JPS58103348A - Preparation of n-substituted amide compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an adhesive, etc. by one stage inexpensively, by subjecting simultaneously an amide compound and a halogen- substituted compound to a catalytic reaction in the presence of a suspended strongly basic substance in an aprotic polar solvent. CONSTITUTION:A strongly basic substance (e.g., Na2O, K2O, etc.), an amide compound (e.g., formamide, acetamide, acrylamide, benzamide, etc.) and a halogen- substituted compound (e.g., chloromethane, chloroethane, chlorobutane, chlorobenzene, etc.) are simultaneously subjected to catalytic reaction in an aprotic polar solvent, to give an N-substituted amide compound. In the operation, the reaction is started while the basic substance is suspended. In this method, the formation of the desired compound can be carried out selectively by making the amount of water in the reaction system of <=5wt% at the beginning of the reaction. Various kinds of the desired compounds can be obtained by the same reactor, so this method is suitable for preparing a small amount of various kinds of products.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for making N-substituted amide compounds. More specifically, the present invention relates to an improved method for producing both N-mono-substituted and N,N-disubstituted amide compounds.

In general, N-substituted amide compounds have a good balance between hydrophilic and hydrophobic groups within the molecule, so they have good compatibility with various substances.
They have strong resistance to hydrolysis, and unsaturated amide compounds have other advantages such as excellent monopolymerization or copolymerizability, so they can be used in adhesives, paints, paper processing agents, fiber processing agents, emulsions, urethane curing agents, and pigment dispersions. It is known to be applied in a wide range of fields such as additives, plastic additives, polymer flocculants, and ion exchange resins. It is also a useful compound as a raw material, intermediate, and product for compounds with complex structures such as pharmaceuticals, agricultural chemicals, amino acids, and natural products, and also as a raw material for amine production. However, since an inexpensive industrial production method for N-substituted amide compounds has not been established, they have not been used in large quantities.

Conventionally, industrially used methods for producing N-substituted amide compounds include the reaction of a carboxylic acid chloride with an amine and the Ritter reaction, but these methods are expensive. At present, the types of compounds that can be produced are limited, and their applications are also limited to specific fields.

In addition, as a general method for producing N-substituted amide compounds,
For example, there is a method for producing an N-substituted amide compound by converting an amide compound into an alkali metal-substituted amide compound by the action of a strong basic substance such as an alkali metal alkoxide, and then reacting with a halogen-substituted compound such as an alkyl halide. Reacti by W. J. Hickinbottom
ons of Organic Compounds 3rd
Edition, Longmans, Green and Co.

(1957) p. 344 and U.S. Pat. No. 3,084.
．． It is known from No. 191. However, these methods require the production process to consist of two steps, the use of protic solvents such as liquid ammonia or alcohol that are highly reactive with halogen-substituted compounds under basic catalysts, and the use of alkali metal amides. There are various disadvantages such as the use of highly basic substances such as hydrides, alkoxides, etc., which are difficult to handle. Therefore, as shown in Comparative Examples 1, 2, and 3 described below, the yield of the desired product is low, the halogen-substituted compound to be reacted is not versatile, and all the desired products are N-monosubstituted amide compounds. In addition, when producing N,N-disubstituted amide compounds, problems arise such as the need to repeat the same production process, so it is not widely adopted industrially as a general method for producing N-substituted amide compounds. This has not yet been achieved.

Furthermore, in recent years, G, L, l5ele, A, Luttrin.
ghous.

5ynthesis 1971 (5), page 266, an amide compound and a strong basic substance are reacted in advance in an aprotic polar solvent to form an alkali metal-substituted amide compound, and then an alkali metal-substituted amide compound such as an alkyl halide is prepared. A two-step process for producing N-alkyl-substituted amide compounds by reaction with N-alkyl-substituted compounds is also known. However, even if such a method is employed, satisfactory results are not obtained, as shown in Comparative Example 2, which will be described later.

Furthermore, in USSR Inventor's Certificate No. 667547, a basic substance such as caustic soda is added as an aqueous solution in a method for producing an N-alkylated organic compound in a polar solvent, and the basic substance starts the reaction in a liquid state. A method is disclosed in which the presence of water in the reaction mixture is said to be highly advantageous for the progress of the reaction. However, according to the research conducted by the present inventors, as is clear from the comparison of Example 1.3.4 and Comparative Example 4, which will be described later, this method tends to produce side reactants, and the target N -low selectivity towards substituted amide compounds;
It has been found that the yield decreases significantly depending on the target N-substituted amide compound.

In view of the actual situation regarding the production of the above-mentioned N-substituted amide compounds, the present inventors conducted intensive studies on the relationship between the amount of water present in the reaction system and the reactivity with the aim of improving the production method. The present invention was achieved by discovering that the effect on selectivity to -substituted amide compounds is extremely large.

That is, the presence of water in the reaction system, which was conventionally thought to be advantageous, causes side reactions contrary to expectations and inhibits the production of the target N-substituted amide compound; In order to suitably carry out this process, it is necessary to react a conventional amide compound with a strong basic substance, and then
The present invention was achieved by discovering that it is necessary to carry out a catalytic reaction of a strong basic substance, an amide compound, and a no-logen-substituted compound at the same time, rather than using a method in which a rogen-substituted compound is reacted.

The present invention provides a method for producing an N-substituted amide compound by simultaneously contacting a strongly basic substance, an amide compound, and a halogen-substituted compound in an aprotic polar solvent, in which the reaction is carried out while the basic substance is suspended. Characterized by starting.

In the present invention, a specific method for starting the reaction while suspending a strong basic substance is to simultaneously supply and mix the three components in an aprotic polar solvent to suspend the strong basic substance and react. method, a method in which a strong basic substance is suspended in an aprotic polar solvent, and then an amide compound and a halogen-substituted compound are simultaneously supplied and reacted, and an amide compound and a halogen-substituted compound are dissolved in an aprotic polar solvent Alternatively, an appropriate method may be employed, such as suspending the mixture and then adding a strong basic substance to the suspension.

The amide compounds that are the object of the present invention are broadly classified into monoamide compounds and polyamide compounds that are higher than diamide compounds.

Examples of the monoamide compound include aliphatic saturated carboxylic acid amide, aliphatic unsaturated carboxylic acid amide, aromatic carboxylic acid amide, alicyclic carboxylic acid amide, urea and its derivatives.

Aliphatic saturated carboxylic acid amides have the general formula CnH2n+, C
It is a compound represented by ONH2, where n is an integer of θ to 20. Furthermore, those having one or more substituents such as a nitro group, a cyano group, an amine group, a carboxylic acid group, a sulfonic acid group, an alkoxy group, and a carboxylic acid ester group are also targeted.

Aliphatic unsaturated carboxylic acid amide has the general formula cllH2n+
1-2m C0NI (re compound represented by 2 (in the formula n
is an integer of 2 to 20, m is an integer of 1 to 5), and contains one or more carbon-carbon double bonds and/or triple bonds in the molecule. Furthermore, those into which one or more substituents such as a nitro group, a cyan group, an amine group, a carboxylic acid group, a sulfone fi[, an alkoxy group, a carboxylic acid ester group, etc.] have been introduced are also targeted.

Aromatic carboxylic acid amide contains an aromatic ring in its molecule, and examples of the aromatic ring include a benzene ring, a naphthalene ring, an anthracene ring, and the like.

Furthermore, one or more substituents such as a nitro group, cyan group, alkoxy group, amino group, carboxylic acid group, sulfonic acid group, carboxylic acid ester group, alkyl group, alkenyl group, or aryl group are introduced into the aromatic ring. It also includes compounds bonded to an aromatic ring such as a kanityl group, a sulfone group, or a sulfide group. Alicyclic carboxylic acid amides are compounds having an alicyclic structure in the molecule, and also include heterocyclic compounds composed of different elements. Moreover, urea and its derivatives are compounds having N-C0-N and N-Co-N-N atomic groups represented by urea.

To illustrate the above-mentioned monoamide compounds, examples of aliphatic saturated carboxylic acid amides include formamide, acetamide, propionamide, methylamide, 74'relamide, isonozylamide, pivalamide, lauramide, myrifutamide, palmitamide, stearamide, and methoxyacetamide. Ethoxyacetamide, methoxypropionamide, ethoxypropionamide, cyanobutinamide, nitrosinnamamide, aminopropionamide, carbamoylpropanesulfonic acid, carbamoylpropanoic acid,
Examples include methyl carbamoylpropanoate.

Aliphatic unsaturated carboxylic acid amides include, for example, acrylamide, methacrylamide, vinylacetamide, crotonamide, decenamide, nonadesenamide, proviolamide, butynamide, hexadienecarboxamide, pebtinamide, heptinamide, ethoxyacrylamide, ethoxymethacrylamide, cyanobutinamide, nitrobutinamide, aminobutinamide. mido, carbamoyl Examples include propenesulfonic acid, carbamoylcrotonic acid, and methyl carbamoylcrotonate.

Examples of aromatic carboxylic acid amides include benzamide, natutamide, anthracenecarboxamide, anthracenecarboxamide, piphenylcarboxamide, phenylacetamide, phenylpropionamide, phenyldecanamide, nitrobenzamide, nitronatsutamide, nitrocinenamamide, cyanobenzamide, methoxy Benzamide, ethoxybenzamide, methoxynatutamide, N,N-dimethylaminobenzamide, N,N-dimethylamitunaphthamide, carbamoylbenzenesulfonic acid, carbamoylnaphthalenesulfonic acid, toluamide,
Glopylbenzamide, decylbenzamide, carbamoylnaphthoic acid, vinylbenzamide, allylbenzamide, butenylbenzamide, phenylcarbamoylphenyl ether, vinylcarbamoylphenyl ether, phenylcarbamoylphenyl sulfone, phenylcarbamoylphenyl sulfide, etc.

Examples of alicyclic carboxylic acid amides include cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, cyclopentenecarboxamide, cyclohexanecarboxamide, cycloheptanecarboxamide, cyclooctanecarboxamide, cyclooctenecarboxamide, pyrrolecarboxamide, furancarboxamide, thiophenecarboxamide, cyclohexanecarboxamide, and cyclohexanecarboxamide. xylacetamide, Cyclohexylpropionamide, pyridine carboxamide, pyridine carboxamide,
Examples include morpholine carboxamide, imidazole carboxamide, and quinoline carboxamide. Examples of urea and its derivatives include urea, biuret, thiobiuret, triuret, semicarbazide, carbohydrazide, and carbazone.

Among these amide compounds exemplified, unsubstituted amide compounds are preferred in that they allow the reaction to occur efficiently.

More preferred are conjugated amide compounds in which the amide group of the amide compound is conjugated to a double bond, such as aliphatic unsaturated amide compounds such as acrylamide, methacrylamide, crotonamide, benzamide, tolylamide, isopropylbenzamide, natutamide, etc. There are aromatic amide compounds such as.

On the other hand, the polyamide compounds include aliphatic saturated polycarboxylic acid amide, aliphatic unsaturated polycarboxylic acid amide, aromatic polycarboxylic acid amide, and alicyclic polycarboxylic acid amide.

Aliphatic saturated polycarboxylic acid amide has the general formula CnHzn
-m+z(CONH2,)m, where n and m are integers, n is 0 to 2o, and m is 2 to 4. Also, nitro group, cyano group, amino group, carboxylic acid group, sulfone Those into which one or more types of acid groups, alkoxy groups, carboxylic acid ester groups, etc. are introduced are also targeted.

Aliphatic unsaturated polycarboxylic acid amide has the general formula CnH2
It is represented by n + 2-m 2 r (CONH2)yyl, where n, m and r are integers, n is 2-2o, m is 2-4, and r is 1-4. Furthermore, those into which one or more of a nitro group, a cyano group, an amino group, a carboxylic acid group, a sulfonic acid group, an alkoxy group, a carboxylic acid ester group, etc. are introduced are also targeted.

Aromatic polyvalent carboxylic acid amide contains an aromatic ring in the molecule, and the aromatic rings include benzene ring, naphthalene ring, anthracene ring, etc., and the number of substitutions in carboxylic acid amide is 2.
~6. Furthermore, one or more substituents such as nitro group, cyano group, amino group, carboxylic acid group, sulfonic acid group, alkoxy group, carboxylic acid ester group, alkyl group, alkenyl group, and aryl group are substituted on the aromatic ring. It also includes compounds whose substituents or aromatic rings are bonded to the aromatic ring via an ether group, sulfone group, sulfide group, etc.

Alicyclic polyvalent carboxylic acid amide is a compound having an alicyclic structure in the molecule, and also includes a heterocyclic compound composed of different elements, and the number of substitutions in the carboxylic acid amide is 2 to 5.

Next, examples of polyamide compounds include oxamide, malonamide, aliphatic saturated carboxylic acid amide,
Sufcinamide, geltalamide, adipamide, pimeramide, speramide, azeramide, sebaamide, carbamoylmethylmethylgeltalamide, butanetetracarboxamide, tetradecane dicarboxamide, octadecane dicarboxamide, methoxyadipamide, cyanoadipamide, nitroadipamide, aminoadipamide, dicarbamoyl butanesulfate fonic acid , dicarbamoylbutanoic acid, dicarbamoylbutyl acetate, etc.

Aliphatic unsaturated polycarboxylic acid amides include, for example, maleamide, fumaramide, citraconamide, mesaconamide, decenedicarboxamide, tetradecenedicarboxamide, octadecenedicarboxamide, butenetetracarboxamide, hexadienedicarboxamide, pentynedicarboxamide, methoxybutenedicarboxamide , cyanoptine dicarboxamide, nitroptenedicarpoxamide, aminoptene dicarpoxamide, dicarbamoylputene sulfonic acid, dicarbamoylputenoic acid, methyl dicarbamoylbutenoate, and the like. Examples of aromatic polycarboxylic acid amides include phthalamide, isophthalamide,
Terephthalamide, natutale dicarboxamide, anthracene dicarboxamide, anthraquinone dicarboxamide, biphenyl dicarboxamide, phenylcitraconamide, naphthalene tricarboxamide, bilomelitutamide, nitrophthalamide, cyanophthalamide, aminophthalamide, methoxyphthalamide, N,N-dimethylaminophthalamide, Dicarbamoylbenzene sulfonic acid, dicarbamoyl benzoic acid, dicarbamoyl benzyl acetate, methyl phthalamide, probyl phthalamide, allyl phthalamide, phenyl dicarbamoylphenyl ether, vinyl dicarbamoylphenyl ether, phenyl dicarbamoylphenyl sulfone, phenyl dicarbamoylphenyl sulfide etc.

Examples of alicyclic polycarboxylic acid amides include cyclopropane dicarpoxamide, cyclopentanedicarpoxamide, camphoramide, cyclohexane dicarpoxamide, cyclohexenedicarpoxamide, pyronedicarpoxamide, pyridine dicarpoxamide, and pyridinetricarboxamide. and so on.

Among these amide compounds exemplified, unsubstituted amide compounds are preferred in that they allow the reaction to occur efficiently.

More preferred are conjugated amidation compounds conjugated to the double bond of the amide group of the amide compound, such as aliphatic unsaturated polyamide compounds such as fumaramide, maleamide, citraconamide, phthalamide, isophthalamide, Examples include aromatic polyamide compounds such as terephthalamide and benzendolcarboxamide.

As the halogen-substituted compound to be reacted with the amide compound, various compounds can be mentioned.
Alkyl halides, polyalkyl halides, halogenated alicyclic compounds, aryl halides, alkylaryl halides, alkynyl halides, alkenylaryl halides, carboxylic acid halides, sulfonic acid halides, halogen-substituted carboxylic acids and their esters,
Examples include halogen-substituted ethers, heterocycle-containing halides, and heteroatom-containing halides.

Alkyl halide has the general formula CnH2n+tX (
X is halogen), and n is an integer of 1 to 2°. Polyhalogenated alkyl has the general formula CnHzn+2-m
Xm (X represents FF gen), n is an integer from 1 to
20, and m is 2-4. A halogenated alicyclic compound is a compound having an alicyclic structure in its molecule, in which one or more halogen atoms are substituted, and the number of carbon members constituting the ring is 3 to 8. The halogenated aryl is an aromatic ring substituted with one or more halogen atoms, and the aromatic ring includes a benzene ring, a naphthalene ring, an anthracene ring, and the like. In addition, an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyan group, an amino group, a carboxylic acid group,
One or more substituents such as sulfonic acid groups, alkoxy groups, and carboxylic acid ester groups are introduced, and those substituents or aromatic rings are ether groups, sulfone groups, sulfide groups, etc. Also included are compounds that are bound to.

Alkylaryl halide has the general formula ArmCnHzn
+2-In-r Xr (X: halogen atom, Ar:
aromatic ring), where n, m and r are integers and n is 1 to 2
0, m is 1-4, and r is 1-4. As the aromatic ring in this case, a benzene ring, a naphthalene ring, an anthracene ring, etc. can be used. In addition, one or more substituents such as an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyano group, an amino group, a carboxylic acid group, a sulfonic acid group, an alkoxy group, a carboxylic acid ester group, and a halogen group are present on the aromatic ring. Also included are compounds in which one or more substituents or aromatic rings have been introduced and are bonded to the aromatic ring via an ether group, sulfone group, sulfide group, etc.

Alkenyl halide has the general formula CnHn +2-m-
An unsaturated halogen-substituted compound represented by 2rXm (X is a halogen atom), where n, m and r are integers and n is 2 to 10.
, m is 1-4, and r is 1-4.

Alkenyl aryl halide, general formula ArmCn
Hzn+z-zs-m-r Xr (X: halogen atom, Ar: aromatic ring), n, m, r and S
is an integer, n is 2 to 20, m is 1 to 4, r is 1 to 4, S
is 1 to 4. As the aromatic ring in this case, a benzene ring, a naphthalene ring, an anthracene ring, etc. can be used. In addition, an alkyl group, an alknyl group, an aryl group,
Those into which one or more types of substituents such as nitro group, cyano group, amino group, carboxylic acid group, sulfonic acid group, alkoxy group, carboxylic acid ester group, orroge7 group are introduced, and their substitutions Also included are compounds in which a group or an aromatic ring is bonded to the aromatic ring through an ether group, sulfone group, sulfide group, etc.

Carboxylic acid halides are divided into aliphatic carboxylic acid halides, aromatic carboxylic acid halides, alicyclic carboxylic acid halides, and the like.

Aliphatic carboxylic acid halides are further divided into aliphatic saturated carboxylic acid halides and aliphatic unsaturated carboxylic acid halides.

Aliphatic carboxylic acid halide has the general formula 〇nH2rl+2
-m-zr(COX)m (X is a halogen atom), n, m and r are integers, n is 2 to 20, m is 1 or more,
r is θ~4, r = 0 corresponds to a saturated carboxylic acid halide and r = 1 to 4 corresponds to an unsaturated carboxylic acid halide. Among aliphatic carboxylic acid rides, those having one or more substituents such as nitro group, cyano group, amino group, carboxylic acid group, alkoxy group, and carboxylic acid ester group are also covered.

Aromatic carboxylic acid halide is a carboxylic acid halide containing an aromatic ring in the molecule, and the number of substitutions of the carboxylic acid halide is 1 or more. In this case, the aromatic ring includes a benzene ring, a naphthalene ring, an anthracene ring, and the like. In addition, one or more substituents such as alkyl groups, alkenyl groups, aryl groups, nitro groups, cyano groups, amino groups, carboxylic acid groups, sulfonic acid groups, alkoxy groups, and carboxylic acid ester groups are introduced into the aromatic ring. It also includes compounds whose substituents or aromatic rings are bonded to the aromatic ring via an ether group, sulfone group, sulfide group, etc.

Alicyclic carboxylic acid halide is a compound having an alicyclic structure in its molecule, in which one or more carboxylic acid halides are substituted, and the number of carbon members constituting the ring is 3 to 8. It also includes heterocyclic compounds composed of different elements.

The sulfonic acid halides include aliphatic and aromatic sulfonic acid halides, and the number of substituents in the sulfonic acid nolide is one or more. Aliphatic sulfonic acid halides include saturated sulfo/acid halides and unsaturated sulfonic acid halides, both of which are subject to the present invention. Aromatic sulfonic acid halides have benzene rings, naphthalene rings,
There are anthracene rings, etc. Also, an alkyl group on the aromatic ring,
One or more substituents such as alkenyl group, aryl group, nitro group, cyano group, amino group, carboxylic acid group, sulfonic acid group, alkoxy group, carboxylic acid ester group, etc.
Also included are compounds with one or more substitutions and compounds in which these substituents or the aromatic ring are bonded to the aromatic ring via an ether group, sulfone group, sulfide group, etc.

For halogen-substituted carboxylic acids and their esters, halogen-substituted carboxylic acids, halogen-substituted carboxylic acid esters, and carboxylic acid halogen devices.

There are converted esters, etc. Halogen-substituted carboxylic acid has the general formula XmCnH2n+t-2r-m (COOH)5
, X is a halogen atom, n, m and r are integers, n is 1 to 201m is 1 to 4, r is 0 to 5, and S is 1 to 4. Also included are its carboxylic acid salts. Halogen-substituted carboxylic acid ester has the general formula XmCnH2
It is represented by n+t-zr-m(COOR)B. X is a halogen atom, n, m and r are integers ', n is 1 to
20. m is 1-4, r is θ-5, and S is 1-4. R
are aliphatic saturated hydrocarbon groups, aliphatic unsaturated hydrocarbon groups, and aromatic hydrocarbon groups, and aromatic hydrocarbon groups include alkyl groups, alkenyl groups, and a! Those into which one or more types of substituents such as J-ru group, nitro group, cyan group, amine group, carboxylic acid group, sulfonic acid group, alkoxy group, carboxylic acid ester group, etc. are introduced, and those substituents It also includes compounds in which the aromatic ring is bonded to an ether group, a sulfone group, a sulfide group, etc., and these may be the same or different groups.

Halogen-substituted carboxylic esters are classified into aliphatic saturated carboxylic esters, aliphatic unsaturated carboxylic esters, aromatic carboxylic esters, and the like. Aliphatic saturated carboxylic acid ester has the general formula CnH2n+tCOOR
It is represented by Xm, where X is a halogen atom, n and m are integers, n is 0-20, and m is 1-4. R is an aliphatic saturated hydrocarbon group, an aliphatic unsaturated hydrocarbon group, an aromatic hydrocarbon group, etc., and the aromatic ring has an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyan group, an amino group, or a carboxylic acid group. , one or more substituents such as a sulfonic acid group, an alkoxy group, or a carboxylic acid ester group are introduced, and those substituents or an aromatic ring are converted into an aromatic ring by an ether group, a sulfone group, a sulfide group, etc. Also included are compounds that are attached.

Aliphatic unsaturated carboxylic acid ester has the general formula C1Hzn
+t-2rcOORXm, where X is a halogen atom, n, m and r are integers, n' is 2 to 20, and m is 1 to 4.
, r is 1-4. R is an aliphatic saturated hydrocarbon group, an aliphatic unsaturated hydrocarbon group, an aromatic hydrocarbon group, etc.
One or more substituents such as an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyano group, an amino group, a carboxylic acid group, a sulfonic acid group, an alkoxy group, or a carboxylic acid ester group are introduced into the aromatic ring. It also includes compounds in which the substituents thereof or the aromatic ring are bonded to the aromatic ring through an ether group, a sulfone group, a sulfite group, etc.

Aromatic carboxylic acid ester has general formula A1 CC00R
It is represented by X, where X is a halogen atom, and m is an integer of 1.
~4. Ar is a hydrocarbon group containing an aromatic ring, and the aromatic ring has an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyano group, an amino group, a carboxylic acid group, a sulfonic acid group, an alkoxy group, a carboxylic acid ester group, etc. Also included are compounds in which one or more of the following substituents have been introduced, and compounds in which these substituents or the aromatic ring are bonded to the aromatic ring via an ether group, sulfone group, sulfide group, etc.

R is an aliphatic saturated hydrocarbon group, an aliphatic unsaturated hydrocarbon group, an aromatic hydrocarbon group, etc. In the aromatic hydrocarbon group, an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyano group, Substituted with one or more substituents such as amine group, carboxylic acid group, sulfonic acid group, alkoxy group, carboxylic acid ester group, etc., and those substituents or aromatic rings are ether groups, sulfonic groups, sulfide groups, etc. It also includes compounds that are bonded to aromatic rings through groups, etc.

Halogen-substituted ethers are ethers substituted with one or more halogens, and are broadly classified into aliphatic and aromatic ethers. Aliphatic halogen-substituted ethers consist of saturated aliphatic ethers and unsaturated aliphatic ethers.

There are two types of unsaturated aliphatic ethers in which a halogen atom is bonded to a saturated hydrocarbon group and an unsaturated hydrocarbon group.

There are two types of aromatic ethers: a combination of an aliphatic residue and an aromatic residue, and a combination of aromatic residues.In addition, there are those in which a halogen atom is substituted in an aliphatic site, and those in which an aromatic site is substituted. There are many combinations of substitutions. One or more substituents such as an alkyl group, an alkenyl group, an aryl group, a nitro group, a cyano group, an amino group, a carboxylic acid group, a sulfonic acid group, an alkoxy group, and a carboxylic acid ester group are present on the aromatic ring.
Also included are compounds in which more than one substituent group or aromatic ring is bonded to the aromatic ring via an ether group, sulfone group, sulfide group, etc.

The heterocycle-containing halide is a halide of a compound having a heterocycle in the molecule, and the number of halogen substitutions is one or more. There are two types: those in which the heterocycle is substituted with a halogen atom, and those in which the halogen atom is bonded to the heterocycle in the form of a haloalkyl group, haloalkenyl group, carboxylic acid halide group, etc. Furthermore, there are three types of heterocycles: those in which the heteroatoms constituting the heterocycle are oxygen atoms, nitrogen atoms, and sulfur. Furthermore, when there are two or more different atoms constituting the heterocycle, they may be different heteroatoms.

The heteroatom-containing halide is represented by the general formula
It is a substituent containing a heteroatom such as a sulfonic acid group, a sulfide group, and a sulfone group. Furthermore, compounds in which two or more halogen atoms are substituted and compounds in which two or more of the above-mentioned substituents containing heteroatoms are introduced are also covered by the present invention.

In the following examples of halogen-substituted compounds, chlorine-substituted, bromine-substituted, and iodine-substituted compounds are all subject to the present invention, but chlorine-substituted compounds are shown as a representative example. Further, when there are two or more substituted halogens, the substituted halogens do not need to be the same, and may be a combination of chlorine-bromine, chlorine-iodine, or bromine-iodine, but all are shown as chlorine substitution.

Examples of alkyl halides include chloromethane, chloroethane, chloropropane, chlorobutane, chloropentane, chlorohexane, chloroheptane, chloroethane,
These include chlorototican, chlorotetradecane, and chlorooctadecane.

Examples of polyalkyl halides include dichloromethane,
Chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, trichloroethane (including dichlorobutane, dichlorohebutane, dichlorohexane, dichlorodecane, etc.).

Examples of halogenated alicyclic compounds include chlorocyclobutane, chlorocyclopentane, chlorocyclohexane, chlorocyclohebutane, chlorocyclooctane, dicyclocyclooctane, chlorocyclopentene, chloromethylcyclohexane, and chloroethylcyclohexane.

Aryl halides include, for example, chlorobenzene, dichlorobenzene, trichlorobenzene, chloronaphthalene, dichloronaphthalene, chloroanthracene, dichloroanthracene, chloroanthraquinone, dichloroanthraquino/, chlorotoluene, dichlorotoluene, chloroethylbenzene, chloroallylbenzene, chlorohexylbenzene. , chlorostyrene, chloroallylbenzene,
Chloromethallylbenzene, chlorobiphenyl, chloronitrobenzene, dichloronitrobenzene, chlorobenznitrile, chlorobenzoic acid, methyl chlorobenzoate, ethyl chlorobenzoate, phenyl chlorobenzoate, chloroaniline, chlorobenzenesulfonic acid, chloroanisole, chlorophenylphenyl ether , chlorophenylphenyl sulfone, chlorophenylphenyl sulfitonate.

Examples of alkylaryl halides include benzyl chloride, benzylidene dichloride, phenethyl chloride, phenylpropyl chloride, chloromethylnaphthalene, chloromethylanthracene, diphenylmethyl chloride, triphenylmethyl chloride, chloromethyltoluene, chloromethylethylbenzene, chloromethylxylene, chloromethyl Methylxylene, nitrobenzyl chloride, chloromethylanisole, chloromethylbenzoic acid, methyl chloromethylbenzoate, ethyl chloromethylbenzoate, phenyl chloromethylbenzoate, chloromethylbenzonitrile, chloromethylaniline, chloromethylbenzenesulfonic acid, chloro methylbiphenyl,
Chlorobenzyl chloride, chloromethyl phenyl phenyl ether, chloromethyl phenyl phenyl sulfone, chloromethyl phenyl phenyl sulfide, etc.

Examples of alkenyl halides include vinyl chloride,
Examples include vinylidene chloride, allyl chloride, chloroallyl chloride, propargyl chloride, methallyl chloride, chloromethallyl chloride, pentenyl chloride, hexene dichloride, and octenyl chloride.

Examples of alkenyl aryl halides include styryl chloride, cinnamyl chloride, naphthylfurogenyl chloride, anthrylpropenyl chloride, phenanthrylpropenyl chloride, ethylstyryl chloride,
Chlorovinyl styrene, nitrostyryl chloride, cyanostyryl chloride, chlorovinylaniline, chlorovinylbenzoic acid, chlorovinylbenzoic ff1-r-thyl, N,N-dimethylaminomethylstyryl chloride, chlorostyryl chloride, phenylstyryl chloride, methoxystyryl These include chloride, chlorovinylphenyl phenyl ether, chlorovinylphenyl phenyl sulfone, and chlorophenylphenyl sulfide.

Carboxylic acid halides include formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, pivaloyl chloride,
Lauroyl chloride, myristoyl chloride, valmitoyl chloride, stearoyl chloride, octenyl chloride, malonyl chloride, succinyl chloride, adipoyl chloride, suberoyl chloride, sebacoyl chloride, nitropropionyl chloride, cyanopropionyl chloride, amine propionyl chloride, adipine Acid monochloride, sulfopropionyl chloride, ethoxypropionyl chloride, methoxycarbonylbutanoyl chloride, acryloyl chloride, propionyl chloride, methacryloyl chloride, crotonoyl chloride, oleoyl chloride, maleoyl chloride, fumaroyl chloride, citraconoyl chloride, mesaconoyl Chloride, decenedicarbonyl chloride, butenetetracarbonyl chloride, nitrocrotonoyl chloride, cyanocrotonoyl chloride, aminocrotonoyl chloride, maleic acid monochloride, sulfocrotonoyl chloride, ethoxyacryloyl chloride, methoxycarbonyl acryloyl chloride, benzoyl chloride, naphtho yl chloride, anthracenecarbonyl chloride, biphenylcarbonyl chloride, phenylacetyl chloride, phenylpropionyl chloride, nitrobenzoyl chloride, nitrosinnamoyl chloride, cyanobenzoyl chloride, amine benzoyl chloride, phthalic acid monochloride, acetoxybenzoyl chloride, methoxybenzoyl chloride, Chloroformylbenzenesulfonic acid, toluoyl chloride, allyl pensoyl chloride, phenylchloroformyl phenyl ether, phenylchloroformylphenyl sulfone, phenylchloroformylphenyl sulfide, phthaloyl chloride, cyclobutane carbonyl chloride, cyclohexane carbonyl chloride, cycloheptane carbonyl chloride, These include cyclooctane carbonyl chloride, cyclooctene carbonyl chloride, pyrrole carbonyl chloride, thiophene carbonyl chloride, pyridine carbonyl chloride, camphoroyl chloride, and pyridine tricarbonyl chloride.

Sulfonic acid chlorides include methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, hexanesulfonyl chloride, decanesulfonyl chloride, ethylenesulfonyl chloride, allylsulfonyl chloride, methallylsulfonyl chloride, crotonsulfonyl chloride, hexenesulfonyl chloride, benzenesulfonyl chloride, and naphthalene. Sulfonyl chloride, anthracenesulfonyl chloride, anthraquinonesulfonyl chloride, tosyl chloride, biphenylsulfonyl chloride, styrenesulfonyl chloride, nitrobenzenesulfonyl chloride, dinitrobenzenesulfonyl chloride, aminobenzenesulfonyl chloride, cyanobenzenesulfonyl chloride methoxybenzenesulfonyl chloride, chlorosulfonylbenzoic acid , chlorosulfonylbenzenesulfonic acid, chlorosulfonylbenzene-methyl, chlorosulfonylbenzoate phenyl, phenylchlorosulfonylphenyl ether, phenylchlorosulfonylphenyl sulfone, phenylchlorosulfonylphenyl sulfide, and the like.

Halogen-substituted carboxylic acids and esters include chloroacetic acid, chloropropionic acid, chlorobutyric acid, chlorovaleric acid, chlorocaproic acid, chloroheptanoic acid, chloropalmitic acid, chloroacrylic acid, chloromalonic acid, chloroacrylic acid, and chloromethacrylic acid. Chlorocrotonic acid, chlorooleic acid, methyl chloroacetate, ethyl chloroacetate, butyl chloroacetate, hexyl chloroacetate, diethyl chloromalonate, vinyl chloroacetate, chloroacetic acid, allyl, methallyl chloroacetate, phenyl chloroacetate, benzyl chloroacetate, Phenyl chloroacetate, phenyl chloropropionate, chloroacetic acid jlJ)! J Le, Chloroacetic acid f
li/l/, nitrophenyl chloroacetate, cyanophenyl chloroacetate, chloroacetoxybenzene sulfonate, piphenyl chloroacetate, aminophenyl chloroacetate, chloroacetoxybenzoic acid, anisyl chloroacetate, diethyl chloromalonate, chloro Methyl acetoxybenzoate, chloroacetoxyphenyl phenyl ether, chloroacetoxyphenylphenyl sulfone, chloroacetoxyphenylphenyl sulfide, chloromethyl formate, chloromethyl acetate, chloromethyl propionate, chloromethyl laurate, chloromethyl stearate, Chloroethyl acetate, chlorobutyl acetate, chloropropenyl acetate, chlorobutenyl acetate, chlorophenyl acetate, chlorobenzyl acetate, chlorophenethyl acetate, chlorotril acetate, chlorostyryl acetate, chloronitrophenyl acetate, chlorocyanophenyl acetate, chlorosulfophenyl acetate, chloroaminophenyl acetate , acetoxychlorobenzoic acid, chloroanisyl acetate, methyl acetoxychlorobenzoate, chloropyphenyl acetate, acetoxychlorophenylphenyl ether, acetoxychlorophenylphenyl sulfone, acetoxychlorophenylphenyl sulfide, chloroethyl acrylate,
Chlorobutyl acrylate, chloromethyl methacrylate,
Chloropropenyl acrylate, chlorobutenyl methacrylate, chlorophenyl acrylate, chlorophenyl oleate, chlorobenzyl crotonate, chloronitrobenzyl crotonate, methacrylate o.

Cyanobenzyl, chlorotril acrylate, chlorostyryl acrylate, chlorobiphenyl acrylate, acryloyloxychlorobenzoic acid, acryloyloxybenzene sulfonate, chloroanisyl acrylate, methyl acryloyloxybenzoate, acryloyloxychlorophenyl phenyl ether, acryloyl Oxychlorophenyl phenyl sulfone, Ac IJ 04-oxychlorophenyl phenyl sulfide, chloromethyl benzoate, chlorobutyl naphthoate, chloropropenyl benzoate, naphthoic acid o o 7' f =, chlorophenyl benzoate, chlorobenzyl benzoate , chlorophenyl naphthoate, chloromethoxycarbonyltoluene,
Chloromethoxycarbonylstyrene, chloromethoxydicarbonylbiphenyl, chloromethyl nitrobenzoate, chloromethyl cyanobenzoate, chloropropenyl aminobenzoate, chloromethoxycarbonylbenzoic acid, chloropropenyl sulfobenzoate, chloromethoxycarbonylphenyl methyl ether, chloromethoxy Methyl carbonylbenzoate, chloromethoxycarbonylphenylphenyl ether, chloromethoxycarbonylphenylphenyl sulfone, chloro, lomethoxycarponylphenylphenyl sulfide, chloronitrobenzyl benzoate, chlorocy'7/phenyl benzoate, mchlorobenzoate, roamino Phenyl, benzoyloxychlorobenzoic acid, chlorosulfophenyl benzoate, chloroethyl benzoate, benzoyloxychlorobenzoic acid M ethyl, chlorotril benzoate, chlorostyric benzoate/', benzoic M chlorobiphenyl, benzoyloxychlorophenyl phenyl ether, benzoyloxy These include chlorophenylphenyl sulfone, pentyloxychlorophenyl phenyl sulfide, chlorostyryl nitrobenzoate, and chlorosulfophenyl cyanobenzoate.

Halogen-substituted ethers include chloromethyl methyl ether, chloromethyl ethyl ether, chloromethyl propyl ether, chloromethyl butyl ether, chloromethyl hexyl ether, chloroethyl ethyl ether, chloroethyl butyl ether, chloromethyl vinyl ether, chloroethyl vinyl ether, chloromethyl allyl ether, Chloromethyl methallyl ether, chloroethyl vinyl ether, chloroethyl allyl ether, chloroethyl methallyl ether, chloroallyl methyl ether, chloromethallyl ethyl ether, chloromethyl phenyl ether, chloromethyl naphthyl ether, chloromethyl benzyl ether, chloromethyl phenethyl ether, Chloroethyl benzyl ether, chlorophenyl methyl ether, chloroallyl methyl ether, chloromethyl phenyl methyl ether, chloromethyl diphenyl methyl ether, chloromethyl tolyl ether, chloromethyl nitrophenyl ether, chloromethyl cyanophenyl ether, chloromethyl amino phenyl ether, chloro Methoxybenzoic acid, chloromethylsulfophenyl ether, chloromethoxyphenylmethyl ether,
Chloromethoxybenzoic acid methyl chloromethyl styryl ether, chloromethoxy phenyl phenyl ether, chloromethoxy phenyl phenyl sulfo/, chloromethoxy phenyl phenyl sulfite, chloronitrophenyl ethyl ether.

Examples of heterocycle-containing halides include chloroallidine,
Chloroquinoline, chloroacridine, diloalane, ethylchlorothiophene, chlorobenzofuran, chlorodioxane, chlorobenzothiophene, chloroethylpiperidine, chloroethylpyridine, N-chloropentylpiperidine, N-10romethylrubazole, N-chloropropylcarbazole , epichlorohydrin, methylepichlorohydrin, chloromethylfuran, chloroethylfuran, chloromethylnitrofuran/, chloroethylthiophene, chloromethylmethylthiophene, bischloromethylthiophene, chlorobutylthiophene, chloromethylbenzophenone, chloromethylphenylcyhtrobenzofuran/ and so on.

Examples of heteroatom-containing compounds include chloropropionitrile, chlorobutyronitrile, chlorovaleronitrile, chloroacrylonitrile, chloronitroethane,
Chloronitroethane, dichloroprobionide, dichloronitroethane, dichloronitropropane, chloroethanesulfonic acid, chloropropanesulfonic acid, chlorobutanesulfonic acid, chloroethylamine, chloropropylamine, N-(chloroethyl)dimethylamine salt, N -(chloroethyl)diethylamine salt, chloromethylmethyl sulfide, chloromethylethyl sulfide,
Examples include chloroethyl ethyl sulfide.

Among these halogen-substituted compounds shown as examples, those containing an aromatic ring are preferably not substituted with a substituent containing a hetero atom in terms of efficient reaction. Among these compounds, halogen-substituted compounds suitable for carrying out the reaction more efficiently include alkyl halides, polyalkyl halides, alkylaryl halides, alkenyl halides, carboxylic acid halides, and heterocycle-containing halogenated compounds. can be used. Among these compounds, the reactivity differs depending on the structure of the carbon in which the halogen atom is substituted. Compounds in which a halogen atom is substituted with a primary or secondary carbon are suitable for the reaction of the present invention.

The reaction solvent used in the present invention may be any aprotic polar solvent, such as acetonyl, dioxane,
Nitromethane, nitroethane, nitrobenzene, pyridine, dimethoxyethane, tetrahydro7ran, tetrahydropyran, 2-methyl-tetrahydrofuran, benzonitrile, N,N-dimethylformamide N
.

N-dimethylacetamide, N,N-diethylformamide, dimethyl sulfoxide, N-methylpyrrolidone,
Glymes such as hexamethylphosphoramide, sulfolane, oxepane, monoglyme, diglyme, triglyme, tetraglyme, etc. can be used.

Among the above-mentioned solvents, more suitable solvents include acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane, and tetraglyme. Since these solvents generally have a strong affinity for water, care must be taken as water may be mixed in due to water absorption or water may be mixed in when using both circulatory toilets.

In the reaction system of the method of the present invention, it is necessary to start the reaction in a state in which a strong basic substance is present in a small amount (at least partially), and the amount of water in such a state is determined by the amount of water in the reaction system. The amount of water is usually about 6% by weight.In this case, if the amount of water exceeds this, side reactions such as hydrolysis of the halogen-substituted compound or amide compound tend to occur, resulting in a significant decrease in yield.

In order to carry out the reaction efficiently and increase the yield of the target product, the water content of the reaction system should be at least 5% by weight, as understood from the descriptions of Examples 3 and 4 and Comparative Example 4, which will be described later. below,
Preferably 2.5% by weight or less, particularly preferably 10.0% by weight
It is necessary to carry out the treatment at OOppH or lower.

The amount of the solvent to be used is not particularly limited, but is in the range of 5 to 95% by weight, preferably 10 to 90% by weight, based on the total amount of the reactants including the solvent.

Next, the strong basic substance used in the present invention is a solid substance, and when dissolved or suspended in water, the pH of the aqueous solution is 1.
It can be used as long as it is 0 or more, preferably 11 or more.

However, when using ion exchange resins and other ion exchangers, this condition does not apply, and this will be described later. Such strong basic substances include, for example, alkali metal oxides, alkaline earth metal oxides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrides, and alkaline earth metal oxides. These include metal hydrides, alkali metal amides, alkali metal alkoxides, ion exchange resins, and other ion exchangers.

To illustrate the above substances, examples of the alkali metal oxide include sodium oxide, potassium oxide, lithium oxide, rubidium oxide, and cesium oxide. Examples of alkaline earth metal oxides include beryllium oxide, magnesium oxide, calcium oxide, strontium oxide, and barium oxide. Alkali metal hydroxides are, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, and cesium hydroxide. Examples of alkaline earth metal hydroxides include beh7lium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide.

Alkali metal amides are, for example, sodium carbonate, potassium carbonate, lithium carbonate, rubidium carbonate, cesium carbonate. Alkali metal hydroxides (e.g. hydrogenated)
These include IJium, potassium hydride, and lithium hydride. Alkaline earth metal hydrides are, for example, hydrogenated PEI
J Lium, magnesium hydride, calcium hydride, etc. Alkali metal amides are alkali metal substituted compounds of ammonia, such as sodium amide, potassium amide, and lithium amide. Alkali metal alkoxides are compounds in which the protons of the hydroxyl groups of alcohols are replaced with alkali metals, such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide,
Potassium t-butoxide and the like.

As the ion exchange resin, OH type of strongly basic resin and free type of strongly basic resin can be used, and preferably resin containing water content is 15% or less.

Other ion exchangers may be substances that exhibit an anion exchange phenomenon, such as anion exchange cellulose, anion exchange Sephadex, anion exchange liquid, basic dolomite, water-reduced iron oxide, water-resourced zirconium oxide, and neutralized with hydrochloric acid. It only needs to be of a type that can perform a reaction.

Among the basic substances described above, those suitable for carrying out the method of the present invention include, for example, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal oxides, alkaline earth metal oxides, alkali Metal carbonates, ion exchange resins, and other ion exchange resin bodies, and more suitable ones include, for example, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal oxides, and alkaline earth metal oxides. , alkali metal carbonates, ion exchange resins, and other ion exchangers.

These strongly basic substances are usually used in the reaction in solid form, and the reaction is initiated while at least a portion of them is suspended in the reaction solution.

In carrying out the present invention, the relative amounts of the raw materials, amide compound, halogen-substituted compound, and strong basic substance, are determined depending on the reactivity between the halogen-substituted compound and the amide compound, or the reaction between the desired product and the N-monosubstituted amide compound. Do you want to do that?
-m varies depending on whether it is an N-disubstituted amide compound, etc.
Although it is difficult to specify, in general, when producing an N-monosubstituted amide compound, the amount of the N-substituted compound to be used is 0.2 to 10 times the mole of the amide compound, preferably 0.
．． The amount of the strong basic substance used is 0.3 to 10 times the amount of the amide compound, preferably 0.3 to 10 times the amount by mole.
It is in the range of 5-7 times the mole.

When producing an N,N-disubstituted amide compound, the amount of halogen-substituted compound used is 1.0-
It is preferably in the range of 1.5 to 15 times by mole, and the amount of the strong basic substance used is 1.5 times the amount of the amide compound.
It is in the range of 20 to 20 times the mole, preferably 2.0 to 1.5 times the mole.

Furthermore, it is also possible to produce N,N-disubstituted amide compounds having different substituents, and in that case, it is only necessary to react two types of halogen-substituted compounds at the same time. The amount used varies depending on the reactivity of the halogen-substituted compound, but in general, it is 1 to 1 for highly reactive compounds.
．． It is in the range of 0 to 20 times the mole, preferably 1.0 to 15 times the mole. Another method for producing N,N-disubstituted amide compounds having different substituents is to first react with a first halogen-substituted compound to obtain an N-mono-substituted amide compound, and then to obtain a second halogen-substituted amide compound. It is also possible to react with compounds. When using an unsaturated amide compound, 1. It is preferable to add a polymerization inhibitor to prevent polymerization of raw materials and products during the reaction and purification steps. The polymerization inhibitor in this case is not particularly limited, but generally includes phenol inhibitors, amine inhibitors, mercaptan inhibitors, copper powder, and the like.

For the reaction method, a normal reaction vessel may be used, or if a strongly basic substance with low solubility is used, it is packed in a column and a mixed solution of an amide compound and a halogen-substituted compound is prepared. A flow type method in which the liquid is passed and circulated may also be used. However, a reaction vessel is more convenient for equipment maintenance and management.

When producing in a reaction vessel, there is no restriction on the order in which raw materials are charged, but when using a highly reactive halogen-substituted compound, it is better to add the halogen-substituted compound last and react to avoid side reactions. This is advantageous in terms of suppression.

The reaction temperature depends on the reactivity of the amide compound and the compound substituted with amide, but if the reaction temperature is low, the reaction progresses slowly, while if the mixing temperature is high, side reactions such as hydrolysis of the amide compound may occur. The resulting product yield is reduced. Therefore, the reaction is usually carried out at a temperature range of -20 to 100°C, preferably -10 to 70°C, and particularly preferably at a temperature range of 0 to 50°C, except for certain nitrogen-substituted compounds. be exposed. As long as it is within this temperature range, it is not necessarily necessary to keep the temperature constant during the reaction; it is sufficient to keep track of the progress of the reaction and appropriately set the reaction temperature to allow the reaction to proceed efficiently.

Further, the reaction time also varies depending on the amide compound and halogen-substituted compound used as well as the reaction temperature, but it is 30 hours at the longest, and usually within 10 hours. The progress of the reaction can be understood by observing changes in the properties of the reaction system and the concentrations of raw materials and target products in the reaction solution by gas chromatography or high performance liquid chromatography.

After the reaction, the metal chloride produced as a by-product is filtered off and distilled under reduced pressure by a conventional method to obtain the desired product with high purity. However, if a metal chloride is dissolved in the reaction solution or if a sublimable raw material amide compound remains, after distilling off the solvent, use a solvent that forms two layers such as benzene-water or chloroform-water. After removing the above substances in combination, distillation under reduced pressure yields the desired product with high purity. Further, when the desired product has a high boiling point or is thermally decomposable, the desired product can be purified by methods such as solvent extraction and recrystallization.

When the reaction solvent has a high affinity for water, such as dimethyl sulfoxide, and the desired product is highly lipophilic, such as an N-alkyl-substituted amide compound, water is added to the reaction solution after the reaction to obtain the desired product. A method in which the target product is separated as an oil layer, or a method in which the target product is extracted and separated using a solvent that forms two layers with water, such as benzene, toluene, or chloroform, can also be applied.

According to the present invention, N
- Substituted amide compounds can be produced in one step at low cost. In addition, it becomes possible to supply N-substituted amide compounds to a variety of uses that could not be applied conventionally.

Furthermore, since the present invention uses the same reaction pattern, it is possible to produce a wide variety of N-substituted amide compounds in the same reactor, which has the advantage of being suitable for the production of a wide variety of products in small quantities.

Next, the present invention will be further explained by examples.

Example 1 Preparation of N-n-propylacrylamide 14 g of potassium hydroxide was added to 150 d of N,N-dimethylformamide and stirred to produce 14.9 ml of acrylamide. 0.059 g of phenothiazine and 31 N of n-propyl bromide were added, and the reaction was carried out at 40° C. for 3 hours with stirring. After the reaction, using a polyethylene glycol 20M column,
As a result of analyzing the reaction solution by gas chromatography,
It was confirmed that a substantial amount of 21 g (yield 92%) of N-r"7'ropylacrylamide was produced. In addition, after filtering the reaction solution, N,N-dimethylformamide and unreacted N-propyl bromide was distilled off.

100 i+j of benzene and 56 ml of distilled water were added to the residue, and after thorough stirring, the layers were separated, and the aqueous layer was extracted twice with 50 g+/ml of benzene, and the benzene layer was collected and dried over magnesium sulfate. The benzene layer was distilled under reduced pressure and heated to 81-83℃/
A 1 m fraction was collected and N-n propylacrylamide 1
8 g (yield 79%) was obtained.

The amount of water in the reaction system in this reaction is about 1000, and in this case, the conversion rate of acrylamide is 95%, and the selectivity to N-n-propylacrylamide is 97%.
%Met.

Comparative Example l Production of N-n-propylacrylamide t-butanol 15011 in which potassium t-butoxide 22Ii was dissolved
Acrylamide 149 was added to / at room temperature. After leaving it to stand until the precipitation of N-potassium acrylamide was completed, 31 g of n-propyl bromide and phenothiazine o, o s 11 were added at room temperature and reacted for 3 hours with stirring, and then the precipitated potassium bromide was separated by filtration. . The filtrate was distilled under reduced pressure, 81-83℃/l++nH, 9 fractions were collected, and N
-n-propylacrylamide 6.011 (yield 25%)
) was obtained.

Comparative Example 2 N,N-dimethylformamide 1501, potassium hydroxide 149, acrylamide 1411°, phenothiazine 0
．． 0511 was added and the reaction was carried out at 40°C.

Thirty minutes after the reaction, a white substance precipitated on the surface of potassium hydroxide, and sufficient stirring could no longer be performed.

After reacting as it was for 1 hour, n-propyl bromide 31& was added and the reaction was further carried out for 2 hours.

When the post-reaction treatment was carried out in exactly the same manner as in the example, N-
Only 20 g (9% yield) of n-propylacrylamide was obtained.

Example 2 Preparation of N-acetoxyethylacetamide N,N-dimethylacetamide 1501/to sodium hydroxide 101
, acetamide 12.8+, phenothiazine 0.059 and 2-chloroethyl acetate
36Il was added and the reaction was carried out at 40° C. for 4 hours with stirring. After the reaction, the reaction solution was filtered to remove insoluble matter, and then N,N-dimethylacetamide and unreacted acetic acid were removed under reduced pressure.
2-chloroethyl was distilled off. Add benzene 100 proof and 5.6 ml of distilled water to the residue, stir well, and separate the liquid.
Furthermore, the aqueous layer was extracted twice with 5Qm/peisen, and the benzene layer was collected and dried over magnesium sulfate. The dried benzene layer was distilled under reduced pressure to obtain 138-b N-acetoxyethylacetamide 229 (yield 74%).
) was obtained. The amount of water in the reaction system in this reaction is 500
It was about 0.09%.

Comparative Example 3 Production of N-acetoxyethylacetamide Liquid ammonia 150 by dissolving sodium amide 7,8.9
ml of acetamide 129 was added and reacted in a pressure-resistant reaction tube at room temperature for 5 hours. 57.9 g of 2-chloroethyl acetate was added to the reaction solution, and the reaction was further carried out at room temperature for 3 hours.

After the reaction, ammonia was distilled off, and a 10% aqueous hydrochloric acid solution was added to the residue to obtain an aqueous solution with a pH of 5. The aqueous solution was extracted twice with 100 ml of ethyl acetate, the ethyl acetate layer was dried over magnesium sulfate, the ethyl acetate was distilled off, and the product was distilled under reduced pressure.
8-140°C/2) was not distilled out.

Example 3 Production of N-n-propylacrylamide The procedure was the same as in Example 1 except that 3.5% by weight of water was added and N,N-dimethylformamide was used (the reaction and post-reaction treatment were carried out in the same manner. The reaction was started with potassium hydroxide partially suspended as in Example 1. The conversion rate in this reaction was 93%.
The selectivity was 90% and the production rate was 84%.

Note that the amount of water in this reaction system was 25% by weight.

Example 4 Production of Nn-propylacrylamide The reaction and post-reaction treatment were carried out in exactly the same manner as in Example except that N,N-dimethylformamide containing 7.0% by weight of water was used.

The reaction was started in the same manner as in Example 1 with potassium hydroxide suspended. The conversion rate in this reaction was 87%, the selectivity was 81%, and the production rate was 70%. Note that the amount of water in this reaction system was 50% by weight.

Comparative Example 4 Production of N-n-propylacrylamide 14 g of acrylamide, 0.05.9 g of phenothiazine and 31.9 g of n-propyl bromide were added to 150 liters of N,N-dimethylformamide, and after stirring and dissolving, 475% potassium hydroxide was added. 199 ml of aqueous solution was added to start the reaction. At that time, the reaction solution formed two layers, and all of the potassium hydroxide was in a liquid state. Thereafter, the operation was performed in exactly the same manner as in Example 1. The conversion rate in this reaction was 63%, the selectivity was 48%, and the production rate was 30%. Note that the amount of water in this reaction system was 7.2% by weight.

Example 5-13 A reaction was carried out using the combinations of raw materials, strong basic substances, and solvents listed in Table 1 under the conditions listed in Table 1.

In addition, in Example 8-12, 0.059 of phenothiazine was added to carry out the reaction. After the reaction, the reaction mixture was treated in the same manner as in Example 1, and the results shown in Table 2 were obtained.

Example 14 Production of N,N-dimethylacetamide 12 g of acetamide in 150114' acetonitrile,
Add 18II of sodium hydroxide and add 50% while stirring.
30 g of methyl chloride was blown into the flask at 0.degree. C., and the reaction was carried out for 3 hours. After the reaction, insoluble matter was filtered off and the filtrate was distilled to 166
-167°C/760 fraction was collected, and N,N-dimethylacetamide 16p (yield 90%) was collected.

Example 15-26 Combinations of raw materials, strong basic substances, and solvents listed in Table 3
The reaction was carried out under triple loading conditions. In addition, Examples 16 and 2
0.23 to 26 were reacted by adding phenothiazine o, o s g.

After the reaction, treatment was carried out in exactly the same manner as in Example 14, and the products listed in Table 4 were separated under the distillation conditions listed in Table 4.

Example 27 Preparation of 2-phenyl-N-n-butylacetamideN,N--;
-Butyl bromide 41p was added, and the reaction was carried out at 40°C for 4 hours. After the reaction, the reaction solution was analyzed by high performance liquid chromatography using a silica column treated with octadecylsilane, and the results showed that 2-phenyl-N-
Actual amount of n-butylacetamide 34g (yield 89%)
I confirmed that it was generated. Further, the reaction solution was filtered to remove insoluble matter, and then N,N-dimethylformamide and unreacted n-butyl bromide were distilled off under reduced pressure. After adding O'Oml of benzene and 591 ml of distilled water to the residue and stirring thoroughly, the layers were separated, and the aqueous layer was further extracted twice with 59 ml of benzene, and the benzene layer was collected and dried over magnesium sulfate. The vacuum distillation residue of the benzene layer was recrystallized with benzene to obtain 2-phenyl-Nn- with a melting point of 56-57°C.
30 g (yield 78%) of butylacetamide was obtained.

Example 28-50 A reaction was carried out using the combinations of raw materials, strong basic substances, and solvents listed in Table 5 under the conditions listed in Table 5.

In Examples 29, 30, 32, 33, 44, and 47, 0.05.9% of phenothiazine was added to carry out the reaction.

After the reaction, treatment was carried out in exactly the same manner as in Example 27, and the products listed in Table 6 were crystallized using the recrystallization solvents listed in Table 6.

Example 5 56 g of N, N, N', N'-tetramethyltumaride was added, and 56 g of methyl chloride was blown in at 40°C with stirring.
A time reaction was performed. After the reaction, insoluble matter was filtered off, and the filtrate was distilled under reduced pressure: After removing the solvent and unreacted raw materials, the distillation residue was recrystallized with ethanol, and N with a melting point of 130-131°C was
, N, N'.

27 g (yield: 79%) of N'-tetramethylfumara was obtained.

Examples 52-55 A reaction was carried out using the combinations of raw materials, strong basic substances, and solvents listed in Table 7 under the conditions listed in Table 7.

After the reaction, treatment was carried out in exactly the same manner as in Example 51, and the products listed in Table 8 were crystallized using the recrystallization solvents listed in Table 8.

Example 56 Preparation of N-allyl-N-ethylacetamide 30 g of potassium hydroxide in 1501 of N,N-dimethylformamide
Acetamide 12Ii1 ethyl bromide 54g, allyl chloride 23g and phenothiazine o, o 5g
was added thereto, and the reaction was carried out at 30° C. for 5 hours with stirring.

After removing insoluble matter from the reaction solution, the filtrate was distilled under reduced pressure.
5-186℃/633 ml HII fraction was collected and N
-Allyl-N-ethylacetamide ls# (yield 70%)
) was obtained.

Example 57 Preparation of N-2-7 anoethyl-N-methyl methacrylamide To 150 ml of N,N-dimethylformamide was added 28.9 ml of potassium hydroxide. Methacrylamide 1793-Chloropropionitrile 23g and phenothiazine 0.05
g was added thereto, and the reaction was carried out at 40°C for 3 hours under stirring.

After the reaction, 20% of the reaction solution was sampled, and after filtering off insoluble matter, the filtrate was distilled under reduced pressure, and the distillation residue was recrystallized with water to give a solution with a melting point of 46-
N-2-Cyanethylmethacrylamide at 48°C1.
s f/ (68% yield) was obtained. 20 J/ml of methyl chloride was blown into the remaining reaction solution at 40° C. with stirring, and the reaction was carried out for 4 hours.

After the reaction, insoluble materials were filtered off, and the filtrate was distilled under reduced pressure to obtain 113-
A 116°C/1 mi fraction was collected and 18 g of N-2-cyanoethyl-N-methylmethacryamide (yield 65%)
I got it.

Example 58 Production of diacetylamide Oxidizing power of lithium 14J to 150m/dioxane? , acetamide 129 was added thereto, and acetyl chloride 16.9 was added dropwise at 5° C. under stirring, followed by reaction for 2 hours.

After the reaction, insoluble matter was filtered off, and the solvent and unreacted raw materials were distilled off from the filtrate. Recrystallize the distillation residue from petroleum ether,
15 g (72% yield) of diacetylamide with a melting point of 80-81'G was obtained.

Examples 59-63 A reaction was carried out using the combinations of raw materials, strong basic substances, and solvents listed in Table 9 under the conditions listed in Table 9.

In addition, in Example 59.60, 005 g of phenothiazine was added to carry out the reaction.

After the reaction, treatment was carried out in exactly the same manner as in Example 58,
The products listed in Table 10 were crystallized using the recrystallization solvents listed in Table 10.

Example 64 Preparation of N-3-acryloylaminopropylcarbazole To 150 IIl of N,N-dimethylformamide was added 41. Potassium hydroxide 14.9°N-3-7"
58.9 g of lomoprovil carhasol was added, and the reaction was carried out at 50° C. for 3 hours with stirring. After the reaction, the insoluble portion was filtered off, the solvent was distilled off from the filtrate, and the distillation residue was recrystallized with a mixed solvent of acetone-〇-hexane to give a melting point of 121.
39 g (yield 70%) of N-3-acryloylaminopropylcarbazole at a temperature of 5-122.5°C was obtained.

Example 65 Preparation of N-3-carboxy-2-propenylacetamide 150 g of N,N-dimethylformamide, 12 g of acetamide, 14 g of potassium hydroxide, 37.9 g of sodium 4-chloro-2-butyrate, and 5 g of phenothiazine
g was added thereto, and the mixture was reacted at 50° C. for 4 hours with stirring.

After the reaction, insoluble matter was filtered off, 311 g of concentrated hydrochloric acid was added to the filtrate, and the solvent and unreacted raw materials were distilled off under reduced pressure. The obtained distillation residue was recrystallized from a mixed solvent of methanol and chloroform to obtain 16 g of N-3-carboxy-2-propenylacetamide with a melting point of 139-140°C (yield: 56
%) was obtained.

Example 66 Production of hippuric acid 24 g of benzamide, 14 II of potassium hydroxide, and 4011 of sodium bromoacetate were added to 150 rats of N,N-dimethylformamide, and the mixture was reacted at 60° C. for 4 hours with stirring. The treatment after the reaction was carried out in the same manner as in Example 65, and the obtained distillation residue was recrystallized from distilled water to give a melting point of 18.
34 g (yield 69%) of hippuric acid at 7°C was obtained.

Example 67 Preparation of N,N-bis-6-carboxyhexylacetamide To 250d of N,N-dimethylformamide were added 12g of acetamide, 30p of potassium hydroxide, and 116I of sodium 7-promopebutanoate, and the mixture was heated at 80°C under stirring for 5 hours. Time reacted. The post-reaction treatment was carried out in the same manner as in Example 65,
The resulting distillation residue was recrystallized from a mixed solvent of acetate/-diethyl ether to obtain N with a melting point of 73-74°C.

N-bis-6-carboxyhexylacetamide 29I
(yield 45%).

Example 68 Preparation of N-allyl crotonamide 17 g of N,N-dimethylformamide (N,N-dimethylformamide) 2001/CJC crotonamide, treated as described below
105 p of soo (trademark name manufactured by Bayer AG), 19 g of allyl chloride and 0.05 p of phenothiazine were added,
The reaction was carried out at 40° C. for 5 hours while stirring.

After the reaction, the filtrate is distilled under reduced pressure after being filtered using an ion exchange resin.
90-91℃/0.8anH1/ fraction was collected and N-
Allylcrotonamide 18. ! i+ (yield 71%) was obtained.

Treatment of ion exchange resin As a strongly basic ion exchange resin, Revacit MP-50
After co-decoding the resin, the resin was made into an OH type using an aqueous IJ solution and thoroughly washed with water. After draining the resin, it was dried at 65° C. for 5 hours.

Example 69 Preparation of N-cyclohexylacetamide Nitroethane 2
129 g of acetamide, 105 g of MP-500 used in Example 68, and 41 g of cyclohexyl bromide were added to 00g and reacted at 60° C. for 5 hours with stirring. After the reaction, the ion exchange resin was filtered off, and the filtrate was distilled under reduced pressure to remove the solvent and unreacted raw materials. The obtained distillation residue was recrystallized from petroleum ether to obtain N-cyclohexylacetamide 16Ii (yield 57%) having a melting point of 108-109°C.

Example 7O Preparation of N-benzylacetamide 12 g of acetamide in 2θ Oml of N,N-dimethylformamide, Revacit MP-5 used in Example 68
105 g of 00 and 32 g of benzyl chloride were added, and the mixture was reacted at 50° C. for 4 hours with stirring. The treatment after the reaction was carried out in exactly the same manner as in Example 69, and the obtained distillation residue was recrystallized from benzene to obtain N-benzylacetamide 221I (yield 73%) having a melting point of 61-62°C.

Example 71 Preparation of N-benzylcrotonamide 17 g of crotonamide in N,N-dimethylformamide 20 o IR1 Revatit MP- used in Example 6B
500 1o5J? , and benzyl chloride 32.9
was added and reacted at 50° C. for 4 hours with stirring. The post-reaction treatment was carried out in exactly the same manner as in Example 69, and the resulting distillation residue was recrystallized from benzine, giving a melting point of 112.5-113.6.
Example 72 Production of N,N-dimethyl methacrylamide 17 g of methacrylamide, 05 g of phenothiazine, and 18 p of sodium hydroxide were added to 150 ml of dimethyl sulfoxide. Then, 30 g of methyl chloride was blown in at 40° C. while stirring, and the reaction was carried out for 3 hours.

After the reaction, insoluble matter was filtered off and benzene 15031/.

150 txl of water was added and thoroughly stirred and treated.

After separation, the benzene layer was collected, and the aqueous layer was further extracted twice with benzene lαOtel. After drying the benzene layer with magnesium sulfate, it was distilled under reduced pressure at 65-67°C/10
Ryu H9 fraction was collected and N.

N-dimethyl methacrylamide t 911 (yield 86%
) was obtained.

Patent Applicant Mitsui Toatsu Kagaku Co., Ltd. Procedural Amendment July 3, 1960 Director General of the Patent Office 1, Indication of Case Showa JA Patent Application No. 19g'l'l
No. 1, No. 2, Name of the invention Process for producing N-substituted amide compounds 3, Relationship with the case of the person making the amendment Patent applicant C37, 2) Mitsui Toatsu Chemical Co., Ltd. 4 Agent address 1-chome Akasaka, Minato-ku, Tokyo 9-20 No. 5 Date of amendment order (]) Page d O, line g of the specification, next to "thyl ether," [bischloromethyl ether, bischloroethyl ether, bischloropropyl ether, bischlorobutyl ether] , bischloroethoxyethane.

(2) Specification No. Q, page 2, line 20, next to [ethyl sulfide], r bischloromethyl sulfite, hischloroethyl sulfide, bischloroethyl carbonate, all added.

(sl The following statement is added on page Sθ of the specification, line 7S, next to “gaagerarumu”).

[However, among unsaturated amide compounds, unsaturated amide compounds with high polymerization activity such as acrylamide and methacrylamide tend to cause side reactions such as hydrogen transfer polymerization due to strong basic substances in addition to radical polymerization due to heat. be.

In such a case, in order to suitably carry out the method of the present invention, it is preferable to use an alkali metal hydroxide, particularly sodium hydroxide or potassium hydroxide, as the strong basic substance.

Furthermore, when a dihalogen-substituted compound is used as the halogen-substituted compound, an N-acyl heterocyclic compound can be produced. In that case as well, it is preferable to use an alkali metal hydroxide, especially sodium hydroxide or potassium hydroxide, as the strong basic substance.

Dihalogen exchange compounds applicable to such reactions include dihaloalkane compounds.

Examples include bishaloalkyl ether compounds and bishaloalkyl sulfide compounds.

When a di-rolyrucan compound is used, N-acyl cyclic imine compounds can be produced, such as N-7-acyl cyclic imine compounds, N-acyl pyrrolidine, N-acyl piperidine, and the like.

If a bishaloalkyl ether compound is used, N-acylmorpholine is used.

Furthermore, when a bishaloalkyl sulfide compound is used, N-acylthiomorpholine and the like can be produced. (4) The following statement is added next to page gi, line 14 of the specification.

"Example 73 Preparation of N-methacryloylpyrrolidine N,N-dimethylformamide lsθIll/to methacrylamide/711./, II-dibromobutane ASt
and 0.0.1 # of phenothiazine, and 23 g of potassium hydroxide was gradually added while stirring in a water bath.

The reaction temperature was maintained at /Q°C and the reaction was carried out for 6 hours.

After the reaction, the insoluble portion was filtered off and the filtrate was distilled.

/ / 0- / / / 'O/ / A; *mH
Collect I fraction.

N-methacryloylpyrrolidine, 23 IC yield, 2) was obtained.

Example q-7g A reaction was carried out under the conditions listed in Table 71 using the combination of raw material 1, strongly basic substance, and solvent listed in Table 1/. In addition, examples and
For 77.7 g, the reaction was carried out by adding the fetched amount of θθ left.

After the reaction, treatment was carried out in exactly the same manner as in Example 73, and the products listed in Table 0 were separated under the distillation conditions listed in Table 7.

Handbook supplementary text (spontaneous) July 3θ, 1981 Mr. Commissioner of the Patent Office.

1. Indication of the case 1966 Patent application No. 1 qJ
'4'4? / No. 2, Name of the invention Process for producing N-substituted amide compounds 3, Relationship with the amended case Applicant (3/, 2) Mitsui Toatsu Chemical Co., Ltd. 4, Agent address: 1 Akasaka, Minato-ku, Tokyo (Voluntary amendment without No. 9-20) Target of B amendment (1) On page tI+ of the specification, line 7, next to “glyme”, “tetramethylurea, tetraethylurea, 7.3
-dimethyl-2-imidazolidinone, /,3-dimethyl-3,+,j,O-tetrahydro-2(,/H)-pyrimidinone".

(2) In the specification column <page 2II, line 1, add "7,3-dimethyl-2-imidazolidinone" next to "tetraglyme".

(3) Next to page 1 of the specification, line 111, 1 (Showa 5
(Next to Example 79, which was added by amendment dated July S, 1997), the following statement is added.

"Example 1O Preparation of N,N'-carponyl dipyrrolidine N,N'-
Di Mechiban Formamide/! ; Urea/3t in Oml
z1. dibromobutane qtt and potassium hydroxide 5
0# was added and the reaction was carried out at 20°C for 1 hour.

After the reaction, the insoluble portion was filtered off, the filtrate was distilled, and 3g-110
0010,≦vmH9 fraction was collected to obtain 29t of N,N-carponyl dipyrrolidine (yield 715'%).

Example/Production of N, N'-carponyludipiperidine/, 3-
Dimethyl-2-imidazolidinone/! ;Urea/3g in 0I11, /,! ;-Dibromopentane 10! ; and potassium hydroxide were added, and the reaction was carried out at 200C for t hours.

Claims (1)

[Scope of Claims] 1. A method for producing an N-substituted amide compound by simultaneously contacting and reacting a strongly basic substance, an amide compound, and a halogen-substituted compound in an aprotic polar solvent, wherein the basic substance 1. A method for producing an N-substituted amide compound, characterized in that the reaction is initiated while the reaction is suspended. 2. The method according to claim 1, wherein the amount of water in the reaction system at the start of the reaction is 5% by weight or less.