JP2013031436A - Method for producing carbamate compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a carbamate compound that is simple and industrially suitable.
The object of the present invention is to react an amine compound and a carbonate compound in the absence of a solvent in the presence of a hydrolase catalyst, thereby producing the target carbamate compound in a high yield and industrially. Is also solved by a method that can be suitably manufactured.
[Selection figure] None

Description

  The present invention relates to a method for producing a carbamate compound by reacting a carbonate compound and an amine compound.

  The carbamate compound is useful, for example, as a raw material for producing an isocyanate compound. Conventionally, as a method for producing a carbamate compound without using toxic phosgene, a method using a solid catalyst such as a metal salt is known (for example, see Patent Documents 1 and 2).

  On the other hand, as a method for obtaining a carbamate compound using a hydrolase, 3 ', 5'-diaminonucleoside (amine compound) and diethyl carbonate are present in the presence of a hydrolase and in the presence of a mixed solvent of pyridine and tetrahydrofuran. A method for synthesizing carbamate by reaction is known (for example, see Non-Patent Document 1).

  There is an example in which diamine and carbonate are reacted in a 1,4-dioxane solvent in the presence of a hydrolase to synthesize an optically active amine by enzymatic asymmetry (see, for example, Non-Patent Document 2).

  Also disclosed is a method for producing a carbamate compound by reacting a carbonate compound using a modified lipase with an amine compound in toluene (see, for example, Patent Document 3).

JP-A-54-88201 JP 2004-262892 A Japanese Patent Application No. 2011-256937

J. et al. Org. Chem., 2004, Vol. 69, 1748-1751. J. et al. Org. Chem., 2009, Vol. 74, 2571-2574.

However, in the method of Non-Patent Document 1, the amount of enzyme relative to the substrate is large and the reaction time is long. Further, since the yield of the product is low, it is difficult to say that the production method is industrially satisfactory.
Similarly, the method of Non-Patent Document 2 requires a large amount of catalyst and a long reaction time. And it is not an industrially preferable method in that 1,4-dioxane which is toxic to the solvent is used.
Thus, examples of synthesizing carbamates with amine compounds and carbonate compounds in the presence of hydrolase catalysts are known, but in any case, the use of a solvent is indispensable, and the decrease in the activity of hydrolase catalysts by the solvent is a problem. Has been. Furthermore, a purification process for separating the solvent and the product, a solvent recovery process from the cost aspect, and the like are essential, and there are industrial problems.

However, the reaction in the absence of a solvent tends to be avoided from the viewpoints of solubility of raw materials such as amine compounds and carbonate compounds, uniformity of the reaction solution, and stirring properties. Therefore, an efficient synthesis example in the absence of a solvent has not been reported so far.
In the reaction of the present invention, when producing a carbamate compound from an amine compound and a carbonate compound, the above problem is solved by performing the reaction in the absence of a solvent.

That is, the present invention can provide a method for producing a carbamate compound with a small amount of enzyme, a high reaction rate, and a high product yield.
In the present invention, since the reaction is carried out in the absence of a solvent, the activity of the catalyst is not reduced by the solvent, and the product purification step is not necessary. Furthermore, a step of recovering the solvent is not necessary, which is advantageous.
As described above, the present invention can provide a method for producing a carbamate compound that is simple and industrially suitable.

  The inventors of the present invention can produce a desired carbamate compound in a good yield and industrially by reacting an amine compound and a carbonate compound in the absence of a solvent in the presence of a hydrolase catalyst. The method which can be performed was discovered and it came to this invention.

That is, the present invention may be substituted with an alicyclic group or an aromatic group having one or more amino groups in one molecule using a hydrolase, or an alicyclic group or an aromatic group. A step of reacting an amine compound selected from the group consisting of an aliphatic amine optionally interrupted with an aliphatic group and an alicyclic amine optionally substituted with an aliphatic group with a carbonate compound in the absence of a solvent. The present invention relates to a method for producing a carbamate compound.
The present invention relates to the method for producing a carbamate compound as described above, wherein the hydrolase is immobilized on a carrier.
The present invention is a hydrolase in which a hydrolase is incorporated in a reaction vessel as a fixed bed and immobilized on a carrier, and the reaction includes a step of circulating an amine compound and a carbonate compound in the reaction vessel. It is related with the manufacturing method of the said carbamate which is reaction.
The present invention relates to the method for producing a carbamate compound as described above, wherein the hydrolase is lipase.
In the present invention, the amine compound is represented by the general formula (1):

(In the formula, R ¹ may have a substituent, a linear or branched alkyl group having 1 to 20 carbon atoms, or a linear or branched chain group having 2 to 20 carbon atoms. An alkenyl group, a linear or branched alkynyl group having 2 to 20 carbon atoms, a cycloalkylalkyl group having 4 to 24 carbon atoms, an aralkyl group having 7 to 21 carbon atoms, or 3 to 3 carbon atoms. 20 cycloalkyl groups,
n is 0 or 1. )
It is related with the manufacturing method of the above-mentioned carbamate compound which is a monoamine compound shown by these.
In the present invention, the amine compound is represented by the general formula (4).

(In the formula, R ³ may have a substituent, a linear or branched alkylene group having 1 to 20 carbon atoms, or a linear alkylene-carbon atom having 1 to 4 carbon atoms. C3-C20 cycloalkylene-C1-C4 linear alkylene group or C1-C4 linear alkylene-C6-C20 arylene-C1-C1 A linear alkylene group having 4 carbon atoms, a cycloalkylene group having 3 to 20 carbon atoms, or a linear alkylene group having 1 to 4 carbon atoms and a cycloalkylene group having 3 to 20 carbon atoms,
m and p are each independently 0 or 1. )
It is related with the manufacturing method of the carbamate compound as described in the above.
In the present invention, the diamine compound is 1,6-hexamethylenediamine, 1,12-dodecamethylenediamine, isophoronediamine, 1,3-bis (aminomethylcyclohexane), 1,4-bis (aminomethylcyclohexane), 4 , 4′-methylenebis (cyclohexaneamine), 2,5-bis (aminomethyl) bicyclo [2.2.1] heptane, 2,6-bis (aminomethyl) bicyclo [2.2.1] heptane, 1, It is related with the manufacturing method of the carbamate compound as described in the above, which is at least one selected from the group consisting of 3-bis (aminomethyl) benzene and 1,4-bis (aminomethyl) benzene.
The present invention relates to the method for producing a carbamate compound as described above, wherein the reaction temperature is 20 to 90 ° C.
The present invention relates to the method for producing a carbamate compound as described above, wherein the carbonate compound is dimethyl carbonate or diethyl carbonate.

  According to the present invention, a carbamate compound can be produced with a small amount of enzyme and good yield. Further, since the activity of the enzyme catalyst is not lowered by the reaction solvent, a high reaction rate can be obtained. Furthermore, the carbamate compound can be produced without requiring a separation step of the product and the reaction solvent and a solvent recovery step.

  In the invention, a hydrolase may be used, which may be substituted with an alicyclic group or aromatic group having at least one amino group in the molecule, or may be interrupted with an alicyclic group or aromatic group. By reacting an amine compound selected from the group consisting of an aliphatic amine, which may be substituted, and an alicyclic amine optionally substituted with an aliphatic group, with a carbonate compound in the absence of a solvent, A carbamate compound is obtained.

The organic compound having one or more amino groups in one molecule (hereinafter referred to as “amine compound”), which is a raw material of the present invention, is an amino group-containing organic having one or more primary amino groups (NH ₂ groups). A compound, which may be substituted with an alicyclic group or aromatic group, or may be interrupted with an alicyclic group or aromatic group, and substituted with an aliphatic group Also selected from the group consisting of amine compounds selected from the group consisting of good alicyclic amines.

In the present invention, an aliphatic amine is a compound having one or more primary amino groups directly bonded to a carbon atom of an aliphatic hydrocarbon group, and the aliphatic hydrocarbon group is an alicyclic group or an aromatic group. It may be substituted with a group, and may be interrupted with an alicyclic group or an aromatic group.
The aliphatic hydrocarbon group is a hydrocarbon group that is linear or branched and may have an unsaturated bond, and is an alkyl group having 1 to 20 carbon atoms, or 2 to 20 carbon atoms. Or an alkynyl group having 2 to 20 carbon atoms.

  An aliphatic amine substituted with an alicyclic group is a compound in which the hydrocarbon group of the aliphatic amine defined above is substituted with an alicyclic group. The alicyclic group is a hydrocarbon group including a ring structure, and is a saturated or unsaturated monocyclic or polycyclic (for example, 2 to 4 ring) hydrocarbon group having 3 to 20 carbon atoms in total. Examples thereof include a cycloalkyl group having 3 to 20 carbon atoms and a cycloalkenyl group having 3 to 20 carbon atoms. Therefore, examples of the aliphatic hydrocarbon group substituted with an alicyclic group include an alkyl group having 1 to 20 carbon atoms substituted with a cycloalkyl group having 3 to 20 carbon atoms.

  An aliphatic amine substituted with an aromatic group is a compound in which the hydrocarbon group of the aliphatic amine defined above is substituted with an aromatic group, and is also referred to as an araliphatic. The aromatic group is a hydrocarbon group having 6 to 20 carbon atoms and a monocyclic or polycyclic aromatic ring structure such as a benzene ring or a naphthalene ring. For example, an aryl group having 6 to 20 carbon atoms is Can be mentioned. Therefore, examples of the aliphatic hydrocarbon group substituted with an aromatic group include an alkyl group having 1 to 20 carbon atoms substituted with an aryl group having 6 to 20 carbon atoms.

  An aliphatic amine interrupted with an alicyclic group is a compound in which the carbon-carbon bond of the hydrocarbon group of the aliphatic amine defined above is interrupted with a divalent alicyclic group. Examples of the divalent alicyclic group include a divalent group obtained by removing one hydrogen atom from the alicyclic group defined above. For example, a cycloalkylene group having 3 to 20 carbon atoms, a carbon atom Examples thereof include a cycloalkenylene group having a number of 3 to 20. Accordingly, examples of the aliphatic group interrupted by the alicyclic group include alkylene having 1 to 15 carbon atoms, cycloalkylene having 3 to 20 carbon atoms, and alkylene group having 1 to 15 carbon atoms.

  An aliphatic amine interrupted with an aromatic group is a compound in which the carbon-carbon bond of the hydrocarbon group of the aliphatic amine defined above is interrupted with a divalent aromatic group. As a bivalent aromatic group, the bivalent group remove | excluding one hydrogen atom from the aromatic group defined above is mentioned, For example, a C6-C20 arylene group is mentioned. Examples of the aliphatic group interrupted by an aromatic group include alkylene having 1 to 15 carbon atoms-arylene having 3 to 20 carbon atoms and alkylene group having 1 to 15 carbon atoms.

In the present invention, an alicyclic amine is a compound having one or more primary amino groups directly bonded to carbon atoms on the ring of a monocyclic or polycyclic alicyclic group, and an aliphatic group It may be replaced with. Examples of the alicyclic group in the alicyclic amine include the same groups as the alicyclic group defined above.
The alicyclic amine substituted with an aliphatic group is a compound in which the alicyclic group of the alicyclic amine defined above is substituted with an aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include the aliphatic hydrocarbon groups defined above. Examples of the alicyclic amine substituted with an aliphatic group include a cycloalkyl group having 3 to 20 carbon atoms substituted with an alkyl group having 1 to 20 carbon atoms.
In the present invention, an alicyclic amine substituted with an aliphatic group and having a primary amino group directly bonded to a carbon atom of the aliphatic group is included in the alicyclic amine.

  The amine compound may contain, for example, a stable bond such as an ether bond or a thioether bond in its molecular skeleton, such as a halogen atom, an alkoxy group, a dialkylamino group, a cyano group, a nitro group, an acetyl group, an aromatic group. It may be substituted with a stable substituent such as an amino group directly bonded to a ring carbon atom.

  In the present invention, the amine compound is desirably a compound having one or two primary amino groups. As an amine compound having one or two primary amino groups, for example, the general formula (1):

(Where
R ¹ may have a substituent, a linear or branched alkyl group having 1 to 20 carbon atoms, a linear or branched alkenyl group having 2 to 20 carbon atoms, A linear or branched alkynyl group having 2 to 20 carbon atoms, a cycloalkylalkyl group having 4 to 24 carbon atoms, an aralkyl group having 7 to 21 carbon atoms, or a cycloalkyl having 3 to 20 carbon atoms Group,
n is 0 or 1. )
A monoamine compound having one primary amino group in the molecule represented by (hereinafter referred to as “monoamine compound”), or the general formula (4):

(Where
R ³ may have a substituent, a linear or branched alkylene group having 1 to 20 carbon atoms, a linear alkylene group having 1 to 4 carbon atoms, and 3 to 20 carbon atoms. Cycloalkylene-C1-C4 linear alkylene group, C1-C4 linear alkylene-C6-C20 arylene-C1-C4 linear An alkylene group, a cycloalkylene group having 3 to 20 carbon atoms, or a linear alkylene group having 1 to 4 carbon atoms-a cycloalkylene group having 3 to 20 carbon atoms,
m and p are each independently 0 or 1. )
And a diamine compound having two amino groups in the molecule (hereinafter referred to as “diamine compound”).

Examples of the linear or branched alkyl group having 1 to 20 carbon atoms in R ¹ include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n- Examples include heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, isopropyl group, isobutyl group, t-butyl group, etc., preferably 1 carbon atom To 12 linear or branched alkyl groups, and more preferably methyl, ethyl, n-propyl, n-butyl, n-hexyl, n-dodecyl, isopropyl and t- It is a butyl group.

Examples of the linear or branched alkenyl group having 2 to 20 carbon atoms in R ¹ include allyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, and isopropanyl group. Is a linear or branched alkenyl group having 2 to 12 carbon atoms, more preferably an allyl group.

Examples of the linear or branched alkynyl group having 2 to 20 carbon atoms in R ¹ include an ethynyl group, a propargyl group, a butenyl group, and a 1-methyl-2-propynyl group, preferably a carbon atom. It is a linear or branched alkynyl group of 2 to 12, more preferably an ethynyl group or a propargyl group.

The cycloalkyl group having 3 to 20 carbon atoms in R ¹ is a monocyclic or polycyclic alicyclic hydrocarbon group which may be substituted with an alkyl group having 1 to 4 carbon atoms, and a cyclopropyl group , A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a bicyclo [2.2.1] heptyl group, a methylcyclohexyl group, a dimethylcyclohexyl group, an ethylcyclohexyl group, etc., preferably a cycloalkyl group having 3 to 12 carbon atoms. And more preferably a cyclohexyl group or a bicyclo [2.2.1] heptyl group.

The cycloalkylalkyl group having 4 to 24 carbon atoms in R ¹ is a linear alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 20 carbon atoms as defined above, Examples thereof include a cyclohexylmethyl group, a cyclohexylethyl group, a trimethylcyclohexylmethyl group, a norbornylmethyl group, and the like, preferably substituted with a cycloalkyl group having 3 to 10 carbon atoms and having 1 to 4 carbon atoms. An alkyl group, more preferably a cyclohexylmethyl group.

Examples of the aralkyl group having 7 to 21 carbon atoms in R ¹ include a group represented by an alkyl group having 1 to 9 carbon atoms substituted with an aryl group having 6 to 12 carbon atoms. Examples of the aryl group having 6 to 12 carbon atoms include a phenyl group, a naphthyl group, and a biphenyl group. Therefore, examples of the aralkyl group having 7 to 21 carbon atoms include a benzyl group, a phenethyl group, and a naphthylmethyl group, preferably an aralkyl group having 7 to 11 carbon atoms, and more preferably a benzyl group. . These groups include various isomers.

The group mentioned as R ¹ may have a further substituent. Examples of the further substituent in R ¹ include an alkoxy group having 1 to 4 carbon atoms such as a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), methoxy group, ethoxy group, propoxy group, butoxy group, A dialkylamino group disubstituted by an alkyl group having 1 to 6 carbon atoms, such as a dimethylamino group, a diethylamino group, or a dipropylamino group, a cyano group, a nitro group, an acetyl group, and R ¹ is an aralkyl group Examples include an amino group directly bonded to a benzene ring.

From the above, R ¹ is preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, n-hexyl group, n-dodecyl group, fluoromethyl group, difluoromethyl group. , Trifluoromethyl group, cyanomethyl group, nitromethyl group, fluoroethyl group, trifluoroethyl group, trichloroethyl group, cyanoethyl group, nitroethyl group, methoxyethyl group, ethoxyethyl group, t-butoxyethyl group, etc. A linear or branched alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, a cycloalkyl group having 4 to 14 carbon atoms, a benzyl group, fluoro Benzyl, chlorobenzyl, bromobenzyl, iodobenzyl, methoxybenzyl, dimethoxybenzyl Group, a nitrobenzyl group, a dinitrobenzyl group, a cyanobenzyl group and an aminobenzyl group, which may have a substituent such as an aralkyl group having 7 to 11 carbon atoms; more preferably a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, n-hexyl group, n-dodecyl group, cyclohexyl group, cyclohexylmethyl group, and benzyl group.

  From the above, the monoamine compound represented by the general formula (1) preferably includes n-hexylamine, n-dodecylamine, cyclohexylmethylamine, and benzylamine.

Examples of the linear or branched alkylene group having 1 to 20 carbon atoms in R ³ include a methylene group, an ethylene group, an n-propylene group, an n-butylene group, an n-pentylene group, and an n-hexylene. Group, n-heptylene group, n-octylene group, n-nonylene group, n-decylene group, n-dodecylene group and other linear alkylene groups, and 2-methylpropylene group, 2-methylhexylene group, tetramethyl group Examples thereof include branched alkylene groups such as ethylene group, preferably linear alkylene groups having 1 to 20 carbon atoms, more preferably methylene group, ethylene group, propylene group, butylene group, pentylene group, A hexylene group, a heptylene group, an octylene group, a nonylene group, a decylene group, and a dodecylene group.

The cycloalkylene group having 3 to 20 carbon atoms in R ³ is a monocyclic or polycyclic hydrocarbon group, which may be substituted with 1 to 4 carbon atoms, and includes a cyclopropylene group, a cyclobutylene group, a cyclo A pentylene group, a cyclohexylene group, and a bicyclo [2.2.1] heptane-2,6-diyl group are exemplified, and a cycloalkylene group having 3 to 12 carbon atoms is preferable, and a cyclohexene group is more preferable. A xylene group and a bicyclo [2.2.1] heptane-2,6-diyl group.

Straight chain alkylene having 1 to 4 carbon atoms of R ³ -cycloalkylene having 3 to 20 carbon atoms-straight chain alkylene group having 1 to 4 carbon atoms, straight chain having 1 to 4 carbon atoms Examples of the alkylene group include a methylene group, an ethylene group, a propylene group, and a butylene group. C1-C4 linear alkylene-C3-C20 cycloalkylene-C1-C4 linear alkylene group includes methylene-cyclopentylene-methylene group, ethylene- Examples thereof include a cyclopentylene-ethylene group, a methylene-cyclohexylene-methylene group, etc., preferably a linear alkylene having 1 to 4 carbon atoms, a cyclohexylene having 3 to 12 carbon atoms, and a carbon atom having 1 to 1 carbon atoms. 4 linear alkylene group, more preferably methylene-cyclohexylene-methylene group.

The linear alkylene having 1 to 4 carbon atoms and the cycloalkylene group having 3 to 20 carbon atoms in R ³ is preferably a linear alkylene having 1 to 4 carbon atoms and having 1 to 4 carbon atoms. A cycloalkylene group having 3 to 12 carbon atoms substituted with an alkyl group, more preferably a methylene-trimethylcyclohexylene group.

The linear alkylene group having 1 to 4 carbon atoms, the arylene group having 6 to 20 carbon atoms, and the linear alkylene group having 1 to 4 carbon atoms in R ³ is preferably 1 to 4 carbon atoms. A linear alkylene-phenylene-C1-C4 linear alkylene group, more preferably a xylylene group. These groups include various isomers.

The hydrocarbon group for R ³ may have a substituent. Examples of the substituent in R ³ include the same groups as the substituents of the hydrocarbon group in R ¹ . In addition, when R ³ is a linear alkylene group having 1 to 4 carbon atoms, an arylene group having 6 to 20 carbon atoms, and a linear alkylene group having 1 to 4 carbon atoms, as a substituent in R ³ And a primary amino group directly bonded to the aromatic carbon atom of the arylene group.

From the above, R ³ is preferably a linear or branched alkylene group having 1 to 20 carbon atoms, a linear alkylene group having 1 to 4 carbon atoms, and a cycloalkylene carbon having 3 to 20 carbon atoms. Straight chain alkylene group having 1 to 4 atoms, straight chain alkylene group having 1 to 4 carbon atoms, arylene group having 6 to 20 carbon atoms, straight chain alkylene group having 1 to 4 carbon atoms, carbon A cycloalkylene group having 3 to 20 atoms or a linear alkylene group having 1 to 4 carbon atoms-a cycloalkylene group having 3 to 20 carbon atoms; and more preferably a linear group having 1 to 12 carbon atoms. An alkylene group, a linear alkylene having 1 to 4 carbon atoms, a cycloalkylene having 3 to 12 carbon atoms, a linear alkylene group having 1 to 4 carbon atoms, and a linear chain having 1 to 4 carbon atoms An alkylene-phenylene-carbon atom A linear alkylene group having 1 to 4 carbon atoms, a cycloalkylene group having 3 to 12 carbon atoms, and a linear alkylene group having 1 to 4 carbon atoms-a linear alkyl group having 1 to 4 carbon atoms. A substituted cycloalkylene group having 3 to 12 carbon atoms; more preferably a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, a hexylene group, a heptylene group, an octylene group, a nonylene group, a decylene group, A dodecylene group, a cyclohexylene group, a methylene-trimethylcyclohexylene group, a cyclohexylenedimethylene group, and a xylylene group;

  The amine compound as a raw material of the present invention is preferably a diamine compound from which a biscarbamate compound as a raw material of diisocyanate can be obtained, and more preferably 1,6-hexamethylenediamine, 1,12-dodecamethylenediamine, isophorone. Diamine, 1,3-bis (aminomethylcyclohexane), 1,4-bis (aminomethylcyclohexane), 4,4′-methylenebis (cyclohexaneamine), 2,5-bis (aminomethyl) bicyclo [2,2, 1] selected from the group consisting of heptane, 2,6-bis (aminomethyl) bicyclo [2,2,1] heptane, 1,3-bis (aminomethyl) benzene, 1,4-bis (aminomethyl) benzene At least one.

  In this invention, when an amine compound is a monoamine compound, the manufacturing method of the carbamate compound of this invention is shown by following Reaction formula [I]. In the reaction formula [I], the monocarbamate compound represented by the general formula (3) is a monoamine compound represented by the general formula (1) and the general formula (2) using a hydrolase in the absence of a solvent. It is obtained by reacting with the carbonate compound shown.

(Wherein R ¹ , R ² and n are as defined above.)

In the general formula (2), examples of the monovalent hydrocarbon group which may have a substituent of R ² include the same groups as R ¹ defined in the general formula (1). The hydrocarbon group for R ² is preferably a linear group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group, and more preferably 1 to 6 carbon atoms. Or it is a branched alkyl group, More preferably, it is a methyl group or an ethyl group.

The hydrocarbon group for R ² may have a substituent. Examples of the substituent of the hydrocarbon group in R ² include 1 to 4 carbon atoms such as a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a methoxyl group, an ethoxyl group, a propoxyl group, and a butoxyl group. And a dialkylamino group disubstituted with an alkyl group having 1 to 4 carbon atoms such as an alkoxy group, a dimethylamino group, a diethylamino group, and a dipropylamino group.

  From the above, the compound represented by the general formula (2) is preferably dimethyl carbonate or diethyl carbonate.

[Reaction Formula II]
In this invention, when an amine compound is a diamine compound, the manufacturing method of the carbamate compound of this invention is shown by following Reaction formula [II]. In the reaction formula [II], the biscarbamate compound represented by the general formula (5) is represented by the diamine compound represented by the general formula (4) and the general formula (2) using a hydrolase in the absence of a solvent. It is obtained by reacting with the carbonate compound shown.

(Wherein R ² , R ³ , m and p are as defined above.)

In the reaction formula [I], the amount of the carbonate compound represented by the general formula (2) is preferably 1 to 100 moles, more preferably 1 to 50, relative to 1 mole of the monoamine compound represented by the general formula (1). Mol, more preferably 2 to 20 mol, particularly preferably 2 to 10 mol.
In the reaction formula [II], the amount of the carbonate compound represented by the general formula (2) is preferably 2 to 200 mol, more preferably 2 to 100, per 1 mol of the diamine compound represented by the general formula (4). Mol, more preferably 4 to 40 mol, particularly preferably 4 to 20 mol.

  Examples of the hydrolase used in the present invention include protease, esterase, lipase, and the like, but preferably from pig liver-derived esterase (PLE), pig liver-derived lipase (PPL), yeast or bacteria. Lipids of releasable microorganisms; more preferably lipases originating from Burkholderia cepacia (Pseudomonas cepacia), such as Amano PS (manufactured by Amano Enzyme), Candida Anne Lipases originating from Candida antarctica (for example, Novozym 435 (manufactured by Novozyme), etc.), Lizomucor Miehei (Rhizomucor Miehei) From lipase (for example, Lipozyme RM IM (manufactured by Novozyme), etc.), Lipase TL originating from Thermomyces lanuginosus (Liposase TL), Mucor Miehei (MM), Lipa from Mucor Miehei (MM) Preferably a lipase originating from Candida antarctica is used. In addition, these hydrolase can use a commercial item as it is as a natural form or an immobilized enzyme, and may use it individually or in mixture of 2 or more types.

  These hydrolases were obtained from recombinant cultures obtained by introducing a gene encoding a hydrolase obtained from a microorganism as described above into an appropriate host such as yeast or filamentous fungus. It may be a thing.

  The recombinant DNA technique used for the recombinant expression of hydrolase is described in, for example, Patent Document 3. The amino acid sequence of the hydrolase is not particularly limited. Specifically, in these sequences, one or several amino acids are deleted, substituted or added, and has hydrolase activity. A protein can be suitably used for the reaction of the present invention. A protein having an amino acid sequence having a sequence identity of, for example, 90% or more, preferably 95%, more preferably 97% or more with these sequences and having hydrolase activity is also suitable for the reaction of the present invention. It can also be used.

  The hydrolase may be used in a natural form or commercially available as an immobilized enzyme after chemical treatment or physical treatment. In the present invention, the hydrolase is preferably immobilized on a carrier, and more preferably, the hydrolase is incorporated in a reaction vessel as a fixed bed, and is hydrolyzed on the carrier. It is an enzyme.

  As the chemical treatment or physical treatment method, for example, a hydrolase is dissolved in a buffer solution (an organic solvent may be present if necessary), and this is directly or stirred and then freeze-dried. And the like. The freeze-drying here is, for example, J.I. Am. Chem. Soc. 122 (8), 1565-1571 (2000), the aqueous solution or water-containing substance is rapidly frozen at a temperature below the freezing point, and the pressure is reduced below the water vapor pressure of the frozen product to sublimate the water and remove it. It is a method of drying a substance. Note that catalytic treatment (reactivity, selectivity, etc.) can be improved by the treatment.

In the reaction formula [I], the amount of the hydrolase used is preferably 0.1 to 1000 mg, more preferably 1 to 200 mg, and more preferably 1 g of the monoamine compound represented by the general formula (1). 10-100 mg.
In the case of reaction formula [II], the amount is preferably 0.1 to 1000 mg, more preferably 1 to 200 mg, and more preferably 10 to 100 mg based on 1 g of the diamine compound represented by the general formula (4).

  The reaction temperature in the reaction of the present invention is not particularly limited as long as the enzyme is not deactivated. However, in order to obtain a desired carbamate compound with good yield, it is preferably 20 ° C to 90 ° C, more preferably 40 ° C to 90 ° C, more preferably 50 ° C to 90 ° C. The reaction pressure is not particularly limited, but is preferably under normal pressure or reduced pressure.

  In the present invention, since the reaction is carried out in the absence of a solvent, it is advantageous in that it is not necessary to separate the reaction product from the solvent.

  In addition, the present invention is advantageous in that the reaction of the present invention is generally homogeneous, can be reused as a catalyst, and can be easily post-treated. That is, the product can be obtained by removing the catalyst by filtration at the end of the reaction and concentrating the obtained filtrate. The product can also be obtained by a crystallization operation from the obtained filtrate.

  The production apparatus used for the reaction of the present invention is not particularly limited, and examples thereof include general production apparatuses such as a reaction vessel and a heating (cooling) apparatus. In the present invention, it is preferably an apparatus in which a hydrolase is immobilized on a carrier and is housed in a reaction vessel as a fixed bed. Therefore, the reaction of the present invention is preferably carried out by the monoamine compound represented by the general formula (1) represented by the general formula (1) or the diamine compound represented by the general formula (4) and the carbonate represented by the general formula (2). This is a reaction including a step of circulating a compound in the reaction vessel.

  Furthermore, the monocarbamate compound represented by the general formula (3) or the biscarbamate compound represented by the general formula (6) obtained by the production method of the present invention can be obtained by, for example, distillation, liquid separation, extraction, crystallization, recrystallization, Further purification can also be achieved by general methods such as crystallization and column chromatography.

Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

The yield of the obtained target product was determined using gas chromatography.
The reaction yield was calculated by quantifying the product amount from a standard product and a calibration curve of the internal standard ratio.
The analysis conditions are as follows.

Gas chromatography condition column: DB-1 30 m × 0.25 mm ID 0.25 μm
Column temperature: 80 ° C. (2 minutes hold) → Temperature increase rate 10 ° C./min→250° C. (hold 2 minutes)
Inlet temperature: 200 ° C Detector: FID Detector temperature: 250 ° C
Carrier gas: helium, linear velocity 30 cm / sec split ratio; 50: 1, injection volume: 1.0 μl

Example 1 (Synthesis of N-hexyl-O-methylcarbamate)
In a glass container having an internal volume of 19 ml equipped with a stirrer, temperature control and cooling device, 200 mg (1.97 mmol) of n-hexylamine and 0.214 g (2.38 mmol) of dimethyl carbonate (DMC), 1 mol of n-hexylamine. 1.2 mol)
Furthermore, after adding 80.0 mg of tetraethylene glycol dimethyl ether as an internal standard substance, 10.0 mg of immobilized lipase (Novozym 435 (trade name); manufactured by Novozyme) was mixed and stirred at 70 ° C. for 24 hours. Reacted. During the reaction, 25 μl of the reaction solution after 3, 6 and 9 hours was taken, filtered with 475 μl of methanol, and 1.0 μl was analyzed by gas chromatography for N-hexyl-O-methylcarbamate. The rate was calculated.
As a result, the reaction yield reached 31% after 3 hours, 47% after 6 hours, and 52% after 9 hours.

Example 2 (Synthesis of N-hexyl-O-methylcarbamate)
The reaction was conducted in the same manner as in Example 1 except that the amount of DMC was 0.535 g (5.94 mmol, 3.0 mol with respect to 1 mol of n-hexylamine) in Example 1.
As a result, the reaction yield reached 36% after 3 hours, 61% after 6 hours, and 73% after 9 hours.

Example 3 (Synthesis of N-hexyl-O-methylcarbamate)
The reaction was conducted in the same manner as in Example 1 except that the amount of DMC in Example 1 was 1.07 g (11.9 mmol, 6.0 mol with respect to 1 mol of n-hexylamine).
As a result, the reaction yield reached 50% after 3 hours, 93% after 6 hours, and 96% after 9 hours.

Example 4 (Synthesis of N-hexyl-O-methylcarbamate)
In a glass container having an internal volume of 19 ml equipped with a stirrer, a temperature controller and a cooling device, 200 mg (1.97 mmol) of n-hexylamine and 1.72 g (19 mmol of n-hexylamine) of dimethyl carbonate (DMC) 9.6 mol)
Furthermore, after adding 40.0 mg of tetraethylene glycol dimethyl ether as an internal standard substance, 10.0 mg of immobilized lipase (Novozym 435 (trade name); manufactured by Novozyme) was mixed and stirred at 70 ° C. for 24 hours. Reacted. During the reaction, 50 μl of the reaction solution after 3, 6, 9 and 24 hours was collected, filtered with 150 μl of methanol, and 1.0 μl was analyzed for N-hexyl-O-methylcarbamate by gas chromatography. The reaction yield was calculated.
As a result, the reaction yield reached 29% after 3 hours, 55% after 6 hours, 77% after 9 hours, and 96% after 24 hours.

Comparative Example 1 (Synthesis of N-hexyl-O-methylcarbamate)
The reaction was conducted in the same manner as in Example 4 except that the amount of DMC was changed from 1.72 g to 0.536 g in Example 4 and 2.0 ml of 1,4-dioxane was added.
As a result, the reaction yield reached only 10% after 3 hours, 18% after 6 hours, 24% after 9 hours, and even 50% after 24 hours.

  From the above results, it was found that a higher reaction rate and a higher yield were obtained when no solvent was added compared to the case where 1,4-dioxane was used as the solvent.

Example 5 (Synthesis of 1,3-bis (methoxycarbonylaminomethyl) benzene)
In a glass container having an internal volume of 19 ml equipped with a stirrer, a temperature controller and a cooling device, 200 mg (1.46 mmol) of 1,3-bis (aminomethyl) benzene and 1.72 g (19 mmol, 1,1) of dimethyl carbonate (DMC) were added. 13 moles per mole of 3-bis (aminomethyl) benzene)
Furthermore, after adding 40.0 mg of tetraethylene glycol dimethyl ether as an internal standard substance, 10.0 mg of immobilized lipase (Novozym 435 (trade name); manufactured by Novozyme) was mixed and stirred at 70 ° C. for 24 hours. Reacted. During the reaction, 50 μl of the reaction solution obtained after 3, 6, 9 and 24 hours was collected, filtered with 150 μl of methanol, and 1.0 μl was subjected to 1,3-bis (methoxycarbonylaminomethyl) benzene by gas chromatography. Was analyzed to calculate the reaction yield.
As a result, the reaction yield reached 8% after 3 hours, 36% after 6 hours, 49% after 9 hours, and 87% after 24 hours.

Comparative Example 2 (Synthesis of 1,3-bis (methoxycarbonylaminomethyl) benzene)
The reaction was performed in the same manner as in Example 5 except that the amount of DMC was changed from 1.72 g to 0.79 g in Example 5 and 2.0 ml of 1,4-dioxane was added.
As a result, the reaction yield reached 2% after 3 hours, 10% after 6 hours, 17% after 9 hours, and only 56% after 24 hours.

  From the above results, it was found that a higher reaction rate and a higher yield were obtained when no solvent was added compared to the case where 1,4-dioxane was used as the solvent.

Example 6 (Synthesis of N-hexyl-O-ethylcarbamate)
In a glass container having an internal volume of 19 ml equipped with a stirrer, temperature control and cooling device, 7 mg of n-hexylamine 200 mg (1.97 mmol) and diethyl carbonate 1.66 g (14 mmol, 1 mol of n-hexylamine) Further, 40.0 mg of tetraethylene glycol dimethyl ether was added as an internal standard substance, and then 10.0 mg of immobilized lipase (Novozym 435 (trade name); manufactured by Novozyme) was mixed and stirred at 70 ° C. For 24 hours. During the reaction, 50 μl of the reaction solution after 3, 6, 9 and 24 hours was sampled and filtered with 150 μl of methanol, and 1.0 μl was analyzed for N-hexyl-O-ethylcarbamate by gas chromatography. The reaction yield was calculated.
As a result, the reaction yield reached 25% after 3 hours, 53% after 6 hours, 71% after 9 hours, and 99% after 24 hours.

Comparative Example 3 (Synthesis of N-hexyl-O-ethylcarbamate)
The reaction was conducted in the same manner as in Example 6 except that the amount of diethyl carbonate was changed from 1.66 g to 0.69 g in Example 6 and 2.0 ml of 1,4-dioxane was added.
As a result, the reaction yield reached 9% after 3 hours, 18% after 6 hours, 23% after 9 hours, and only 55% after 24 hours.

  From the above results, it was found that a higher reaction rate and a higher yield were obtained when no solvent was added compared to the case where 1,4-dioxane was used as the solvent.

Example 7 (Synthesis of 1,3-bis (methoxycarbonylaminomethyl) cyclohexane)

In a glass container having an internal volume of 19 ml equipped with a stirrer, temperature control and cooling device, 400 mg (2.81 mmol) of 1,3-bis (aminomethyl) cyclohexane and 1.62 g (18 mmol, 1,2) of dimethyl carbonate (DMC) were added. (6.5 mol per 1 mol of 3-bis (aminomethyl) cyclohexane)
Furthermore, 40.0 mg of tetraethylene glycol dimethyl ether was added as an internal standard substance, and then 50.0 mg of immobilized lipase was mixed and reacted at 50 ° C. for 24 hours with stirring. During the reaction, 50 μl of the reaction solution after 5, 8, 12 and 24 hours was collected, filtered with 150 μl of dimethylformamide, and 1.0 μl of 1,3-bis (methoxycarbonylaminomethyl) by gas chromatography. The reaction yield was calculated by analyzing cyclohexane.

  As the immobilized lipase, a commercially available immobilized lipase and a modified lipase derived from Candida antarctica described in Patent Document 3 were used. The preparation and immobilization of the modified lipase are as described in Patent Document 3.

  When “Novozyme 435 (Novozyme)” was used as the immobilized lipase, the reaction yield was 5% after 5 hours, 7% after 8 hours, 16% after 12 hours, and 45% after 24 hours. Reached.

  When “UCAL-ER: Q193E / L278R mutant lipase immobilized product (carrier weight ratio supported enzyme amount 10% by mass)” was used as the immobilized lipase, the reaction yield was 4% after 5 hours and 8 hours later. It reached 8%, 23% after 12 hours, and 77% after 24 hours.

  When “UCAL-FEK: W104F / Q193E / L278K mutant lipase (carrier weight ratio supported enzyme amount 10% by mass)” was used as the immobilized lipase, the reaction yield was 3% after 5 hours and 8 hours later. It reached 6%, 14% after 12 hours, and 36% after 24 hours.

  From the above results, it was found that a high reaction rate and a high yield were exhibited even in the absence of a solvent.

  The present invention relates to a method for obtaining a carbamate compound from an amine compound and a carbonate compound. The carbamate compound obtained by the production method of the present invention is useful, for example, as a raw material for producing isocyanates that do not use toxic phosgene.

Claims (9)

  It may be substituted with an alicyclic group or aromatic group having one or more amino groups in one molecule, or interrupted with an alicyclic group or aromatic group using a hydrolase A carbamate compound comprising the step of reacting an amine compound selected from the group consisting of a good aliphatic amine and an alicyclic amine optionally substituted with an aliphatic group with a carbonate compound in the absence of a solvent Manufacturing method.   The method for producing a carbamate compound according to claim 1, wherein the hydrolase is immobilized on a carrier.   The hydrolase is a hydrolase incorporated in a reaction vessel as a fixed bed and immobilized on a carrier, and the reaction is a reaction including a step of circulating an amine compound and a carbonate compound in the reaction vessel. The manufacturing method of the carbamate of Claim 1 or 2.   The method for producing a carbamate compound according to any one of claims 1 to 3, wherein the hydrolase is lipase. The amine compound has the general formula (1):

(In the formula, R ¹ may have a substituent, a linear or branched alkyl group having 1 to 20 carbon atoms, or a linear or branched chain group having 2 to 20 carbon atoms. An alkenyl group, a linear or branched alkynyl group having 2 to 20 carbon atoms, a cycloalkylalkyl group having 4 to 24 carbon atoms, an aralkyl group having 7 to 21 carbon atoms, or 3 to 3 carbon atoms. 20 cycloalkyl groups,
n is 0 or 1. )
The manufacturing method of the carbamate compound of any one of Claim 1 to 4 which is a monoamine compound shown by these. The amine compound has the general formula (4)

(In the formula, R ³ may have a substituent, a linear or branched alkylene group having 1 to 20 carbon atoms, or a linear alkylene-carbon atom having 1 to 4 carbon atoms. C3-C20 cycloalkylene-C1-C4 linear alkylene group or C1-C4 linear alkylene-C6-C20 arylene-C1-C1 A linear alkylene group having 4 carbon atoms, a cycloalkylene group having 3 to 20 carbon atoms, or a linear alkylene group having 1 to 4 carbon atoms and a cycloalkylene group having 3 to 20 carbon atoms,
m and p are each independently 0 or 1. )
The manufacturing method of the carbamate compound of any one of Claim 1 to 4 which is a diamine compound shown by these.   The diamine compound is 1,6-hexamethylenediamine, 1,12-dodecamethylenediamine, isophoronediamine, 1,3-bis (aminomethylcyclohexane), 1,4-bis (aminomethylcyclohexane), 4,4′- Methylenebis (cyclohexaneamine), 2,5-bis (aminomethyl) bicyclo [2.2.1] heptane, 2,6-bis (aminomethyl) bicyclo [2.2.1] heptane, 1,3-bis ( The method for producing a carbamate compound according to claim 6, which is at least one selected from the group consisting of aminomethyl) benzene and 1,4-bis (aminomethyl) benzene.   The method for producing a carbamate compound according to any one of claims 1 to 7, wherein the reaction temperature is 20 to 90 ° C.   The method for producing a carbamate compound according to any one of claims 1 to 8, wherein the carbonate compound is dimethyl carbonate or diethyl carbonate.