JP2018046794A - Method for producing (meth) acrylic amide, (meth) acrylic amide polymer, and method for producing (meth) acrylic amide polymer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a (meth) acrylic amide with improved efficiency and quality, using bacterial cells containing nitrile-hydratase and/or processed bacterial cells thereof as catalysts; and a method for producing an acrylic amide polymer using the (meth) acrylic amide, where the acrylic amide polymer has a good hue, achieves both of water solubility and high molecular weights, and has excellent quality.SOLUTION: A method for producing a (meth) acrylic amide includes the hydration reaction between water with an electric conductivity of 100 μS/cm or less and (meth) acrylonitrile, by bacterial cells containing nitrile-hydratase and/or processed bacterial cells thereof.SELECTED DRAWING: None

Description

  The present invention provides a method for producing (meth) acrylamide having excellent quality by efficiently hydrating (meth) acrylonitrile using a bacterial cell and / or a treated product thereof as a catalyst, and the (meta) The present invention relates to a (meth) acrylamide polymer obtained by polymerizing acrylamide and a method for producing the polymer.

  As one of the main production methods of amide compounds, a hydration method using a nitrile compound as a raw material is used in many cases, and as an industrial production method of an amide compound such as acrylamide, for example, a metal such as Raney copper A method of hydrating a nitrile compound such as acrylonitrile using a copper catalyst, or a method of hydrating a nitrile compound using a microbial cell containing nitrile hydratase and / or a treated product thereof as a catalyst in recent years is known. It has been.

  The method of using bacterial cells and / or treated products thereof as a catalyst has attracted industrial attention because of high conversion and selectivity of nitrile compounds such as acrylonitrile.

In order to efficiently produce higher quality acrylamide using the nitrile hydratase-containing cells and / or treated cells thereof as a catalyst, catalytic action of the cells and / or treated cells thereof is effective. It is necessary to remove as much impurities as possible.
Acrylamide is mainly used as a raw material for acrylamide polymers, but in recent years, acrylamide polymers have been required to have higher quality. For example, there are flocculants in the use of acrylamide polymers, but acrylamide polymers used as flocculants have recently been required to have higher molecular weight while maintaining water solubility in accordance with the demand for improved performance. It has been. In addition, acrylamide polymers have applications such as papermaking additives. However, in order to further improve the quality of the obtained paper, a polymer having a better hue is required as the papermaking additive. Yes.

  As a method for improving the quality of acrylamide obtained by using a bacterial cell containing nitrile hydratase and / or a treated product thereof as a catalyst, or a method for improving the quality of an acrylamide polymer, for example, Patent Document 1 discloses that A method for producing an amide compound in which a nitrile hydratase is allowed to act on a nitrile compound after the concentration of hydrocyanic acid is reduced by a chemical method has been proposed. Patent Document 2 discloses an acrylamide polymer in which acrylonitrile having an oxazole concentration of 5 mg / kg or less and a hydrocyanic acid concentration of 1 mg / kg or less is hydrated by an enzymatic method to form acrylamide, and a monomer containing the acrylamide is polymerized. The manufacturing method of this is proposed. Further, Patent Document 3 proposes a method for producing an amide compound characterized in that, in the method for producing an amide compound from a nitrile compound in an aqueous medium, the benzene concentration in the aqueous medium is 4.0 ppm or less. Yes.

  However, in these prior arts, from the viewpoint of efficiently hydrating acrylonitrile by eliminating factors that inhibit the catalytic action of microbial cells including nitrile hydratase, only reduction of specific components in the nitrile compound is possible. However, a sufficient effect is not necessarily obtained.

JP 11/123098 pamphlet International Publication No. 2004/090148 Pamphlet JP 2012/029695 pamphlet

  In the efficient production of amide compounds using nitrile hydratase, there is another phenomenon that the amide compound productivity of nitrile hydratase decreases due to other factors that cannot be solved by the prior art. It was rare. In addition, there is still room for improvement from the viewpoint of improving the quality of (meth) acrylamide and (meth) acrylamide polymers.

  An object of the present invention is to produce a (meth) acrylamide having higher efficiency and higher quality using a microbial cell containing nitrile hydratase and / or a treated product thereof as a catalyst, and the (meth) acrylamide. Is to provide a method for producing a (meth) acrylamide polymer excellent in quality, excellent in hue, compatible with both water solubility and high molecular weight.

  The present inventors have conducted intensive research to solve the above problems. As a result, the inventors have found that the above problem can be solved by a method for producing (meth) acrylamide having the following steps, and have reached the present invention.

That is, the present invention is as follows.
[1] A (meth) acrylamide characterized in that water having a conductivity of 100 μS / cm or less and (meth) acrylonitrile are reacted with a microbial cell containing nitrile hydratase and / or a treated product thereof. Production method [2] Nitrile hydratase is a Pseudonocardia genus or Rhodococcus genus nitrile hydratase [1] The production method of [1] [3] The (meth) acrylamide described in [1] is homopolymerized, Or a (meth) acrylamide polymer obtained by copolymerizing with at least one unsaturated monomer copolymerizable with an amide compound [4] homopolymerizing the (meth) acrylamide described in [1] above, or Copolymerized with at least one unsaturated monomer copolymerizable with an amide compound (meth) acrylamide system Method for producing polymer

In the present invention, (meth) acrylamide is efficiently obtained by reducing the electrical conductivity of raw material water below a specific level in a reaction using nitrile hydratase-containing cells and / or treated cells thereof as a catalyst. Can be manufactured. In addition, by producing an amide polymer using (meth) acrylamide obtained from raw material water whose electric conductivity is suppressed by the above-described method, the hue is excellent, and both water solubility and high molecular weight are compatible. An excellent acrylamide polymer can be obtained.

Hereinafter, the manufacturing method of (meth) acrylamide of this invention is demonstrated.
[Production method of (meth) acrylamide]
In the method for producing (meth) acrylamide of the present invention, water and (meth) acrylonitrile having an electric conductivity of 100 μS / cm or less are hydrated with a microbial cell containing nitrile hydratase and / or a treated product thereof. A step of causing
<Bacteria and / or treated cells containing nitrile hydratase>
In the present invention, nitrile hydratase-containing cells and / or treated cells thereof (hereinafter also simply referred to as “cell catalysts”) are catalysts for hydration of (meth) acrylonitrile to (meth) acrylamide. Used as

  Nitrile hydratase refers to an enzyme (protein) having the ability to hydrolyze a nitrile compound to produce a corresponding amide compound (hereinafter also referred to as “nitrile hydratase activity”).

The microbial cell containing nitrile hydratase is not particularly limited as long as it produces nitrile hydratase and retains nitrile hydratase activity in an aqueous solution of a nitrile compound and an amide compound. The nitrile hydratase-producing cells include the genus Nocardia, the genus Corynebacterium, the genus Bacillus, the thermophilic Bacillus, the Pseudomonas genus, and the Micrococcus genus. , Rhodococcus genus represented by Rhodochrous species, Acinetobacter genus, Xanthobacter genus, Streptomyces genus, Rhizobium genus, Klebsiella genus, Klebsiella Representative of the genus Enterobacter, Erwinia, Aeromonas, Citrobacter, Achromobacter, Agrobacterium or thermophila Genus Pseudonocardia, Bacteridium, Brevibak Bacteria such as belonging to the helium (Brevibacterium) genus can be mentioned. These may be used alone or in combination of two or more.
In addition, a transformant in which a nitrile hydratase gene cloned from these bacterial cells is highly expressed in an arbitrary host, and one or more of the constituent amino acids of the nitrile hydratase using other DNA by using recombinant DNA technology And a transformant in which a mutant nitrile hydratase having further improved amide compound resistance, nitrile compound resistance, and temperature resistance is expressed by substitution, deletion, deletion or insertion. In addition, as an arbitrary host mentioned here, Escherichia coli can be mentioned as a representative example as in Examples described later, but is not particularly limited to Escherichia coli, and Bacillus subtilis and other Bacillus genera. Other strains such as fungi, yeasts and actinomycetes are also included. As an example of such a case, MT-10822 [This strain was founded on February 7, 1996, 1-3-1 Higashi 1-chome, Tsukuba, Ibaraki Prefecture, Institute of Biotechnology, Institute of Industrial Technology, Ministry of International Trade and Industry (currently Kisarazu, Chiba Prefecture). 2-5-8 Kazusa-shi, Kazusa-shi Based on the Budapest Treaty on International Approval for Deposits of Bacteria in Patent Procedures under the Accession Number FERMBP-5785 to the Biotechnology Center of the National Institute of Technology and Evaluation Have been deposited. ].

  Among these bacterial cells, in terms of having a highly active and highly stable nitrile hydratase, cells belonging to the genus Pseudonocardia and the nitrile hydratase gene cloned from the bacterial cells can be used in any host. Highly expressed transformants and transformant transformants expressing mutant nitrile hydratase are preferred. In addition, the said transformant is preferable at the point which raises the stability of nitrile hydratase more and the activity per microbial cell is higher.

  Also preferred are Rhodococcus rhodochrous J-1, which can highly express nitrile hydratase in the cells, and transformants in which the nitrile hydratase gene cloned from the cells is highly expressed in any host. . The microbial cells producing the nitrile hydratase can be prepared by a general method known in the fields of molecular biology, biotechnology, and genetic engineering.

  The recombinant vector according to the present invention contains a gene encoding nitrile hydratase, and can be obtained by linking a gene encoding nitrile hydratase to the vector. The vector is not particularly limited. For example, a gene encoding nitrile hydratase in a commercially available expression plasmid represented by pET-21a (+), pKK223-3, pUC19, pBluescriptKS (+), pBR322, etc. Thus, the expression plasmid of nitrile hydratase can be constructed. The host organism to be used for transformation is not limited as long as the recombinant vector is stable and capable of self-propagation and can express foreign DNA traits. For example, E. coli is a good example. The transformant having the ability to produce nitrile hydratase can be obtained by introducing it into Bacillus subtilis, yeast or the like.

  Bacteria that produce nitrile hydratase as described above may be appropriately cultured and grown by known methods to produce nitrile hydratase. As a medium used in this case, either a synthetic medium or a natural medium can be used as long as it contains a suitable amount of carbon source, nitrogen source, inorganic salts and other nutrients. For example, after inoculating the cells in a normal liquid medium such as LB medium or M9 medium, an appropriate culture temperature (generally 20 ° C. to 50 ° C., but in the case of thermophilic bacteria, 50 ° C. or higher) However, it can also be prepared by culturing. Culturing can be carried out in a liquid medium containing the above-mentioned culture components using a conventional culture method such as shaking culture, aeration and agitation culture, continuous culture or fed-batch culture. The culture temperature of the transformant is preferably 15 to 37 ° C. The culture conditions are not particularly limited, and may be appropriately selected depending on the type of culture and the culture method, as long as the strain can grow and produce nitrile hydratase.

  In the present invention, in order to react the bacterial body producing the above-mentioned nitrile hydratase with a nitrile compound, various treatments such as collection of bacteria by centrifugation, etc., and crushing to produce a crushed bacterial body, The microbial cells that have been subjected to any of these treatments are collectively referred to as processed microbial cells.

  The form of the disrupted cell is not particularly limited as long as it contains a nitrile hydratase-producing cell. For example, the culture solution containing the cell itself, the culture solution is centrifuged and separated and recovered. And those obtained by washing the collected cells with physiological saline or the like.

<Water (raw water)>
Generally, salt components such as calcium and sodium are dissolved in a small amount in natural water and tap water, and these components are mainly dissolved in an ionic state, so water in which salt components are dissolved is electrically conductive. The degree becomes higher. The electric conductivity of water used in the present invention is 100 μS / cm or less, preferably 50 μS / cm or less, more preferably 10 μS / cm or less. When the electrical conductivity of water is 100 μS / cm or less, it can be used for the hydration reaction as it is. If the electrical conductivity of the water is greater than 100 μS / cm, the water is purified and the electrical conductivity is lowered. The method for purifying water is not particularly limited, and a known method can be used. Examples thereof include distillation, treatment with an ion exchange resin, and filtration with a reverse osmosis membrane. The electrical conductivity of water can be measured by, for example, an alternating current two-electrode method or an electromagnetic induction method.
<PH regulator>
The pH adjuster is used to adjust the pH of the reaction solution to a suitable range for keeping the activity of the cell catalyst good.
When the pH suitable for the reaction is less than 7, an acid can be used as a pH adjuster.
As the acid used as the pH adjuster, either an inorganic acid or an organic acid can be used. Examples of inorganic acids include hydrohalic acids such as hydrogen chloride, hydrogen bromide, and hydrogen iodide, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, hypobromite, bromite, bromine Examples thereof include halogenated oxoacids such as acid, perbromic acid, hypoiodic acid, iodic acid, iodic acid, and periodic acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid. Examples of organic acids include formic acid, acetic acid, propionic acid, acrylic acid, methacrylic acid, crotonic acid, succinic acid, malonic acid, fumaric acid, maleic acid, citric acid, lactic acid, benzoic acid and other carboxylic acids such as methanesulfonic acid, Examples include sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. The acid used as the pH adjusting agent can be used in any state of gas, solid and liquid, but considering the ease of supply to the reaction vessel, it is preferable to use the acid in the liquid state. The acid in the state is more preferably used as an aqueous solution. In consideration of controllability of pH adjustment of the reaction tank, it is more preferable to use a liquid acid as an aqueous solution. The concentration of the acid when used as an aqueous solution is not particularly limited, but it is difficult to adjust the pH when a high concentration aqueous solution is used. Therefore, it is preferably 0.1 wt% or more and 99 wt% or less, more preferably 1 wt% or more and 90 wt%. Hereinafter, it is more preferably 1 wt% or more and 50 wt% or less.
When the pH suitable for the reaction is higher than 7, a base can be used as a pH regulator.

As the base used as the pH adjuster, either an inorganic base or an organic base can be used. Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, lithium carbonate, and sodium carbonate. And alkali metal carbonates such as potassium carbonate, alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, and ammonia. Examples of the organic base include trimethylamine, triethylamine, aniline, and pyridine. The base used as the pH adjusting agent can be used in any state of gas, solid, and liquid, but considering the ease of supply to the reaction vessel, it is preferable to use the base in the liquid state. The base in a state is more preferably used as an aqueous solution. In consideration of controllability of pH adjustment of the reaction tank, it is more preferable to use a liquid base as an aqueous solution. The concentration of the base when used as an aqueous solution is not particularly limited, but pH adjustment becomes difficult when a high-concentration aqueous solution is used. Therefore, it is preferably 0.1 wt% or more and 99 wt% or less, more preferably 1 wt% or more and 90 wt%. Hereinafter, it is more preferably 1 wt% or more and 50 wt% or less.
<Reaction tank>
As the reaction tank, a single-stage reaction tank composed of one reactor may be used, or a multi-stage reaction tank composed of a plurality of reactors may be used. As the reactor, a tank reactor or a tube reactor may be used. As the tank reactor, a reactor equipped with a stirrer is preferable. When the tank reactor has a stirrer, the stirrer blade of the stirrer can be of any shape, for example, propeller blade, flat paddle blade, pitched paddle blade, flat turbine blade, pitched turbine blade, ribbon blade, anchor blade , Full zone wings. One stirring blade may be provided, or a plurality of stirring blades may be provided.

  You may install the external circulation line provided with the circulation pump for returning a part of reaction liquid to a reaction tank in a reaction tank.

When an external circulation line equipped with a pump is installed in the reaction tank, the pump provided in the external circulation line is not particularly limited. For example, a turbo pump such as a centrifugal pump, a tilt pump or an axial pump And positive displacement pumps such as reciprocating pumps and rotary pumps.
When an external circulation line equipped with a pump is installed in the reaction tank, a part of the reaction solution is taken out from the reaction tank using the pump provided in the external circulation line and reacted via the external circulation line. Returned to the tank. It is preferable that a temperature control device is installed in the external circulation line installed in the reaction tank. As the temperature control device, a heat exchanger is preferably used. Examples of the heat exchanger include a multi-tube cylindrical type, a spiral tube type, a spiral plate type, a plate type, and a double pipe type.
When installing an external circulation line equipped with a pump in a multistage reaction tank composed of a plurality of reactors, all of the external circulation lines equipped with a pump may be installed in each reactor. It may be installed in only one reactor. In the case of multiple reactors, if the external circulation line equipped with a pump is installed only in one of the reactors, it is installed in the first reactor (the most upstream reactor). It is preferred that

  Using a reaction tank composed of a first-stage tank reactor and a second-stage tube reactor, the reaction liquid taken out from the tank reactor is further reacted in the tube reactor, and the tank reaction A reaction tank in which an external circulation line equipped with a pump is installed in the vessel is more preferable because the conversion rate can be improved.

  The tank reactor and the tube reactor may or may not be equipped with a heat exchanger as long as the nitrile hydratase activity of the bacterial cell catalyst is maintained. In order to control, the reactor preferably comprises a heat exchanger. As the heat exchanger, for example, a multi-tubular cylindrical type, a spiral tube type, a spiral plate type, a plate type, a double pipe type or the like is preferably installed on the external circulation line. The thing of the form directly installed in reactors, such as a formula and a coil type, is mentioned. When the reactor is a tubular reactor, the reactor itself can be composed of a multi-tubular cylindrical or double-tube heat exchanger.

  As the reaction method, for example, (1) a method in which the reaction is carried out after the whole amount of the cell catalyst, the reaction raw material [(meth) acrylonitrile and raw material water] and the pH regulator are charged into the reaction tank at once (batch reaction), (2 ) After the cell catalyst, reaction raw material [(meth) acrylonitrile and raw water] and a part of the pH regulator are charged into the reaction tank, the remaining cell catalyst, reaction raw material [(meth) acrylonitrile continuously or intermittently And raw water] and a method of reacting by supplying a pH regulator (semi-batch reaction), (3) cell catalyst, reaction raw material ((meth) acrylonitrile and raw water) and pH regulator continuously or intermittently Supply and reaction solution [including cell catalyst, unreacted raw material, pH regulator, and (meth) acrylamide produced. The method of continuously reacting without taking out the whole amount of the reaction solution in the reaction tank (continuous reaction) can be mentioned. Among these, a continuous reaction is preferable because it is easy to industrially produce an amide compound in large quantities and efficiently.

  The reaction is performed in the presence of a cell catalyst. The use form of the cell catalyst is preferably a suspension bed. For example, in the case of continuous reaction, a suspension of the cell catalyst may be prepared and the suspension supplied to the reaction vessel.

  When a multistage reaction tank composed of a plurality of reactors is used as the reaction tank, the structure includes (a) a cell catalyst, reaction raw materials ((meth) acrylonitrile and raw water) and a pH regulator. The reaction solution [including the cell catalyst, the unreacted raw material, the pH adjuster, the produced (meth) acrylamide, etc.] ] To the lower reactor, (b) cell catalyst, reaction raw material ((meth) acrylonitrile and raw water) and pH regulator in two or more reactors (via other reactors) (Without) parallel mode of supplying directly.

  For example, in the case where a continuous reaction is performed using a multistage reaction tank, the supply destination of the cell catalyst, the reaction raw material ((meth) acrylonitrile and raw material water) and the pH adjuster is the first-stage reactor (most upstream). It is not limited only to the (reactor located), The reactor after the 2nd stage (reactor located downstream) may be sufficient.

  Although the reaction tank temperature which is the liquid temperature in a reaction tank is based also on the heat resistance of a microbial cell catalyst, it is normally set to 0-50 degreeC, Preferably it is set to 10-40 degreeC. When the reaction vessel temperature is in the above range, it is preferable in that the nitrile hydratase activity of the bacterial cell catalyst can be maintained well.

  The reaction tank temperature refers to the liquid temperature in the reactor when the reaction tank is composed of only one reactor, and in the case where the reaction tank is composed of a plurality of reactors. Refers to the liquid temperature. The reaction vessel temperature can be measured, for example, by a thermocouple method (eg, K type). The reaction vessel temperature can be measured at an arbitrary location in the reaction vessel, and specifically can be measured at the reaction vessel outlet (reaction liquid outlet).

  The reaction is generally performed under normal pressure, but can also be performed under pressure in order to increase the solubility of (meth) acrylonitrile. The pH in the reaction vessel is not particularly limited as long as it is a suitable range for maintaining the activity of the bacterial cell catalyst, but is preferably in the range of pH 5 to pH 10. When the pH is within the above range, it is preferable in that the nitrile hydratase activity can be favorably maintained.

  When the reaction tank is composed of only one reactor, the pH of the reaction tank refers to the pH in the reactor, and when the reaction tank is composed of a plurality of reactors, Of pH. The pH of the reaction vessel can be measured by, for example, an indicator method, a hydrogen electrode method, a quinhydrone electrode method, an antimony electrode method, or a glass electrode method. The pH of the reaction vessel can be measured at any location in the reaction vessel, and specifically can be measured at the reaction vessel outlet (reaction liquid outlet).

The reaction time (retention time of the reaction solution) is usually 0.5 to 50 hours, preferably 2 to 25 hours. When a multistage reaction vessel is used, the reaction time refers to the total reaction time (retention time of the reaction liquid) in all reactors.
<Cell catalyst storage tank>
The cell catalyst storage tank has a catalyst supply pipe that holds a cell catalyst suspension and supplies the cell catalyst suspension to the reaction tank. The cell catalyst storage tank may or may not have a temperature control device, but from the viewpoint of controlling the liquid temperature of the suspension of cell catalyst, It is preferable to have it.
When the bacterial cell storage tank has a temperature control device, the temperature control apparatus may be provided on an external circulation line that the bacterial cell storage tank may have, or may be provided in the bacterial cell storage tank itself. Examples of the temperature control device in the bacterial cell storage tank include a heat exchanger. As the heat exchanger, for example, an external circulation line of a bacterial cell storage tank such as a multi-tubular heat exchanger, a spiral tube heat exchanger, a spiral plate heat exchanger, a plate heat exchanger, a double tube heat exchanger, etc. Or a type installed directly in a cell catalyst storage tank such as a jacket type heat exchanger or a coil type heat exchanger.
The bacterial cell catalyst storage tank may have a stirrer or may not have a stirrer, but it is preferable to have a stirrer from the viewpoint of controlling the liquid temperature of the bacterial cell catalyst. When the cell catalyst storage tank has a stirrer, the stirring blade of the stirrer can be of any shape, for example, propeller blade, flat paddle blade, pitched paddle blade, flat turbine blade, pitched turbine blade, ribbon blade, anchor blade , Full zone wings. One stirring blade may be provided, or a plurality of stirring blades may be provided.
<Supply of reaction raw materials>
The raw water supplied to the reaction tank may be supplied alone to the reaction tank, or may be supplied to the reaction tank after being mixed with (meth) acrylonitrile. When supplying raw material water to the reaction tank alone, there is no particular restriction on the position of the supply port to the reaction liquid in the reaction tank of the raw water supply pipe, and even if it is installed above the reaction liquid, May be installed.
The method for supplying raw water when supplying raw water alone to the reaction vessel is not particularly limited, and a known method can be used. As a method of supplying the raw water to the reaction tank, a device having a liquid transport function can be used. For example, a centrifugal pump, a tilting pump, an axial pump, or a turbo pump, a reciprocating pump, a rotary pump, etc. Pumps such as positive displacement pumps and conveyors such as screw conveyors can be used. As a method for supplying the raw water to the reaction tank, the raw water can be supplied without using the equipment having the liquid transport function. When equipment with a liquid transport function is not used, for example, a raw water storage tank for storing raw water is installed at the top of the reaction tank, the raw water storage tank and the reaction tank are connected by a raw water supply pipe, and gravity is used. There is a method of supplying by dropping. Or the method of supplying using the pressure difference of the raw material water storage tank and reaction tank which arise by pressurizing a raw material water storage tank is mentioned.

There may be one raw water supply pipe for supplying raw water to the reaction tank, or a plurality of raw water supply pipes may be provided for one reaction tank. There may be one supply port for the raw water supply pipe per supply pipe, or a plurality of supply ports may be provided. There is no restriction | limiting in particular in the shape of the supply port of a raw material water supply pipe, Any can be used suitably if it is a shape normally used.
As a method of mixing raw material water and (meth) acrylonitrile in the case of supplying raw water and (meth) acrylonitrile to the reaction vessel after mixing, a known method can be used, for example, stirring and mixing using a stirring vessel And a method of mixing raw material water and (meth) acrylonitrile in a pipe. In the case of using a stirring tank, the shape of the stirring tank is not particularly limited, but a cylindrical stirring tank is generally used, and it can be used in any case of a vertical cylindrical shape and a horizontal cylindrical shape. it can. The stirring tank may be provided with a baffle plate or may not be provided with a baffle plate.

In the case of using a stirring tank, a stirring blade having an arbitrary shape can be selected, and examples thereof include a propeller blade, a flat paddle blade, a pitched paddle blade, a flat turbine blade, a pitched turbine blade, a ribbon blade, an anchor blade, and a full zone blade. It is done. One stirring blade may be provided, or a plurality of stirring blades may be provided.
In order to mix raw water and (meth) acrylonitrile in piping, raw water and (meth) acrylonitrile can be mixed directly by combining raw water supply pipe and (meth) acrylonitrile supply pipe. Examples thereof include a method of positively mixing by installing a line mixer such as a static mixer.

  When mixing raw material water and (meth) acrylonitrile and supplying it to the reaction vessel, (meth) acrylonitrile may be completely dissolved in water after mixing with water, but not necessarily completely dissolved in water. It is not necessary to be mixed, and it may be mixed at an arbitrary ratio. The ratio of water: (meth) acrylonitrile is preferably 100: 1 to 1: 100, more preferably 50: 1 to 1:50, and even more preferably 10: 1 to 1:10 by volume.

  A known method can be used as the method for supplying the mixture of raw water and (meth) acrylonitrile when the raw water and (meth) acrylonitrile are mixed and then supplied to the reaction vessel. The method illustrated by the supply method of raw material water in the case of supplying water independently to a reaction tank can be used.

In the case of supplying raw water and (meth) acrylonitrile to the reaction vessel after mixing, the supply pipe for supplying the mixture of raw water and (meth) acrylonitrile to the reaction vessel may be one per reaction vessel. There may be more than one. The supply port of the supply pipe may be one for each supply pipe, or a plurality of supply ports may be provided. There is no restriction | limiting in particular in the shape of the supply port of a supply pipe | tube, Any can be used suitably if it is a shape normally used.
The (meth) acrylonitrile supplied to the reaction vessel may be supplied to the reaction vessel after being mixed with the raw water, or may be supplied alone to the reaction vessel. When supplying (meth) acrylonitrile alone to the reaction tank, the position of the supply port to the reaction liquid in the reaction tank of the (meth) acrylonitrile supply pipe is not particularly limited. It may be installed in the reaction solution.
The method for supplying (meth) acrylonitrile in the case of supplying (meth) acrylonitrile alone to the reaction vessel is not particularly limited, and a known method can be used. Specifically, the above raw water is reacted. The method illustrated by the method of supplying to a tank can be used.
There may be one (meth) acrylonitrile supply pipe for supplying (meth) acrylonitrile to the reaction tank, or a plurality of (meth) acrylonitrile supply pipes per reaction tank. One (meth) acrylonitrile supply pipe may be provided for each supply pipe, or a plurality of supply ports may be provided. There is no restriction | limiting in particular in the shape of the supply port of a (meth) acrylonitrile supply pipe, Any can be used suitably if it is a shape normally used.
<Supply of pH regulator>
The pH adjusting agent supplied to the reaction tank may be supplied to the reaction tank alone, or may be supplied to the reaction tank after being mixed with the aqueous medium and / or the mixture containing the aqueous medium supplied to the reaction tank. . When supplying the pH regulator alone to the reaction tank, the position of the supply port to the reaction liquid in the reaction tank of the pH regulator supply pipe is not particularly limited. You may install in a reaction liquid.
The supply method of the pH adjuster when supplying the pH adjuster alone to the reaction vessel is not particularly limited, and a known method can be used. Specifically, the above raw water is supplied to the reaction vessel. The method exemplified in the supplying method can be used.
The number of pH adjusting agent supply pipes for supplying the pH adjusting agent to the reaction vessel may be one per reaction vessel or may be plural. The supply port of the supply pipe for the pH adjusting agent may be one for each supply pipe, or a plurality of supply ports may be provided. The shape of the supply port of the pH adjusting agent supply pipe is not particularly limited, and any shape that is usually used can be suitably used.
The aqueous medium in which the pH adjuster is mixed when the pH adjuster is mixed with the aqueous medium and / or the mixture containing the aqueous medium and then supplied to the reaction vessel is preferably raw water. A mixture containing an aqueous medium in which a pH regulator is mixed is, for example, a reaction liquid containing a mixture of raw water and (meth) acrylonitrile, a bacterial cell catalyst, an unreacted raw material, a pH regulator, and produced (meth) acrylamide. Is mentioned.

As a method of mixing the pH regulator and the raw water when the pH regulator is mixed with the raw water and then fed to the reaction vessel, a known method can be used. The method illustrated by the method of mixing (meth) acrylonitrile can be used.
A known method can be used as the method for supplying the mixture of the pH adjuster and the raw water when the pH adjuster is mixed with the raw water and then supplied to the reaction vessel. The method illustrated with the supply method of the raw material water in the case of supplying to a reaction tank independently can be used.
The pH adjusting agent to be supplied to the reaction tank and the aqueous medium and / or the mixture containing the aqueous medium may be mixed at an arbitrary ratio, and preferably the pH adjusting agent: the aqueous medium and / or the mixture containing the aqueous medium. The ratio is 1: 1 to 1: 100,000,000, more preferably 1:10 to 1: 10,000,000 in volume ratio.

  As a method of mixing the mixture of the pH regulator, the raw water and (meth) acrylonitrile when the pH regulator is mixed with the raw water and (meth) acrylonitrile and then supplied to the reaction vessel, a known method may be used. Specifically, the method exemplified in the method of mixing the raw material water and (meth) acrylonitrile can be used.

As a method of mixing the pH adjuster and the reaction solution when supplying to the reaction tank after mixing with the reaction solution containing the pH adjuster and the bacterial cell catalyst, the unreacted raw material, the pH adjuster and the generated (meth) acrylamide, etc. For example, the following method can be used. An external circulation line equipped with a pump for returning a part of the reaction solution to the reaction tank is installed in the reaction tank, and the reaction is performed as a mixture containing an aqueous medium by combining the external circulation line and the pH regulator supply pipe. Examples include a method in which a part of the reaction liquid taken out from the tank is used and a part of the reaction liquid and the pH adjuster are directly mixed in the external circulation line. A part of the reaction liquid and the pH regulator directly mixed in the external circulation line are supplied to the reaction tank as they are using the external circulation line.

<Supply of bacterial cell catalyst>
The supply of the bacterial cell catalyst is not particularly limited, and a known method can be used. As a method for supplying the bacterial cell catalyst to the reaction tank, a device having a liquid transport function can be used. For example, a turbo pump such as a centrifugal pump, a diagonal flow pump or an axial flow pump, a reciprocating pump or a rotary pump Pumps such as positive displacement pumps and conveyors such as screw conveyors can be used. As a method of supplying the bacterial cell catalyst, it can be supplied without using the device having the liquid transport function. When a device having a liquid transport function is not used, for example, a cell storage tank for storing cell catalysts is installed at the top of the reaction tank, the cell storage tank and the reaction tank are connected by a cell catalyst supply pipe, There is a method of supplying by dropping using. Or the method of supplying using the pressure difference of the microbial cell storage tank and reaction tank which arises by pressurizing a microbial cell storage tank or depressurizing a reaction tank is mentioned.

The amount of the bacterial cell catalyst used varies depending on the reaction conditions, the type of catalyst and its form, but is usually 10 to 50,000 ppm by weight, preferably 10 to 50,000 ppm by weight, preferably in terms of the dry cell weight of the cells. 50 to 30,000 ppm by weight.
In the method for producing (meth) acrylamide of the present invention, the obtained (meth) acrylamide is recovered and purified by, for example, concentration operation (eg, evaporation concentration), activated carbon treatment, ion exchange treatment, filtration treatment, and crystallization operation. It can be carried out.

As described above, (meth) acrylamide can be obtained from (meth) acrylonitrile which is a reaction raw material.
[(Meth) acrylamide polymer]
The (meth) acrylamide polymer of the present invention is obtained by homopolymerizing (meth) acrylamide obtained as described above or copolymerizing with at least one unsaturated monomer copolymerizable with an amide compound. Can be manufactured.
<Unsaturated monomer>
Examples of the unsaturated monomer copolymerizable with (meth) acrylamide include unsaturated carboxylic acids such as acrylic acid, methacrylic acid, itaconic acid, maleic acid, fumaric acid, and salts thereof;
Sulfonic acids such as vinyl sulfonic acid, styrene sulfonic acid, acrylamidomethylpropane sulfonic acid and their salts;
Alkylaminoalkyl esters of (meth) acrylic acid, such as N, N-dimethylaminoethyl methacrylate, N, N-diethylaminoethyl methacrylate, N, N-dimethylaminoethyl acrylate, or their quaternary ammonium derivatives;
N, N-dialkylaminoalkyl (meth) acrylamides such as N, N-dimethylaminopropylmethacrylamide, N, N-dimethylaminopropylacrylamide, or their quaternary ammonium derivatives;
Hydrophilic acrylamides such as acetone acrylamide, N, N-dimethylacrylamide, N, N-dimethylmethacrylamide, N-ethylmethacrylamide, N-ethylacrylamide, N, N-diethylacrylamide, N-propylacrylamide;
N-acryloylpyrrolidine, N-acryloylpiperidine, N-acryloylmorpholine;
Hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxypropyl acrylate;
Methoxypolyethylene glycol (meth) acrylate, N-vinyl-2-pyrrolidone;
Acrylamide;
Methacrylamide;
N, N-di-n-propylacrylamide, Nn-butylacrylamide, Nn-hexylacrylamide, Nn-hexylmethacrylamide, Nn-octylacrylamide, Nn-octylmethacrylamide, N- N-alkyl (meth) acrylamide derivatives such as tert-octylacrylamide, Nn-dodecylacrylamide, Nn-dodecylmethacrylamide;
N, N-diglycidylacrylamide, N, N-diglycidylmethacrylamide, N- (4-glycidoxybutyl) acrylamide, N- (4-glycidoxybutyl) methacrylamide, N- (5-glycidoxy N- (ω-glycidoxyalkyl) (meth) acrylamide derivatives such as pentyl) acrylamide, N- (6-glycidoxyhexyl) acrylamide;
(Meth) acrylate derivatives such as methyl acrylate, ethyl acrylate, butyl acrylate, lauryl acrylate, 2-ethylhexyl acrylate, glycidyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, lauryl methacrylate, 2-ethylhexyl methacrylate, glycidyl methacrylate;
Examples thereof include olefins such as acrylonitrile, methacrylonitrile, vinyl acetate, vinyl chloride, vinylidene chloride, ethylene, propylene, and butene, styrene, α-methylstyrene, butadiene, and isoprene.

These monomers may be used alone or in combination of two or more.
<Polymerization initiator>
As the polymerization initiator, for example, a radical polymerization initiator can be used.

Examples of radical polymerization initiators include peroxides such as potassium persulfate, ammonium persulfate, hydrogen peroxide, and benzoyl peroxide; azobisisobutyronitrile, 2,2′-azobis (4-amidinopropane) dihydrochloride, Azo free radical initiators such as 4,4′-azobis (sodium 4-cyanovalerate);
Examples thereof include so-called redox catalysts in which the peroxide is used in combination with a reducing agent such as sodium bisulfite, triethanolamine, and ferrous ammonium sulfate.

  The above polymerization initiators may be used alone or in combination of two or more. The amount of the polymerization initiator is usually in the range of 0.001 to 5% by weight based on the total weight of the monomers.

  In the case of a single polymerization initiator, the polymerization temperature is usually in the range of 0 to 120 ° C, more preferably in the range of 5 to 90 ° C. Further, the polymerization temperature does not always need to be maintained at a constant temperature, and may be appropriately changed as the polymerization proceeds. Usually, however, the polymerization temperature tends to increase as the polymerization proceeds. Therefore, it may be cooled as necessary.

  The molecular weight of the (meth) acrylamide polymer of the present invention is not particularly limited, but is usually in the range of 100,000 to 50 million, and preferably in the range of 500,000 to 30 million.

The (meth) acrylamide polymer thus obtained is a polymer that has both water-solubility and high molecular weight, and is excellent in hue, and has a flocculant, paper additive, and oil recovery. It can be suitably used as an agent or the like.
[Production method of (meth) acrylamide polymer]
As a manufacturing method of the (meth) acrylamide type polymer of this invention, aqueous solution polymerization and emulsion polymerization can be used, for example.

Among these, in the case of aqueous solution polymerization, the total concentration of (meth) acrylamide and the unsaturated monomer added as needed is usually 5 to 90% by weight.

The atmosphere during the polymerization is not particularly limited, but from the viewpoint of rapidly proceeding the polymerization, the polymerization is preferably performed in an inert gas atmosphere such as nitrogen gas.
The polymerization time is not particularly limited, but is usually in the range of 1 to 20 hours.

  The pH of the aqueous solution at the time of polymerization is not particularly limited, but polymerization may be carried out by adjusting the pH if necessary. In that case, the pH adjusting agent described in the above (meth) acrylamide production method can be used.

  Next, examples of the present invention will be specifically described, but the present invention is not limited to these examples.

[Example 1]
[Preparation of microbial cells containing nitrile hydratase]
In accordance with the method described in Example 1 of JP-A-2001-340091, no. Three clone cells were obtained and similarly cultured by the method of Example 1 to obtain wet cells containing nitrile hydratase.

[Purification of water]
As a distillation apparatus, a glass 5 L round bottom flask equipped with a Dimroth type cooling coagulator and a packed tower corresponding to 8 stages was prepared.

The apparatus was charged with 3 kg of tap water in a round bottom flask and distilled. An oil bath was used for heating, and the fraction until the distillation temperature reached 100 ° C. was defined as the first fraction. 2 kg of a fraction having a distillation temperature of 100 to 101 ° C. was obtained as a main fraction.
The electric conductivity of tap water was measured by an alternating current two power source method and found to be 180 μS / cm. Further, when the main sample was analyzed in the same manner, the electric conductivity was 10 μS / cm. Hereinafter, the water after the distillation treatment is referred to as purified water a.

[Production of acrylamide]
In order to obtain a final product having an acrylamide concentration in the aqueous solution of 50% by weight, the reaction was performed under the following conditions.

    A 1 L glass flask equipped with a stirrer was prepared as the first reactor, and a Teflon (registered trademark) tube 20 m having an inner diameter of 5 mm was prepared as the second reactor. The raw water supply pipe, the pH regulator supply pipe, the acrylonitrile supply pipe, and the cell catalyst supply pipe are each directly connected to the first reactor.

  The first reactor was charged with 400 g of purified water a in advance. The wet cells obtained by the above culture method were suspended in tap water. This suspension was continuously fed at a rate of 10 g / h while stirring in the first reactor. Acrylonitrile was continuously supplied at a rate of 32 g / h, and purified water a was continuously supplied at a rate of 38 g / h. The temperature of the reaction solution during the reaction was controlled by immersing both the first reactor and the second reactor in a water bath having a temperature of 10 to 20 ° C. A 0.1 M NaOH aqueous solution was used as a pH adjuster, the supply amount was adjusted so that the reaction pH was 7.5 to 8.5, and the solution was continuously supplied to the first reactor.

  In order to keep the liquid level of the first reactor constant, the reaction solution is continuously withdrawn from the first reactor at a rate of 80 g / h and continuously supplied to the second reactor. The reaction was allowed to proceed further within.

  Analysis was performed under the following HPLC conditions 50 hours after the start of the reaction. The conversion to acrylamide at the outlet of the first reactor was 95%, and the acrylonitrile concentration at the outlet of the second reactor was below the detection limit (10 ppm). The following).

Here, the analysis conditions were as follows.
・ Acrylamide analysis conditions:
High-performance liquid chromatograph: LC-10A system (manufactured by Shimadzu Corporation)
(UV detector wavelength 250 nm, column temperature 40 ° C.)
Separation column: SCR-101H (manufactured by Shimadzu Corporation)
Eluent: 0.05% (volume basis) -phosphoric acid aqueous solution / acrylonitrile analysis conditions:
High-performance liquid chromatograph: LC-10A system (manufactured by Shimadzu Corporation)
(UV detector wavelength 200 nm, column temperature 40 ° C.)
Separation column: Wakosil-II 5C18HG (manufactured by Wako Pure Chemical Industries)
Eluent: 7% (volume basis) -acetonitrile, 0.1 mM-acetic acid,
An aqueous solution containing 0.2 mM sodium acetate at various concentrations

[Production of acrylamide polymer]
The reaction mixture obtained by the above method was treated with activated carbon under acidic conditions (pH = 5) to remove wet cells, and further neutralized with a 0.1 M NaOH aqueous solution to concentrate 50% by weight of acrylamide. An aqueous solution was obtained.

  Tap water was added to the resulting aqueous acrylamide solution to give an aqueous acrylamide solution having a concentration of 20% by weight. 500 g of this 20 wt% acrylamide aqueous solution was placed in a 1 L polyethylene container, and while maintaining the temperature at 18 ° C., dissolved oxygen in the liquid was removed through nitrogen, and immediately placed in a heat insulating block made of polystyrene foam.

Then 200 × 10 ⁻⁶ mpm (molar ratio to acrylamide) 4,4′-azobis (sodium 4-cyanovalerate), 200 × 10 ⁻⁶ mpm dimethylaminopropionitrile, and 80 × 10 ⁻⁶ mpm Of ammonium persulfate were each dissolved in a small amount of tap water and quickly poured into a 1 L polyethylene container in this order. Nitrogen gas was previously passed through these reagents, and before and after injection, a small amount of nitrogen gas was also passed through the polyethylene container to prevent oxygen gas from being mixed.

  When the reagent was injected, after the induction period of several minutes, the temperature inside the polyethylene container was observed to rise, so the supply of nitrogen gas was stopped. When the polyethylene container was held in the heat insulation block for about 100 minutes, the temperature inside the polyethylene container reached about 70 ° C. Therefore, the polyethylene container was taken out from the heat insulation block and immersed in 97 ° C. water for 2 hours to further proceed the polymerization reaction. Thereafter, it was immersed in cold water and cooled to stop the polymerization reaction.

  The water-containing gel of acrylamide polymer thus obtained was taken out from the polyethylene container, divided into small chunks and ground with a meat grinder. The ground hydrogel containing acrylamide polymer was dried with hot air at 100 ° C. for 2 hours and then pulverized with a high-speed rotary blade pulverizer to obtain a dry powdery acrylamide polymer. The obtained dry powdery acrylamide polymer was passed through a sieve, and a 32-42 mesh sample was collected and used as a polymer sample for subsequent tests.

[Example 2]
[Purification of water]
As an ion exchange device, a packed column of cation exchange resin and a packed column of anion exchange resin were prepared, and 500 cc of resin was packed in each packed column. The cation exchange resin tower and the anion exchange resin tower were connected.

3 kg of tap water was passed through the cation exchange resin tower and then the anion exchange resin tower at a flow rate of 300 cc / h to obtain 2.5 kg of ion exchange treated water.
The electric conductivity of tap water was measured by an alternating current two power source method and found to be 180 μS / cm. Further, when the ion exchange treated water was analyzed in the same manner, the electric conductivity was 3 μS / cm. Hereinafter, the ion exchange treated water is referred to as purified water b.

[Production of acrylamide]
In the production of acrylamide of Example 1, acrylamide was produced in the same manner as in Example 1 except that purified water b was used instead of purified water a. When HPLC analysis was performed 50 hours after the start of the reaction, the conversion to acrylamide at the outlet of the first reactor was 95%, and the acrylonitrile concentration at the outlet of the second reactor was below the detection limit (10 ppm or less). .

[Production of acrylamide polymer]
In the production of the acrylamide polymer of Example 1, instead of using the acrylamide aqueous solution obtained from purified water a, the acrylamide polymer was used in the same manner as in Example 1 except that the acrylamide aqueous solution obtained from purified water b was used. Coalescence was produced. The obtained water-containing gel of acrylamide polymer was treated in the same manner as in Example 1 to obtain a polymer sample for use in the subsequent tests.

[Example 3]
[Purification of water]
As a reverse osmosis membrane treatment apparatus, a reverse osmosis membrane having an effective area of 200 cm 2 was prepared.

3 kg of tap water was passed through the reverse osmosis membrane at a flow rate of 300 cc / h to obtain 2 kg of reverse osmosis membrane treated water.
The electric conductivity of tap water was measured by an alternating current two power source method and found to be 180 μS / cm. When the reverse osmosis membrane treated water was analyzed in the same manner, the electric conductivity was 8 μS / cm. Hereinafter, the reverse osmosis membrane treated water is referred to as purified water c.

[Production of acrylamide]
In the production of acrylamide in Example 1, acrylamide was produced in the same manner as in Example 1 except that purified water c was used instead of purified water a. When HPLC analysis was performed 50 hours after the start of the reaction, the conversion to acrylamide at the outlet of the first reactor was 95%, and the acrylonitrile concentration at the outlet of the second reactor was below the detection limit (10 ppm or less). .

[Production of acrylamide polymer]
In the production of the acrylamide polymer of Example 1, instead of using an acrylamide aqueous solution obtained from purified water a, an acrylamide polymer was used in the same manner as in Example 1 except that an acrylamide aqueous solution obtained from purified water c was used. Coalescence was produced. The obtained water-containing gel of acrylamide polymer was treated in the same manner as in Example 1 to obtain a polymer sample for use in the subsequent tests.

[Comparative example]
In the production of acrylamide of Example 1, acrylamide was produced in the same manner as in Example 1 except that tap water was used instead of purified water a. When HPLC analysis was performed 50 hours after the start of the reaction, the conversion to acrylamide at the outlet of the first reactor was 92%, and the acrylonitrile concentration at the outlet of the second reactor was 15 ppm.
Since acrylonitrile was detected at the outlet of the second reactor, the supply rate of the wet cell suspension was changed from 10 g / h to 12 g / h in order to complete the reaction. Acrylamide was produced. When HPLC analysis was performed 50 hours after the start of the reaction, the conversion to acrylamide at the outlet of the first reactor was 95%, and the acrylonitrile concentration at the outlet of the second reactor was below the detection limit (10 ppm or less). Completed.
In the production of the acrylamide polymer of Example 1, instead of using an acrylamide aqueous solution obtained from purified water a, an acrylamide polymer was used in the same manner as in Example 1 except that an acrylamide aqueous solution obtained from tap water was used. Was manufactured. The obtained water-containing gel of acrylamide polymer was treated in the same manner as in Example 1 to obtain a polymer sample for use in the subsequent tests.

<Testing method for acrylamide polymer>
Evaluation of water solubility, measurement of standard viscosity, and evaluation of color tone of the polymer samples obtained in Examples 1, 2, 3 and Comparative Examples were performed by the following methods.

  Water solubility: Water solubility is 600 ml of tap water in a 1 L beaker, and 0.66 g of polymer sample (0.6 g of pure content) is added while stirring at 25 ° C. using a stirring blade of a predetermined shape, at 400 rpm. Stirring was performed for 2 hours, and the resulting solution was filtered through a 150-mesh wire mesh, and water solubility was judged from the amount of insoluble matter and filterability. That is, ◎ is completely dissolved, ◯ is close to completely dissolved, there is an insoluble matter, △ is what can be filtered, △, the passage of the filtrate is slow, the insoluble matter is effectively filtered The thing which cannot be made was set as x.

  Standard viscosity: The filtrate obtained by the above water solubility test is a polymer aqueous solution having a concentration of 0.1% by weight. To this, sodium chloride corresponding to a concentration of 1M is added, and a BL type viscometer is used with a BL adapter at 25 ° C. The viscosity was measured at a rotor rotational speed of 60 rpm (standard viscosity). The standard viscosity obtained by such a method is conventionally used as a value correlated with the molecular weight.

Color tone: Regarding the color tone of the polymer, the polymer powder was visually evaluated.
The evaluation results are shown in Table 1.

Claims (4)

Production of (meth) acrylamide, characterized in that water having a conductivity of 100 μS / cm or less and (meth) acrylonitrile are hydrated by a microbial cell containing nitrile hydratase and / or a treated product thereof. Method The method according to claim 1, wherein the nitrile hydratase is a nitrile hydratase derived from Pseudonocardia or Rhodococcus. A (meth) acrylamide polymer obtained by homopolymerizing the (meth) acrylamide according to claim 1 or copolymerizing with at least one unsaturated monomer copolymerizable with an amide compound. A method for producing a (meth) acrylamide polymer, characterized in that the (meth) acrylamide according to claim 1 is homopolymerized or copolymerized with at least one unsaturated monomer copolymerizable with an amide compound.