was 87.0%.

Example 26

In Example 25, reaction and post-treatment were carried out similarly to Example 25, except that 24.4 g (375 mmol) of KCN was used instead of NaCN. The conversion rate was 80.8% and the yield of 3-cyanotetrahydrofuran was 54.8%.

Example 27

In Example 25, except that 31.9 g (375 mmol) of acetone cyanhydrin was used instead of NaCN, and 41.9 g (275 mmol) of 1,8- diazabicyclo [5.4.0] undeca-7-ene was used. Reaction and post-treatment were performed similarly to Example 25. The conversion rate was 81.7% and the yield of 3-cyanotetrahydrofuran was 54.5%.

Example 28

In Example 17, in which dimethyl sulfoxide (hereinafter abbreviated as DMSO) was used as the solvent, the reaction and post-treatment were carried out in the same manner as in Example 17, except that the reaction temperature was 120 ° C. The conversion rate was 98.1% and the yield of 3-cyanotetrahydrofuran was 89.3%.

Example 29

In Example 17 using DMSO as a solvent, the reaction and the post-treatment were carried out in the same manner as in Example 17 except that the reaction temperature was 110 ° C and the reaction time was 8 hours. The conversion rate was 94.3% and the yield of 3-cyanotetrahydrofuran was 86.3%.

Example 30

The reaction and post-treatment were carried out in the same manner as in Example 17 except that the amount of NaCN used was 13.5 g (275 mmol) in Example 17 using DMSO as a solvent. The conversion rate was 99.7% and the yield of 3-cyano tetrahydrofuran was 87.0%.

Example 31

In Example 25, reaction and post-treatment were carried out similarly to Example 25, except that 60.6 g (250 mmol) of 3- (p-toluenesulfonate) -tetrahydrofuran was used instead of 3-chlorotetrahydrofuran. The yield of 3-cyano tetrahydrofuran was 71.3%.

Example 32

In Example 25, reaction and post-treatment were performed like Example 25 except having used 55.0 g (250 mmol) of 3- (trifluoromethane sulfonate) -tetrahydrofurans instead of 3-chlorotetrahydrofuran. The yield of 3-cyano tetrahydrofuran was 68.0%.

[Production example of 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative from malic acid derivative]

Example 33

[Step 1 (Step of Reducing Malic Acid)]

56.0 g (418 mmol) of malic acid, 400 mL of water, and 40 g of 5% ruthenium carbon powder were placed in a 1 L autoclave. After nitrogen-substituting the reactor, the reaction system was pressurized with hydrogen of 1 MPa gauge pressure. After heating up the reaction liquid to 100 degreeC, reaction was performed for 24 hours by making hydrogen pressure into 12 Mpa gauge pressure. After the completion of the reaction, the catalyst was filtered to obtain 34.2 g (322 mmol) of 1,2,4-butane triol as an oil of 185-190 ° C / 2.4 kPa by vacuum distillation. Yield 77%.

[Step 2 (Step of Cyclizing Triol)]

31.8 g (300 mmol) of 1,2,4-butane triol and 0.3 g of p-toluene sulfonic acid monohydrate obtained by the said 1st process were put into the 75 mL 3-necked flask provided with the cooling discharge pipe. The reaction system was heated to 140 ° C under reduced pressure of 6.6 kPa, and cyclization reaction of 1,2,4-butane triol was performed. The reaction was carried out in the form of reactive distillation, and the cyclized product 3-hydroxytetrahydrofuran was discharged out of the reaction system through the cooling discharge pipe together with the produced water. The water was removed by distillation from the 3-hydroxy tetrahydrofuran containing the obtained water, and 25.6 g (291 mmol) of 3-hydroxy tetrahydrofuran was obtained. Yield 97%.

[3rd process (process of halogenating 3-hydroxy tetrahydrofuran)]

24.7 g (280 mmol) of 3-hydroxytetrahydrofuran and 85 mL of DMF which were obtained by the said 2nd process were put into the 200 mL three-necked flask. After the flask was immersed in an ice bath, 36.7 g (308 mmol) of thionyl chloride was added dropwise to the N, N-dimethylformamide solution over 30 minutes, and the reaction was continued for 6 hours at room temperature after the completion of dropping. After completion | finish of reaction, after sulfuric acid and hydrogen chloride produced | generated by nitrogen bubbling were sent out, 27.1 g (254 mmol) 3-chlorotetrahydrofuran was obtained as an oil component of 125-130 degreeC by atmospheric distillation. Yield 91%.

Examples of each step of producing a 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative from a malic acid derivative will be specifically described below. By appropriately combining each of these steps after Example 33 and Example 34, it is possible to synthesize 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivatives from malic acid derivatives.

Example 34

[Step 1]

In the first step of Example 33, the reaction was carried out in the same manner as in the first step of Example 33 except that 40 g of 5% rhodium carbon powder was used instead of 40 g of 5% ruthenium carbon powder as the catalyst and the hydrogen pressure was 16 MPa gauge pressure. And distillation. The yield of 1,2,4-butane triol was 56%.

Example 35

[Step 1]

In the first step of Example 33, the reaction and distillation were carried out in the same manner as in the first step of Example 33 except that the reaction temperature was changed to 120 ° C. and the reaction time was changed to 6 hours. The yield of 1,2,4-butane triol was 63%.

Example 36

[Step 1]

In the first step of Example 33, reaction was carried out in the same manner as in the first step of Example 33 except that 400 mL of ethanol was used instead of 400 mL of water as the solvent, and the hydrogen pressure was changed to 16 MPa gauge pressure and the reaction time was changed to 90 hours. Distillation was performed. The yield of 1,2,4-butane triol was 90%.

Example 37

[Step 1]

In the first step of Example 33, 400 mL of ethanol was used instead of 400 mL of water, and the hydrogen pressure was changed to 16 MPa gauge pressure, the reaction temperature was changed to 120 ° C., and the reaction time was changed to 70 hours. Reaction and distillation were performed similarly to the 1st process. The yield of 1,2,4-butane triol was 90%.

Example 38

[Step 1]

In a 500 mL autoclave, 25 g of dimethyl malic acid 50.0 g (308 mmol), tetrahydrofuran 200 mL, CuO / ZnO / Al ₂ O ₃ (CuO / ZnO / Al ₂ O ₃ were 52.8 wt%, 28.1 wt%, 19.1 wt%), respectively. Put in. After nitrogen-substituting the reactor, the reaction system was pressurized with hydrogen of 1 MPa gauge pressure. After heating up the reaction liquid to 180 degreeC, reaction was performed for 4 hours by making hydrogen pressure into 10 Mpa. After the reaction was completed, the catalyst was filtered off and distilled under reduced pressure. The yield of 1,2,4-butane triol was 80%.

Example 39

[Step 2]

In the second step of Example 33, reaction and distillation were performed in the same manner as in the second step of Example 33 except that 0.3 g of sulfuric acid was used instead of p-toluenesulfonic acid monohydrate. The yield of 3-hydroxytetrahydrofuran was 98%.

Example 40

[Step 2]

In the second step of Example 33, reaction and distillation were carried out in the same manner as in the second step of Example 33, except that 0.5 g of trifluoro methanesulfonic acid samarium was used in place of p-toluenesulfonic acid monohydrate. The yield of 3-hydroxytetrahydrofuran was 97%.

Example 41

[Step 2]

In the second step of Example 33, reaction and distillation were performed in the same manner as in the second step of Example 33 except that 1.0 g of H-type mordenite was used instead of p-toluenesulfonic acid monohydrate. The yield of 3-hydroxytetrahydrofuran was 95%.

Example 42

[Step 2]

In the second step of Example 33, the reaction and distillation were performed in the same manner as in the second step of Example 33 except that the pressure at the reaction was replaced with 13.2 kPa. The yield of 3-hydroxytetrahydrofuran was 95%.

Example 43

[Step 3]

In the third step of Example 33, the reaction was carried out in the same manner as in the third step of Example 33, except that 22.1 g (280 mmol) of pyridine and 50 mL of toluene were used instead of DMF. After the completion of the reaction, the sulfur dioxide and hydrogen chloride produced by nitrogen bubbling were extracted, and then the precipitated pyridinium salt was removed by filtration and distilled under atmospheric pressure to obtain 3-chlorotetrahydrofuran. Yield 93%.

Example 44

[Step 3]

After mixing 50 mL of concentrated hydrochloric acid and 76.4 g (560 mmol) of zinc chloride in a 250 mL three-necked flask, 24.7 g (280 mmol) of 3-hydroxytetrahydrofuran was added dropwise to this solution. After refluxing for 2 hours, the upper layer was separated and heated to reflux with concentrated sulfuric acid. The product was distilled off and 3-chlorotetrahydrofuran was obtained. Yield 78%.

Example 45

[Step 3]

24.7 g (280 mmol) of 3-hydroxytetrahydrofuran and 53.5 g (280 mmol) of tosyl chloride were dissolved in 150 mL of ether, and a 50 mL solution of pyridine 44.3 g (560 mmol) of ether was added dropwise at 0 占 폚. After completion of the reaction, the pyridine hydrochloride was filtered off, the solvent was distilled off, and the residue was recrystallized from ether. 40.0 g (165 mmol) of 3- (p-toluenesulfonate) -tetrahydrofuran was obtained. Yield 59%.

Example 46

[Step 3]

3.6 g (150 mmol) of sodium hydride was suspended in 200 mL of ether, and a 50 mL solution of 12.4 g (140 mmol) of 3-hydroxytetrahydrofuran was slowly added dropwise thereto at 0 ° C. 33.7 g (200 mmol) of trifluoromethanesulfonyl chlorides were added dropwise, and the mixture was refluxed for 3 hours. After cooling, water was added to separate the ether layer, and ether was distilled off to obtain 26.2 g (119 mmol) of 3- (trifluoromethanesulfonate) -tetrahydrofuran by distillation under reduced pressure. Yield 85%.

3-aminomethyltetrahydrofuran derivatives useful as agrochemical intermediates can be obtained and used for the synthesis of agrochemicals.

Claims (14)

A process for producing a 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative represented by the general formula (3a) prepared from the maleic acid derivative by the first step to the third step below: [Step 1] General Formula (4) Formula 9

(Wherein, R ^1, R ^2, R ^3, R ^8, R ^9, which may be the same or be different from each other, represent a hydrogen atom or a hydrocarbon group having 1 to 4.) -COOR ⁸ of malic acid derivative represented by the group And -COOR ⁹ groups to reduce the general formula (5) Formula 10

In the formula, R ¹ , R ² and R ³ may be the same or different from each other and represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms. [Second Step] The triols represented by the general formula (5) obtained by the first step were subjected to intramolecular dehydration reaction in the presence of an acid catalyst, thereby providing a general formula (6). Formula 11

3-hydroxytetrahydrofuran corresponding to the used triols represented by (In formula, R <^1> , R <^2> , R <^3> may be same or different, and represents a hydrogen atom or a C1-C4 hydrocarbon group.) Prepare derivatives. [Third Step] The 3-hydroxytetrahydrofuran derivative represented by the general formula (6) obtained by the second step is reacted with a halogenating agent or an alkyl or arylsulfonylating agent, and the hydroxyl group is halogenated or alkyl or arylsulfonate. To general formula (3a) (Formula 12)

(In formula, R <^1> , R <^2> , R <^3> may be same or different and represents a hydrogen atom or a C1-C4 hydrocarbon group. X is a halogen atom or a C1-C6 alkylsulfonate group or C6-C6 A 3-halogenated or 3-alkyl or arylsulfonated tetrahydrofuran derivative represented by () is shown. delete delete delete delete A general formula (1) characterized by reacting a 3-alkyl or arylsulfonated tetrahydrofuran derivative obtained by the process according to claim 1, an organic or inorganic cyano compound. (Formula 2)

(In formula, R <^1> , R <^2> , R <^3> may be same or different, and represents a hydrogen atom or a C1-C4 hydrocarbon group, and R <^4> , R <^5> , R <^6> , R <^7> is a hydrogen atom.) The manufacturing method of 3-cyano tetrahydrofuran derivative shown. The method of claim 6, An alkali metal cyanoide is used as an organic or inorganic cyano compound, and the manufacturing method of 3-cyano tetrahydrofuran derivative characterized by making it react in presence of the solvent whose dielectric constant is 20 F * m <^-1> or more. The method of claim 7, wherein A method for producing a 3-cyanotetrahydrofuran derivative in which a solvent having a dielectric constant of 20 F · m ⁻¹ or more is aprotic. Reducing the cyano group of the 3-cyanotetrahydrofuran derivative obtained by the manufacturing method of any one of Claims 6-8, General formula (2) characterized by the above-mentioned. (Formula 7)

(In formula, R <^1> , R <^2> , R <^3> may be same or different and represents a hydrogen atom or a C1-C4 hydrocarbon group. R <^4> , R <^5> , R <^6> , R <^7> is a hydrogen atom.) Method for producing the 3-aminomethyltetrahydrofuran derivative represented. delete The method of claim 9, Preparation of 3-aminomethyltetrahydrofuran derivative which reduces the cyano group of 3-cyanotetrahydrofuran derivative with hydrogen in the presence of ammonia and in the presence of a metal or metal compound of Group 9 or 10 of the periodic table as a catalyst Way. The method of claim 11, A process for producing a 3-aminomethyltetrahydrofuran derivative wherein the catalyst is a metal or metal compound of cobalt or nickel. The method of claim 11, A method for producing a 3-aminomethyltetrahydrofuran derivative wherein ammonia is ammonia water. The method of claim 13, The manufacturing method of the 3-aminomethyl tetrahydrofuran derivative which reacts in presence of 0.05-2 weight part of water with respect to 1 weight part of 3-cyano tetrahydrofuran derivatives.