Method for producing amide compound

Abstract

Provided is a method for producing an amide compound from a nitrile compound in the presence of a biocatalyst having nitrile hydratase activity, the method being characterized in that the amide compound is produced from a nitrile compound in the presence of a biocatalyst having nitrile hydratase activity, at least in the case of a liquid composition that becomes a reaction liquid. When the concentration of the nitrile compound in the gas phase part of the reaction tank containing the reaction liquid in the presence of air is within the explosion range, the hydration reaction is carried out under the condition that the oxygen concentration in the gas phase part of the reaction tank is 10 vol% or less. The nitrile compound is preferably, for example, acrylonitrile or methacrylonitrile.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for producing an amide compound from a nitrile compound using a biocatalyst having nitrile hydratase activity.

[0002] This application claims priority based on Japanese Patent Application No. 2023-043449 and Japanese Patent Application No. 2023-043350 filed in Japan on March 17, 2023, and the contents thereof are incorporated herein by reference. BACKGROUND

[0003] In recent years, a method for producing a compound using a biocatalyst has advantages such as mild reaction conditions, a simplified reaction process, and high purity of a reaction product due to a small amount of by-products, and is used for the production of many compounds.

[0004] In the production of an amide compound, the use of a biocatalyst has been actively studied since the discovery of an enzyme that converts a nitrile compound to an amide compound, i.e., nitrile hydratase (Patent Documents 1 to 4, etc.). In addition, the process has also been actively studied, and various schemes such as batch reaction, semi-batch reaction, multi-tank continuous reaction, and pipe reactor have been proposed.

[0005] For example, Patent Document 5 discloses a method for producing acrylamide using a multi-tank continuous reaction device, acrylonitrile is supplied in a plurality of tanks on the upstream side of the reaction, and acrylonitrile is not supplied in a plurality of tanks on the downstream side, and the reaction solution is allowed to mature.

[0006] In addition, Patent Document 6 discloses a method for producing acrylamide by controlling the progress of acrylonitrile concentration in the reaction, but in this method, in order to reduce the generation of acrylic acid, time is taken for the reaction of acrylonitrile to proceed.

[0007] Patent Document 7 shows an amide compound production method using dried bacterial cells.

[0008] Prior Art Documents

[0009] Patent Documents

[0010] Patent Document 1: Japanese Patent Application Laid-Open No. H11-123098

[0011] Patent Document 2: Japanese Patent Application Laid-Open No. H7-265091

[0012] Patent Document 3: Japanese Patent No. S56-38118

[0013] Patent Document 4: Japanese Patent Application Laid-Open No. H11-89575

[0014] Patent Document 5: International Publication No. 2015 / 190067

[0015] Patent Literature 6: Japanese Patent Application Laid-Open No. 2017-535249

[0016] Patent Literature 7: Japanese Patent Application Laid-Open No. 2017-529847 SUMMARY

[0017] PROBLEMS TO BE SOLVED BY THE INVENTION

[0018] However, acrylonitrile is very highly toxic, highly flammable, has a low solubility in water, and is low in polarity, and is easily dispersed. In the case where a raw material that is highly flammable such as acrylonitrile is used, in order to prevent ignition of a reaction liquid containing the raw material and to ensure safety, some countermeasures are required. For example, if the raw material in the reaction liquid is made to be low in concentration, it is also possible to perform the reaction outside the explosion range, but there is a problem in that the reaction rate becomes slow and the productivity decreases.

[0019] In addition, an amide compound such as acrylamide, which is a target product, is easily polymerized. In order to suppress this polymerization, not only a polymerization inhibitor is added, but also the presence of oxygen to some extent is effective.

[0020] In order to prevent the polymerization of the obtained acrylamide, it is preferable that the oxygen concentration be high to some extent. However, in an environment where the oxygen concentration is high, the risk of ignition of the raw material, that is, acrylonitrile, dispersed into the gas phase increases. Therefore, in order to achieve safety and high productivity, it is important to control the gas composition in the gas phase portion in the reaction tank. However, an appropriate oxygen concentration range to avoid such a situation has not been known so far.

[0021] An object of the present application is to provide a method of safely producing an amide compound while maintaining a high productivity.

[0022] MEANS FOR SOLVING THE PROBLEMS

[0023] The present inventors have made intensive studies in view of the problems of the prior art, and as a result, have found that by appropriately adjusting the oxygen concentration in the gas phase portion in the reaction tank, it is possible to safely perform the reaction, thereby completing the present application. That is, the present application relates to the following [1] to [8].

[0024] [1] A method of producing an amide compound, which is a method of producing an amide compound from a nitrile compound in the presence of a biological catalyst having nitrile hydratase activity, characterized by

[0025] at least in a case where the concentration of the nitrile compound in the gas phase portion of the reaction tank containing the reaction liquid in the presence of air is included in the explosion range,

[0026] the hydrating reaction is performed under a condition where the oxygen concentration in the gas phase portion of the reaction tank becomes 10 vol% or less.

[0027] [2] A method for producing an amide compound, which is a method for producing an amide compound from a nitrile compound in the presence of a biological catalyst having nitrile hydratase activity, wherein

[0028] The concentration of the nitrile compound in the reaction solution for producing an amide compound from a nitrile compound by a hydration reaction is a concentration satisfying the following formula (1),

[0029] Y ≤ 50X - 35 (mass %) (1)

[0030] (wherein X represents the concentration (mass %) of the nitrile compound with respect to the total mass of the reaction solution, and Y represents the concentration (mass %) of the amide compound with respect to the total mass of the reaction solution.)

[0031] [3] The method for producing an amide compound according to [1] or [2], wherein

[0032] the concentration of the nitrile compound in the reaction solution is (1) or (2) below,

[0033] (1) the concentration of the nitrile compound with respect to the total mass of the reaction solution is 1.7 mass % or more,

[0034] (2) the concentration X of the nitrile compound with respect to the total mass of the reaction solution is 0.7 to less than 1.7 mass %, and Y ≤ 50X - 35 (mass %) is satisfied,

[0035] (wherein Y represents the concentration (unit: mass %) of the amide compound with respect to the total mass of the reaction solution.)

[0036] [4] The method for producing an amide compound according to any one of [1] to [3], characterized in that

[0037] the biological catalyst used in the reaction is a biological catalyst in which the ratio of the hydration reaction rate represented by S1 / S2 is 0.2 or more when the hydration reaction rate in the following reaction solution A is S1 and the hydration reaction rate in the following reaction solution B is S2,

[0038] reaction solution A: a reaction solution at 20°C containing an amide compound at 47 mass % with respect to the total mass of the reaction solution, a nitrile compound at 2 mass %, and the remainder water,

[0039] reaction solution B: a reaction solution at 20°C containing an amide compound at 0 mass % with respect to the total mass of the reaction solution, a nitrile compound at 2 mass %, and the remainder water.

[0040] [5] The method for producing an amide compound according to any one of [1] to [4], wherein

[0041] the time required for the concentration of the nitrile compound contained in the reaction solution to be halved by the hydration reaction is within 1.5 hours.

[0042] the time required for the concentration of the nitrile compound contained in the reaction solution to be halved by the hydration reaction is within 1.5 hours.

[0043] [6] The production method of an amide compound according to any one of [1] to [5], wherein the nitrile compound is a compound having a double bond, and the nitrile compound is stored in a storage container having an oxygen concentration of 1 to 10% by volume in a gas phase portion in the presence of a quinone-based polymerization inhibitor.

[0044] [7] The production method of an amide compound according to any one of [1] to [6], wherein the nitrile compound is acrylonitrile or methacrylonitrile.

[0045] [8] The production method of an amide compound according to any one of [1] to [7], wherein the amide compound is acrylamide or methacrylamide.

[0046] In addition, the present application relates to [Al] to [A5] below in another aspect.

[0047] [Al] A production method of an amide compound, which is a method of producing an amide compound by subjecting a nitrile compound to a hydration reaction in a reaction solution in the presence of a biological catalyst having nitrile hydratase activity, wherein the oxygen concentration of a gas phase portion of at least one reaction tank in which the reaction solution is housed is set to 1 to 10% by volume.

[0048] [A2] A production method of an amide compound, which is a method of producing an amide compound by subjecting a nitrile compound to a hydration reaction in a reaction solution in the presence of a biological catalyst having nitrile hydratase activity, wherein the oxygen concentration of a gas phase portion of at least one reaction tank in which the reaction solution is housed is set to 1 to 10% by volume in a case where a condition of (1) or (2) below is satisfied.

[0049] (1) when the concentration of the nitrile compound with respect to the total mass of the reaction solution is 1.7% by mass or more, or (2) when the concentration X of the nitrile compound with respect to the total mass of the reaction solution is 0.7% by mass or more and less than 1.7% by mass, and Y ≤ 50X - 35 is satisfied (where X represents the concentration X, and Y represents the concentration (unit: % by mass) of the amide compound with respect to the total mass of the reaction solution).

[0050] [A3] The method for producing an amide compound according to [Al] or [A2], wherein the nitrile compound supplied to the reaction solution is a compound having a double bond, and the nitrile compound is stored in a storage container in the presence of a quinone-based polymerization inhibitor, and the oxygen concentration in the gas phase portion of the storage container is 1 to 10% by volume.

[0051] [A4] The method for producing an amide compound according to any one of [Al] to [A3], wherein the nitrile compound is acrylonitrile or methacrylonitrile.

[0052] [A5] The method for producing an amide compound according to any one of [Al] to [A4], wherein the amide compound is acrylamide or methacrylamide.

[0053] Further, the present application relates to [Bl] to [B5] in still another aspect.

[0054] [Bl] A method for producing an amide compound, which is a method for producing an amide compound by subjecting a nitrile compound to hydration reaction in a reaction solution Z in the presence of a biological catalyst having nitrile hydratase activity, wherein the biological catalyst exhibits a hydration reaction rate SI in a reaction solution A described below, and exhibits a hydration reaction rate S2 in a reaction solution B described below, and the ratio of the reaction rates indicated by SI / S2 is 0.2 times or more, and the hydration reaction is carried out at a temperature higher than the flash point of the reaction solution Z under the composition of the atmosphere in at least one reaction tank equipped with the reaction solution Z.

[0055] [Reaction solution A] a reaction solution at 20°C containing 47% by mass of the amide compound, 2% by mass of the nitrile compound, and the remainder water, relative to the total mass,

[0056] [Reaction solution B] a reaction solution at 20°C containing 0% by mass of the amide compound, 2% by mass of the nitrile compound, and the remainder water, relative to the total mass.

[0057] [B2] The method for producing an amide compound according to [Bl], wherein the time required for the mass of the nitrile compound added to the reaction solution Z to be halved by the hydration reaction is 1.5 hours or less, or the time required for the concentration of the nitrile compound contained in the reaction solution Z to be halved by the hydration reaction is 1.5 hours or less.

[0058] [B3] The method for producing an amide compound according to [Bl] or [B2], wherein the biological catalyst is added to the reaction solution Z in the form of a bacterial cell, and the amount of the bacterial cell added is 0.4 g or less in terms of the dry weight of the bacterial cell, per 1 kg of the amide compound produced from the reaction solution Z.

[0059] [B4] The method for producing an amide compound according to any one of [Bl] to [B3], wherein the nitrile compound is acrylonitrile or methacrylonitrile.

[0060] [B5] The method for producing an amide compound according to any one of [Bl] to [B4], wherein the amide compound is acrylamide or methacrylamide.

[0061] Effects of Invention

[0062] According to the method of the present application, an amide compound can be safely produced from a nitrile compound in a state where high productivity is maintained (without reducing the productivity). DETAILED DESCRIPTION

[0063] The first mode of the present application is a method for producing an amide compound by subjecting a nitrile compound to a hydration reaction in a reaction solution in the presence of a biological catalyst having nitrile hydratase activity.

[0064] Hereinafter, an example of an embodiment of the present mode will be described.

[0065] (1) Biological catalyst having nitrile hydratase activity

[0066] In the present embodiment, an amide compound is produced from a nitrile compound in the presence of a biological catalyst having nitrile hydratase activity. At this time, in order to obtain high productivity, sometimes a nitrile compound as a raw material is caused to exist in a reaction solution at a high concentration in at least one reaction tank.

[0067] By causing a nitrile compound to exist in a reaction solution at a high concentration, the nitrile compound volatilizes, and in the reaction tank, a nitrile compound at a high concentration also exists in the gas phase thereof. Then, also by the influence of oxygen existing in the gas phase, the risk of the nitrile compound catching fire or exploding becomes high.

[0068] In the present embodiment, it is preferable to rapidly convert the nitrile compound existing in the reaction solution into an amide compound by using a catalyst having specific properties described later, so as to reduce such a risk as much as possible. The catalyst is, for example, preferably a catalyst having a high reaction speed, and more preferably a biological catalyst in which the reduction in the hydration reaction speed of the nitrile compound is small even in a state where an amide compound is accumulated by performing a hydration reaction.

[0069] A catalyst having a fast reaction speed means that the conversion speed from a nitrile compound to an amide compound per unit time is fast.

[0070] For example, in the present embodiment, by using a catalyst having specific performance described later, the time taken for the concentration of the nitrile compound in the reaction solution at the moment when the addition of the nitrile compound is ended or interrupted to decrease by 50% or the time taken for the concentration of the nitrile compound in the reaction solution at the moment when the reaction is started to decrease by 50% is preferably set to be within 1.5 hours, more preferably within 1.2 hours, more preferably within 1 hour, more preferably within 45 minutes, further preferably within 30 minutes.

[0071] In addition, the biological catalyst in which the decrease in the hydration reaction rate of the nitrile compound is small even in the case where the hydration reaction is performed under the condition where the amide compound is accumulated, for example, preferably has a hydration reaction rate of the nitrile compound in an aqueous solution containing 47% by mass of the amide compound that is 0.2 times or more of the hydration reaction rate of the nitrile compound in an aqueous solution containing 0% by mass of the amide compound. More preferably, a biological catalyst having a hydration reaction rate of 0.25 times or more, further preferably 0.3 times or more can be used.

[0072] As such a biological catalyst, a biological catalyst in which the activity of the nitrile hydratase is adjusted by a genetic modification technique as described later can also be used, and the adjustment can also be achieved by adjusting the amount (or concentration) of the catalyst used.

[0073] In the present embodiment, the nitrile hydratase refers to an enzyme having the ability to hydrate the nitrile compound to generate the corresponding amide compound. The biological catalyst having the activity of the nitrile hydratase can be the nitrile hydratase protein itself, or an animal cell, a plant cell, an organelle, or a cell body of a microorganism containing the nitrile hydratase, and a processed product thereof.

[0074] As the processed product, an animal cell, a plant cell, an organelle, or a broken product obtained by crushing the cell body of a microorganism, or an enzyme (crude enzyme or purified enzyme) extracted from the cell body; a substance obtained by immobilizing the animal cell, the plant cell, the organelle, the cell body of the microorganism, or the enzyme itself to a carrier, and the like can be exemplified.

[0075] In addition, the processed product also includes an animal cell, a plant cell, an organelle, or a cell body of a microorganism (sometimes referred to as "inactivated cell body") that has lost the ability to proliferate by a treatment with a medicament.

[0076] As the immobilization method, an embedding method, a cross-linking method, a carrier binding method, and the like can be exemplified. The embedding method refers to a method in which the enzyme is coated with a high molecular film. The cross-linking method refers to a method in which the enzyme is cross-linked with a reagent having two or more functional groups (multifunctional cross-linking agent). The carrier binding method refers to a method in which the enzyme is bound to a water-insoluble carrier.

[0077] As the carrier for immobilization (immobilization carrier), for example, glass beads, silica gel, polyurethane, polyacrylamide, polyvinyl alcohol, carrageenan, alginic acid, agar, and gelatin, etc. can be exemplified.

[0078] As a representative example of such microorganisms, for example, microorganisms belonging to Rhodococcus genus, Gordona genus, Pseudomonas genus, Pseudonocardia genus, Geobacillus genus, Bacillus genus, Bacteridium genus, Micrococcus genus, Brevibacterium genus, Corynebacterium genus, Nocardia genus, Microbacterium genus, Fusarium genus, Agrobacterium genus, Acinetobacter genus, Xanthobacter genus, Streptomyces genus, Rhizobium genus, Klebsiella genus, Enterobacter genus, Erwinia genus, Pantoea genus, Candida genus, Aeromonas genus, Citrobacter genus, Achromobacter genus, etc. having nitrile hydratase activity can be exemplified.

[0079] More specifically, the following can be mentioned: Nocardia sp. N-775 described in Japanese Patent Publication No. 56-17918, Rhodococcus rhodochrous J-1 described in Japanese Patent Publication No. 06-55148, Rhodococcus rhodochrous NCIMB 41164 described in International Publication Bulletin No. WO2005 / 054456, Klebsiella sp. MCI 2609 described in Japanese Patent Laid-Open No. 05-30982, Aeromonas sp. MCI 2614 described in Japanese Patent Laid-Open No. 05-30983, Citrobacter freundii MCI 2615 described in Japanese Patent Laid-Open No. 05-30984, Agrobacterium rhizogenes IAM 13570 and Agrobacterium faciens described in Japanese Patent Laid-Open No. 05-103681, Xanthobacter flavus JCM 1204 described in Japanese Patent Laid-Open No. 05-161495, Erwinia nigrifluens MAFF 03-01435, Enterobacter sp. MCI 2707 described in Japanese Patent Laid-Open No. 05-236975, Streptomyces sp. MCI 2691 described in Japanese Patent Laid-Open No. 05-236976, Rhizobium sp. MCI 2610 described in Japanese Patent Laid-Open No. 05-236977, and Rhizobium sp.MCI 2643, Rhizobium loti IAM 13588, Rhizobium leguminosarum IAM 12609, and Rhizobium merioti IAM 12611, Candida guilliermondii NH-2, Pantoea agglomerans NH-3, and Klebsiella pneumoniae NH-26T2 described in Japanese Patent Laid-Open No. 05-15384, Agrobacterium radiobacter SC-C15-1 described in Japanese Patent Laid-Open No. 06-14786, Bacillus smithii SC-J05-1 described in Japanese Patent Laid-Open No. 07-25494, Pseudonocardia thermophila ATCC 19285 described in Japanese Patent Laid-Open No. 08-56684, Pseudonocardia thermophila JCM 3095 described in Japanese Patent Laid-Open No. 09-275978, and the like.

[0080] The strain of Rhodococcus rhodochrous J-1 described in Japanese Patent No. 30655148 was deposited in the Patent Microorganism Depository, Independent Administrative Agency National Institute of Technology and Evaluation (1-1-3, Higashi 1-Chome, Tsukuba-shi, Ibaraki-ken, Japan) on September 18, 1987, under the accession number "FERM BP-1478".

[0081] The strain of Rhodococcus rhodochrous NCIMB 41164 described in International Publication No. WO2005 / 054456 was deposited in the National Collection of Industrial, Food and Marine Bacteria, Ltd. (NCIMB) (NCIMB Ltd Ferguson Building Craibstone Estate Bucksburn Aberdeen AB21 9YA) on March 5, 2003, under the accession number NCIMB 41164.

[0082] Pseudonocardia thermophila JCM 3095 described in Japanese Patent Laid-Open No. 09-275978 was deposited in the Patent Microorganism Deposit Center of the National Institute of Technology and Evaluation (1-1-1 Higashi, Tsukuba, Ibaraki) on February 7, 1996, under the accession number "FERM BP-5785".

[0083] In the present embodiment, one or more than two selected from the above-mentioned microorganisms having desired properties can be used alone or in combination.

[0084] The gene encoding the nitrile hydratase can be introduced into the microbial cell and expressed by a general molecular biology method (for the molecular biology method, see the following: Sambrook, Fritsch and Maniatis, "Molecular Cloning: A Laboratory Manual" 2nd Edition (1989), Cold Spring Harbor Laboratory Press). That is, in the present embodiment, an enzyme obtained by expressing a nucleic acid encoding a natural nitrile hydratase (wild type) or a mutant thereof (improved type) in the microbial cell can also be used.

[0085] In the present embodiment, one or more than two selected from the above-mentioned enzymes can be used alone or in combination.

[0086] The amino acid sequence of the wild type nitrile hydratase is disclosed in the database of NCBI (http: / / www.ncbi.nlm.nih.gov / ), and the like.

[0087] For example, the accession number of the α subunit derived from Rhodococcus rhodochrous Jl (FERM BP-1478) is "P21219", and that of the β subunit is "P21220". In addition, the accession number of the α subunit derived from Rhodococcus rhodochrous M8 (SU1731814) is "ATT79340", and that of the β subunit is "AAT79339". Further, the accession number of the α subunit derived from Pseudomonas thermophila JCM 3095 is "1IREA", and that of the β subunit is "1IREB".

[0088] As the transformant into which the wild-type nitrile hydratase gene is introduced, there are, for example, Escherichia coli MT10770 (FERM P-14756) transformed with nitrile hydratase of the genus Achromobacter (Japanese Patent Application Laid-Open No. 8-266277), Escherichia coli MT10822 (FERM BP-5785) transformed with nitrile hydratase of the genus Pseudonocardia (Japanese Patent Application Laid-Open No. 9-275978), or microorganisms transformed with nitrile hydratase of the genus Rhodococcus rhodochrous (Japanese Patent Application Laid-Open No. 4-211379), but are not limited to these.

[0089] There are known improved (mutant) nitrile hydratases in which amino acid substitution is performed on the wild-type nitrile hydratase (Japanese Patent Application Laid-Open No. 2010-172295, Japanese Patent Application Laid-Open No. 2007-143409, Japanese Patent Application Laid-Open No. 2007-043910, Japanese Patent Application Laid-Open No. 2008-253182, Japanese Patent Application Laid-Open No. 2019-088326, Japanese Patent Application Laid-Open No. 2019-088327, WO05 / 116206, WO12 / 164933, WO12 / 169203, WO15 / 186298, and the like).

[0090] In the method of the present embodiment, microorganisms into which these improved nitrile hydratases are introduced can also be used.

[0091] These microorganisms having nitrile hydratase activity or the processed products thereof can of course be used in the amidation reaction immediately after the preparation of the microbial cells, and can also be stored after the preparation of the microbial cells and used in the amidation reaction as needed. The method of culturing the microorganisms for the preparation of the microbial cells can be appropriately selected depending on the type of the microorganism. Seed culture can also be performed before the main culture.

[0092] The microbial cells of the microorganism having nitrile hydratase activity or the processed products thereof can be used in a batch reaction, and can also be used in a continuous reaction. In addition, the reaction form can be appropriately selected from a fluidized bed, a fixed bed, a suspended bed, and the like. The temperature of the catalyst in the reaction solution at this time is not particularly limited as long as it does not hinder the mixing of the aqueous medium and the nitrile compound.

[0093] As for the biological catalyst, a method for measuring the reaction speed of the biological catalyst, that is, whether the decrease in the hydration reaction speed of the nitrile compound is small even in the state in which the amid compound is accumulated, is exemplified. Here, acrylonitrile is used as the nitrile compound, and acrylamide is used as the amid compound.

[0094] A 100 mL aqueous solution containing 2 mass% of acrylonitrile and 0 mass% of acrylamide and a 100 mL aqueous solution containing 2 mass% of acrylonitrile and 47 mass% of acrylamide were prepared. To these, a catalyst solution containing a predetermined amount of catalyst was added, and the reaction was started.

[0095] After the start of the reaction, sampling was performed a plurality of times over a certain period of time. The sampling time can be set to, for example, 1 minute to 40 minutes, preferably 2 minutes to 30 minutes, and further preferably 3 minutes to 20 minutes. The sample solution was filtered with a filter, and phosphoric acid was added to stop the reaction. Then, the concentrations of acrylonitrile and acrylamide present in the reaction solution were measured using gas chromatography or liquid chromatography. From the obtained values, the conversion rate from the nitrile compound to the amide compound was calculated, and the speed ratio was obtained.

[0096] (2) Nitrile compound

[0097] The nitrile compound used as a raw material in the production method of the present embodiment is not particularly limited as long as it is a compound that is converted to an amide compound by a catalyst having nitrile hydratase activity. For example, aliphatic saturated nitriles such as acetonitrile, propionitrile, succinonitrile, and adiponitrile; aliphatic unsaturated nitriles such as acrylonitrile and methacrylonitrile; aromatic nitriles such as benzonitrile and phthalonitrile; and heterocyclic nitriles such as nicotinonitrile can be exemplified. The nitrile compound in the present embodiment is preferably a C2 to C4 nitrile compound such as acetonitrile, propionitrile, acrylonitrile, methacrylonitrile, n-butyronitrile, and isobutyronitrile, and particularly, acrylonitrile, methacrylonitrile, and acetonitrile show effects in the present embodiment.

[0098] In the case of a polymerizable nitrile compound such as (meth)acrylonitrile, a polymerization inhibitor is preferably added. As the polymerization inhibitor, stable radicals such as catechol, quinone, benzoquinone, and diphenyl picrylhydrazine; hindered amines; and phenothiazine can be exemplified. Among these, quinones are preferable, and hydroquinones are more preferable, and among these, methoxyhydroquinone and the like are further preferable.

[0099] The amount of the polymerization inhibitor to be added is not particularly limited, and can be appropriately selected depending on the kind of the nitrile compound, the kind of the polymerization inhibitor, the storage conditions, and the like. For example, in the case of using a quinone, 1 to 1000 ppm, and preferably 10 to 100 ppm, relative to acrylonitrile can be set.

[0100] In the case of using a quinone as the polymerization inhibitor, the polymerization inhibiting effect can be sufficiently exerted by the presence of oxygen.

[0101] Therefore, as the nitrile compound used in the present application, a nitrile compound that has been stored in the presence of dissolved oxygen and a quinone-based polymerization inhibitor is preferably used. In order to make dissolved oxygen present in the solution, when the nitrile compound is stored in a solution, it is preferable to contain a quinone-based polymerization inhibitor in the solution, and to store it in a state in which 1 to 10% by volume of oxygen is present in the gas phase portion of the storage container.

[0102] (3) Raw water

[0103] The water used as a raw material (raw water) is used for the hydration reaction with acrylonitrile when acrylamide is produced. As the water, pure water; an aqueous solution obtained by dissolving an acid, a salt, or the like in water; or the like can be exemplified. As the acid, phosphoric acid, acetic acid, citric acid, boric acid, acrylic acid, formic acid, or the like can be exemplified. As the salt, sodium salt, potassium salt, ammonium salt, or the like of the acid can be exemplified. As the specific examples of the water, there is no particular limitation, and, for example, pure water, ultrapure water, tap water, or the like; a buffer solution such as Tris buffer, phosphoric acid buffer, acetic acid buffer, citric acid buffer, boric acid buffer, or the like can be exemplified. The pH (20°C) of the raw water is preferably 5 to 9. The raw water can contain dissolved oxygen. The dissolved oxygen has an effect of inhibiting the polymerization of the nitrile compound as a raw material and the amide compound as a product, and thus it is not necessary to remove the dissolved oxygen by means such as aeration.

[0104] (4) Production of amide compound from nitrile compound using biocatalyst

[0105] The method for producing an amide compound from a nitrile compound using a biocatalyst having nitrile hydratase activity, which is related to the present embodiment, can be any one of a batch reaction, a semi-batch reaction, a multi-tank continuous reaction, a reaction using a pipe reactor, or the like.

[0106] In the case of using a batch reaction or a semi-batch reaction, it has an advantage that, particularly in the latter half, since the gas phase concentration of the nitrile compound is significantly reduced, it is possible to limit the time with high risk to the initial stage of the reaction.

[0107] The so-called multi-tank continuous reaction is a reaction in which a device having a plurality of continuous reaction tanks is used, raw materials (containing a nitrile compound, water (raw water), and a biocatalyst) are continuously or intermittently supplied to the reaction tanks, the reaction mixture (hereinafter also referred to as "reaction liquid") in the reactor is not all taken out, but is continuously or intermittently taken out while being transferred to the next reaction tank, and the reaction is performed.

[0108] In the multi-tank continuous reaction, since a plurality of reaction tanks is used, it has an advantage that it is possible to limit the region with high risk (for example, a tank in which fire or explosion is likely to occur).

[0109] The device used in the multi-tank continuous reaction has two or more reactors connected in series, and an amide compound is produced from a nitrile compound and water by a continuous reaction using a biocatalyst in each reactor. In more detail, in the continuous reaction device, a method in which raw materials for reaction are added to the reactor located at the most upstream side and the reactor connected thereto to start the reaction, and the reaction is performed while the reaction liquid is moved to the reactors located at the downstream side in order can be exemplified. Then, the reaction liquid containing the produced acrylamide is recovered from the reactor located at the most downstream side.

[0110] The number of reactors is not particularly limited and can be appropriately selected depending on the reaction conditions and the like. For example, it is preferable that the number of reactors be 2 to 20, more preferable 2 to 12, further preferable 2 to 10, and further preferable 2 to 8. In the reactors, reactors connected in parallel can be present as needed. The reactors can be independent reactors or reactors divided by a partition wall into a plurality of reactors. In the case of reactors divided by a partition wall, each space divided by the partition wall is regarded as one reactor.

[0111] The tank in which the supply of the nitrile compound, the biocatalyst, the raw material water, and other additives is performed is not limited to one tank at the most upstream side, but can be one tank or a plurality of tanks. The tank at the latter half (downstream side) is used for the reaction cut-off and maturation, and the reaction solution containing the product can be taken out from the tank at the most downstream side (the final tank) or a tank present at the upstream side thereof.

[0112] The number of tanks in which the supply of the raw material is performed and the number of tanks in which maturation and the like are performed can be appropriately selected depending on the reaction conditions, the reaction scale, and the like.

[0113] The form of the reactor is not particularly limited, and various forms of reactors such as a stirring type, a fixed layer type, a flow layer type, a moving layer type, a column type, and a pipe type can be used. Among them, a stirring type in which the dispersion and mixing of the raw material are promoted is preferable. Different forms of reactors can be combined and connected.

[0114] As the stirring device, a stirring blade is preferable. The shape of the stirring blade is not particularly limited, and for example, a paddle, a disc turbine, a propeller, a spiral belt, an anchor, a Pfaudler, and the like can be exemplified.

[0115] As one embodiment of the present mode, for example, in the case where acrylonitrile as a nitrile compound is used as a raw material to produce acrylamide, both acrylonitrile and acrylamide are compounds that easily polymerize. Polymerization is an exothermic reaction, and once polymerization starts, it is not easy to stop, and thus a serious disaster can occur.

[0116] In order to prevent polymerization, even if the temperature of the entire reaction system is lowered to, for example, 10°C or less, since the flash point of acrylonitrile is 0°C, there is still a possibility of fire or explosion. In addition, at a low temperature, a sufficient reaction rate based on the biocatalyst cannot be obtained. Furthermore, the produced acrylamide is easily precipitated by crystallization at a low temperature.

[0117] On the other hand, in the case where the reaction is performed at a temperature at which a sufficient reaction rate can be obtained, for example, at a temperature of about 20 to 30°C, if the amount of acrylonitrile added to the reaction solution is reduced in order to suppress the amount of volatilization of acrylonitrile, a sufficient productivity cannot be obtained.

[0118] Therefore, the preferred embodiments and conditions of the present mode will be described below.

[0119] In the reaction tank in which the hydration reaction of the nitrile compound is carried out, it is important to adjust the oxygen concentration in the gas phase portion. More specifically, at least in the case where the concentration of the nitrile compound in the gas phase portion of the reaction tank containing the reaction liquid is included in the explosive range, it is necessary to carry out the reaction under the condition that the oxygen concentration in the gas phase portion of the reaction tank becomes 10% by volume or less. Here, the total volume of the gas phase portion of the reaction tank is the volume obtained by subtracting the volume of the reaction liquid (liquid phase) from the total volume of the reaction tank.

[0120] By making the oxygen concentration in the gas phase portion of the reaction tank 10% by volume or less, it is possible to suppress the ignition or explosion of the nitrile compound as a raw material. The oxygen concentration is preferably 1 to 10% by volume, and more preferably 1 to 5% by volume.

[0121] In the present specification, the terms "volume%", "volume", and "volume" are not distinguished unless otherwise specified, and are terms that can be converted to each other.

[0122] In addition, in the present specification, the term "explosion range" means the concentration region sandwiched between the upper limit of the concentration of the nitrile compound that causes explosion as the upper limit of explosion and the lower limit of the concentration as the lower limit of explosion. For example, in the case of acrylonitrile as the nitrile compound, the "explosion range" is 3.0 to 17.0% by volume.

[0123] In the production method of the present embodiment, it is preferable that the concentration of the nitrile compound in the reaction liquid satisfy the following formula (1).

[0124] Y ≤ 50X - 35 (mass%) (1)

[0125] (wherein X represents the concentration (mass%) of the nitrile compound with respect to the total mass of the reaction liquid, and Y represents the concentration (mass%) of the amide compound with respect to the total mass of the reaction liquid.)

[0126] In addition, in the case where the following (1) or (2) is satisfied, by adjusting the oxygen concentration in the gas phase portion of the reaction tank to 10% by volume or less, it is possible to more reliably suppress the ignition or explosion of the nitrile compound as a raw material.

[0127] (1) The concentration of the nitrile compound with respect to the total mass of the reaction liquid is 1.7 mass% or more.

[0128] (2) the concentration X of the nitrile compound with respect to the total mass of the reaction liquid is 0.7 mass% or more and less than 1.7 mass%, and Y ≤ 50X - 35 (mass%) is satisfied (where X represents the concentration X, and Y represents the concentration of the amide compound with respect to the total mass of the reaction liquid (unit: mass%)).

[0129] Here, the above (2) is derived from the concentration of the nitrile compound and the amide compound having a flash point of 40°C or less, and is made based on the obtained concentration. The flash point is measured by a publicly known method such as Cleveland open, Tag closed, Seta, or the like. On the other hand, since it takes labor to actually measure all of a wide range of compositions, the concentration of the nitrile compound in the gas phase can be measured by changing the temperature and using a detector tube, a gas chromatograph, and the like, and it is determined whether it falls within the explosive composition based on the composition, or the flash point is estimated based on the gas-liquid equilibrium calculated by Wilson, or the like.

[0130] For example, in the case where acrylonitrile as the nitrile compound is used to produce acrylamide as the amide compound, in a reaction liquid containing a 3-component system of water-acrylonitrile-acrylamide, the flash point of acrylonitrile is higher than 40°C when the concentration of acrylonitrile is less than 0.7 mass%. That is, if the concentration of acrylonitrile contained in the reaction liquid is made to be less than 0.7 mass%, the production of the amide compound can be safely performed even if the temperature of the reaction liquid is set to be less than 40°C, for example, 20 to 30°C.

[0131] Here, regarding the above flash point, the acrylonitrile vapor pressure of the mixed liquid can be calculated by Wilson-RK method using ASPEN plus of ASPENTEC Co. in a high concentration region. The acrylonitrile concentration in the gas phase portion is calculated by a detector tube in a low concentration region of 200 ppm or less. It is preferable to confirm that they do not contradict each other. Further, the flash point is calculated based on the lower limit of the explosive range of the publicly known acrylonitrile explosive range data.

[0132] In the above reaction liquid, in the case where the concentration of acrylonitrile is 1.7 mass% or more, the flash point of acrylonitrile is 40°C or less regardless of the concentration of acrylamide, and the risk of fire or explosion of acrylonitrile becomes high. Therefore, it is preferable to adjust the oxygen concentration contained in the gas phase portion to be 10% or less with respect to the total capacity of the gas phase portion of the reaction tank. Thereby, the amide compound can be safely produced.

[0133] In the case where the concentration of acrylonitrile in the above reaction liquid is 0.7 mass% or more and less than 1.7 mass%, the flash point of acrylonitrile is lower than 40°C in the case where Y ≤ 50X - 35 (X represents the concentration of the nitrile compound in the reaction liquid (unit: mass%), and Y represents the concentration of the amide compound in the reaction liquid (unit: mass%)). Therefore, the concentration of oxygen contained in the gas phase portion is preferably adjusted to 10% or less with respect to the total volume of the gas phase portion of the reaction tank. Thus, the amide compound can be safely produced.

[0134] The method of adjusting the oxygen concentration of the gas phase portion of the reaction tank is not particularly limited, and for example, the oxygen concentration can be adjusted by flowing an inactive gas into the gas phase portion of the reaction tank.

[0135] The kind of the inactive gas to be flowed in is not particularly limited, and for example, nitrogen, argon, neon, helium, krypton, xenon, radon, or the like can be used. These inactive gases can be used alone or in combination with two or more kinds. The device and method for flowing the inactive gas are not particularly limited, and can be appropriately selected depending on the reaction device, the reaction scale, or the like.

[0136] The reaction to be subjected to the adjustment of the oxygen concentration of the gas phase portion is not particularly limited, and can be applied to any of batch reaction, semi-batch reaction, multi-tank continuous reaction, and reaction using a pipe-type reactor.

[0137] The reaction tank to be subjected to the adjustment of the oxygen concentration of the gas phase portion is not particularly limited, and all of the reaction tanks used can be subjected to the adjustment, or a part of the reaction tanks used can be subjected to the adjustment.

[0138] For example, in the case where the amide compound is produced by the multi-tank continuous reaction, a plurality of reaction tanks are used. In this case, the oxygen concentration of the gas phase portion can be adjusted in all of the reaction tanks, or the oxygen concentration of the gas phase portion can be adjusted in the reaction tank in which the amount of volatilization of the nitrile compound is large, such as the reaction tank in which the nitrile compound is added. That is, the oxygen concentration of the gas phase portion can be adjusted in the reaction tank present on the upstream side of the reaction, and the oxygen concentration of the gas phase portion can not be adjusted in the reaction tank present on the downstream side of the reaction in which the amount of the nitrile compound remaining in the reaction liquid (or the gas phase portion) is small.

[0139] A water-soluble monocarboxylic acid salt having a carbon number of 2 or more can be added to the reaction liquid. The timing of adding the water-soluble monocarboxylic acid salt is not particularly limited, and the water-soluble monocarboxylic acid salt can be added to the reactor located on the most upstream side so as to move the water-soluble monocarboxylic acid salt contained in the reaction liquid to the downstream side together with the reaction liquid, thereby allowing the water-soluble monocarboxylic acid salt to be contained in the reaction liquid in each reactor. Alternatively, the water-soluble monocarboxylic acid salt can be added to each reactor before or after the start of the reaction.

[0140] By adding the water-soluble monocarboxylic acid salt having a carbon number of 2 or more, the stability of the acrylamide in the reaction liquid can be improved.

[0141] The water-soluble monocarboxylic acid salt can be any one of a saturated monocarboxylic acid salt and an unsaturated monocarboxylic acid salt. As the saturated carboxylic acid, acetic acid, propionic acid, n-hexanoic acid, and the like can be exemplified. As the unsaturated carboxylic acid, acrylic acid, methacrylic acid, and the like can be exemplified. As the salt, sodium salt, potassium salt, ammonium salt of the above-mentioned saturated monocarboxylic acid or unsaturated monocarboxylic acid can be exemplified. These water-soluble monocarboxylic acid salts can be used singly or in combination of two or more.

[0142] The amount of the water-soluble monocarboxylic acid salt to be added is preferably 20 to 5000 mg / kg, in terms of acid, relative to the acrylamide produced.

[0143] The pH of the reaction for hydrating acrylonitrile to produce acrylamide is preferably 6 to 9, more preferably 7 to 8.5. The pH measurement method includes indicator method, metal electrode method, glass electrode method, semiconductor sensor method, and the like, and the measurement is preferably performed using the glass electrode method which is widely used in industry.

[0144] The reaction temperature (temperature of the reaction solution) at the time of hydrating acrylonitrile is not particularly limited, and is preferably 10 to 50°C, more preferably 15 to 45°C, and further preferably 20 to 40°C. By setting the reaction temperature to 10°C or higher, the reaction activity of the biocatalyst can be sufficiently increased. In addition, by setting the reaction temperature to 50°C or lower, the inactivation of the biocatalyst can be prevented. In addition, in order to reduce the heat removal load of the reactor, the water or acrylonitrile to be supplied is preferably supplied at 5°C or more lower than the reaction temperature.

[0145] In the present embodiment, in the case where a batch reaction is used, the time taken for the concentration of the nitrile compound in the reaction solution at the start of the reaction to decrease to 50% or less is preferably 1.5 hours or less, more preferably 1.2 hours or less, more preferably 1 hour or less, more preferably 45 minutes or less, and further preferably 30 minutes or less.

[0146] In addition, in the case where a semi-batch reaction, a multi-tank continuous reaction, or a pipe reactor is used, the time taken for the concentration of the nitrile compound in the reaction solution at the time when the addition of the nitrile compound is ended or interrupted to decrease to 50% or less, or the time taken for the concentration of the nitrile compound in the reaction solution at the start of the reaction to decrease to 50% is preferably 1.5 hours or less, more preferably 1.2 hours or less, more preferably 1 hour or less, more preferably 45 minutes or less, and further preferably 30 minutes or less.

[0147] In either case, the reaction proceeds, and the amide compound gradually accumulates in the reaction liquid, but even in the presence of the amide compound in the reaction liquid, the time taken for the concentration of the nitrile compound in the reaction liquid at the time when the addition of the nitrile compound is ended or interrupted to decrease to 50% or less of the concentration of the nitrile compound in the reaction liquid at the time when the reaction is started, or the time taken for the concentration of the nitrile compound in the reaction liquid at the time when the addition of the nitrile compound is ended or interrupted to decrease to 50% or less of the concentration of the nitrile compound in the reaction liquid at the time when the reaction is started, is preferably 1.5 hours or less, more preferably 1.2 hours or less, more preferably 1 hour or less, more preferably 45 minutes or less, and further preferably 30 minutes or less.

[0148] In order to convert the nitrile compound into the amide compound at a faster reaction rate like this, there are not only a method of using a large amount of catalyst, a method of additional addition of catalyst, a method of using an enzyme having a high nitrile hydratase activity or a biocatalyst containing the same, but also a method of using a catalyst which is not easily hindered by a high concentration of the amide compound.

[0149] The activity of the catalyst is actually compared by the unit, not by the actual weight of the catalyst. On the other hand, the less the actual amount added, the more advantageous in terms of removal of the catalyst and the like after the reaction is ended.

[0150] Therefore, it is preferable to use a catalyst which has a high activity and is less hindered by the amide compound. More specifically, it is preferable to produce the amide compound at a catalyst amount of preferably 2.0 g or less, more preferably 1.0 g or less, more preferably 0.50 g or less, more preferably 0.40 g or less, more preferably 0.35 g or less, further preferably 0.30 g or less, relative to 1 kg of the amide compound.

[0151] In the case where the addition of the nitrile compound is interrupted, it is preferable to leave an interval of 1.5 hours or more, preferably 1 hour or more, more preferably 45 minutes or more, before the addition of the nitrile compound is restarted. This is because the concentration of the nitrile compound in the reaction liquid can be sufficiently decreased.

[0152] After the addition of the nitrile compound is ended, it is preferable to continue the reaction for 1.5 hours or more, preferably 1 hour or more, more preferably 45 minutes or more. Also, this is because the concentration of the nitrile compound in the reaction liquid can be sufficiently decreased.

[0153] The total amount of the addition of the acrylonitrile is determined by the final concentration of the acrylamide, but the final acrylamide concentration is 30% by mass or more, preferably 40% by mass or more, and more preferably 45% by mass or more.

[0154] By being performed at a saturation solubility of acrylonitrile in water to a maximum concentration of 7% or less, the reaction in a homogeneous system becomes possible, but is not limited thereto.

[0155] At the end of the supply of acrylonitrile, the concentration of acrylonitrile in water decreases from that time. If this decrease is sharp, the evaporation of acrylonitrile and the risk of fire and explosion of acrylonitrile in the gas phase decrease accordingly.

[0156] As to the effect thereof, in the intermittent reaction or semi-intermittent reaction, the maturation time in the latter half of the reaction is obtained, and in the continuous reaction, the portion in which the reaction maturation of the latter half of the reaction device is performed is obtained. The more sharply the concentration of acrylonitrile decreases, the more the dangerous region or the dangerous time is limited.

[0157] For example, the flash point of an aqueous solution containing 48% of acrylamide and 2% of acrylonitrile under the atmosphere is 37°C, but the flash point of water containing 49% of acrylamide and 1% of acrylonitrile sharply rises to 56°C, and along with this, the safety also improves.

[0158] The acrylonitrile partial pressure is also the value in water at 25°C, and is 3.8 hundred Pa at 2% of acrylonitrile, and halves to 1.9 hundred Pa at 1% of acrylonitrile, and thus the loss and the like are also reduced.

[0159] Note that the atmosphere refers to the standard composition of the earth's atmosphere containing about 21% of oxygen.

[0160] As one embodiment of the present mode, in a method of producing an amide compound by causing a nitrile compound to undergo a hydration reaction in a reaction liquid (hereinafter, sometimes also referred to as "reaction liquid Z") in the presence of a biological catalyst having nitrile hydratase activity, the biological catalyst, for example, contains an enzyme having nitrile hydratase activity, and can be added in the form of a living bacterium surviving in the reaction liquid Z or in the form of a resting bacterium body by medicating in a manner not losing the enzyme activity.

[0161] When the biological catalyst is added in an arbitrary predetermined amount in the following reaction liquid A and the following reaction liquid B, respectively, the biological catalyst preferably exhibits the following properties. That is, the hydration reaction rate in the following reaction liquid A is preferably S1, and the hydration reaction rate in the following reaction liquid B is S2, and the reaction rate ratio represented by S1 / S2 is 0.2 or more. The reaction rate ratio is more preferably 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, in this order.

[0162] As a specific example of such a biological catalyst, J1 bacteria used in the examples described later can be cited.

[0163] [Reaction liquid A] A reaction liquid at 20°C (may be 19 to 21°C), containing 47% by mass (may be 46 to 48% by mass) of the amide compound, 2.0% by mass (may be 1.9 to 2.1% by mass) of the nitrile compound, and the remainder water, with respect to the total mass of the reaction liquid.

[0164] [Reaction liquid B] A reaction liquid at 20°C (may be 19 to 21°C) containing 0 mass% of the amide compound, 2.0 mass% (may be 1.9 to 2.1 mass%) of the nitrile compound, and the rest of water, with respect to the total mass of the reaction liquid.

[0165] The hydration reaction rates S1 and S2 in the reaction liquids A and B are values obtained by taking the time when the biocatalyst is added in a predetermined amount and stirred in the reaction liquids A and B as the reaction start time, sampling a part of the reaction liquids A and B after 10 minutes, and measuring the amount of the amide compound generated in 10 minutes.

[0166] The mass of water contained in the reaction liquids A and B is the mass remaining after the mass of the components other than water is removed from the total mass of the reaction liquid. The reaction liquids A and B can contain any component other than the nitrile compound and the amide compound, or can not contain any component. As the any component, a pH buffer is preferable. The concentration of the pH buffer can be, for example, 0.1 mM to 200 mM.

[0167] By using the biocatalyst having a reaction rate ratio of 0.2 or more, the nitrile compound in the reaction liquid Z can be rapidly consumed, and the flash point of the reaction liquid Z can be rapidly increased. Thus, in at least one reaction tank in which the reaction liquid Z is charged, the hydration reaction can be rapidly shifted to a temperature higher than the flash point of the reaction liquid Z in the composition of the atmosphere.

[0168] The preferred nitrile compound fed to the reaction liquid Z of the present embodiment can be one or two or more, and is preferably at least one of acrylonitrile and methacrylonitrile.

[0169] The amide compound generated in the reaction liquid Z of the present embodiment preferably has an unsaturated bond, and is preferably at least one of acrylamide and methacrylamide.

[0170] The amount of the nitrile compound fed (added) to the reaction liquid Z can be, for example, 0.10 to 50 mass% with respect to the total mass of the reaction liquid Z put in a predetermined reaction tank, preferably 1.0 to 45 mass%, more preferably 2.0 to 40 mass%, and further preferably 2.0 to 37 mass%. Here, the total mass of the reaction liquid Z includes the mass of the fed nitrile compound.

[0171] If it is more than the lower limit value of the above range, the manufacturing efficiency of the amide compound is improved, and the concentration of the product amide compound is improved.

[0172] Further, if it is less than the upper limit value of the above range, the concentration of the amide compound in the aqueous solution becomes in the preferable range.

[0173] The content of the nitrile compound contained in the reaction liquid Z is reduced as the reaction proceeds, and is, for example, 0.0001% by mass (1 ppm) to 50% by mass, 2 ppm to 45% by mass, 5 ppm to 40% by mass, or 10 ppm to 37% by mass, with respect to the total mass of the reaction liquid Z put into the predetermined reaction tank.

[0174] The amount of water contained in the reaction liquid Z can be, for example, 10.0 to 99.9% by mass, preferably 20.0 to 99.5% by mass, more preferably 30.0 to 80.0% by mass, and further preferably 40.0 to 70.0% by mass, with respect to the total mass of the reaction liquid Z contained in the predetermined reaction tank.

[0175] If it is higher than the lower limit of the above range, the operability of the generated amide compound is good.

[0176] In addition, if it is lower than the upper limit of the above range, the efficiency of the hydration reaction of the nitrile compound and the efficiency of the product amide compound stream and the like are improved.

[0177] The reaction temperature of the reaction liquid Z can be higher than the flash point of the reaction liquid Z under the composition of the atmosphere.

[0178] As an example, in the case of batchwise progress in which the nitrile compound is fed into the reaction liquid Z once, the hydration reaction of the nitrile compound in the reaction liquid Z proceeds, and the concentration of the nitrile compound decreases, and the flash point of the reaction liquid Z rises. That is, there is a tendency that the concentration of the nitrile compound is high and the flash point is low in the early to middle stages of the reaction. The reaction temperature can be higher than the flash point during this period. In addition, in the late to final stages of the reaction, the flash point of the reaction liquid Z rises, and thus the reaction temperature during this period can be lower than the flash point after the rise.

[0179] As another example, in the case of non-batchwise (continuous) progress in which the nitrile compound is continuously or in multiple times fed into the reaction liquid Z, the reaction can be performed at a temperature higher than the flash point of the reaction liquid Z in a stable period in which the balance between the supply and consumption (generation of the amide compound) of the nitrile compound is obtained and the reaction is stabilized. In addition, in the case of non-batchwise progress in which a plurality of reaction tanks are connected in series, the concentration of the nitrile compound in each reaction tank can be independently controlled, managed, and measured. In at least one of the plurality of reaction tanks, the reaction can be performed at a temperature higher than the flash point of the reaction liquid Z.

[0180] The flash point of the reaction liquid Z is measured by a publicly known method such as Cleveland open type, Tag closed type, Seta type, and the like. On the other hand, since it takes labor to actually measure all of a wide range of compositions, the concentration of the nitrile compound in the gas phase can be measured by changing the temperature and using a detection tube, a gas chromatograph, and the like, and the flash point can be estimated based on whether the composition falls within the explosive composition or not.

[0181] The time during which the reaction is carried out at a temperature higher than the flash point of the reaction liquid Z in the entire reaction time (e.g., 10 minutes to 100 hours) of the reaction liquid Z can be 0.1% or more, 1% or more, 5% or more, 10% or more, 20% or more, or 30% or more. The upper limit of this time is not particularly limited, and the shorter the time, the higher the safety, but 90% or less is standard.

[0182] The temperature of the reaction liquid Z, i.e., the reaction temperature, can be controlled, managed, and measured by a temperature control device installed in a reaction tank containing the reaction liquid Z. As the temperature control device, a heater, a Peltier element, a thermostat, or the like can be exemplified.

[0183] In the reaction liquid Z, the time required for the mass (content) or concentration of the nitrile compound at an arbitrary time to be halved is preferably 1.5 hours or less, more preferably 1.2 hours or less, more preferably 1.0 hour or less, more preferably 45 minutes or less, and further preferably 30 minutes or less. The shorter the time required for halving, the more the flash point of the reaction liquid Z can be increased in a short time, and the higher the safety.

[0184] Here, the arbitrary time is not particularly limited, and, for example, the time when the feeding (adding) of the total amount of the nitrile compound in a batch system is completed or the time when the reaction is stabilized in a continuous system can be exemplified. Note that the mass or concentration of the nitrile compound decreases due to the reaction of the nitrile hydratase to generate the amide compound. The mass or concentration can be determined by, for example, a conventional method such as gas chromatography or liquid chromatography by sampling a small amount of the reaction liquid Z.

[0185] In the case where the biocatalyst added to the reaction liquid Z is a cell, the amount of the cell added to the reaction liquid Z can be grasped as an amount relative to 1 kg of the amide compound generated in the reaction liquid Z. In the case where the product is constant, the smaller the amount of the biocatalyst added to the reaction liquid Z, the more economical and the higher the manufacturing efficiency.

[0186] In the present embodiment, the amount of the cell as the biocatalyst added to the reaction liquid Z relative to 1 kg of the amide compound generated in the reaction liquid Z is preferably 2.0 g or less, more preferably 1.0 g or less, more preferably 0.50 g or less, more preferably 0.40 g or less, more preferably 0.35 g or less, and further preferably 0.30 g or less.

[0187] Here, the amount of the amide compound generated in the reaction liquid Z can be calculated by determining the amount of the amide compound contained in the reaction liquid Z at the end of the reaction in a batch system by a conventional method such as gas chromatography or liquid chromatography.

[0188] Example

[0189] The present application will be described more specifically by Examples and Comparative Examples below, but the present application is not limited to the following Examples. In the Examples, "%" means "mass %".

[0190] [Preparation of biocatalyst]

[0191] (1) Preparation of cell catalyst derived from Rhodococcus rhodochrous Jl

[0192] Pre-culture conditions:

[0193] (Culture medium composition)

[0194] Fructose: 2%, poly-peptone: 5% (Nippon Pharmaceutical Co., Ltd.), yeast extract: 0.3% (Oriental Yeast Co., Ltd.), KH2PO4: 0.1%, K2HPO4: 0.1%, MgSO4 H2O: 0.1%, pH 7.

[0195] (Culture method)

[0196] Into a 500 mL Erlenmeyer flask, 100 mL of the culture medium was dispensed, and sterilized with a cotton plug in an autoclave at 121°C for 20 minutes. Rhodococcus rhodochrous Jl (FERM BP-1478) was inoculated, and cultured at 30°C with shaking for 48 hours.

[0197] Main culture conditions:

[0198] (Culture medium composition)

[0199] Initial culture medium: yeast extract: 0.2%, KH2PO4: 0.1%, K2HPO4: 0.1%, MgSO4-7H2O: 0.1%, CoCl2-6H2O: 0.002%, ammonium sulfate: 0.025%, fructose: 2%, urea: 2%, ethanol: 0.4%, Pluronic L61: 0.1% (Asahi Denka Kogyo K.K.), pH 7. Note that "Pluronic" is a registered trademark.

[0200] Post-addition culture medium: fructose: 20%, ethanol: 5%, ammonium sulfate: 6%, pH 6.5.

[0201] (Culture method)

[0202] The initial medium 2 L was divided into 3 L of a small-scale fermenter and sterilized with an autoclave at 121°C for 20 minutes. Of these, fructose, ethanol, and urea were separately sterilized by filtration (using ADVANTEC Toyo Kaisha, Ltd. 0.45 μm filter paper) and added to the medium. Culturing was performed at a tank pressure of 0.098 MPa, a stirring number of 600 rpm, a gas flow rate of 1 VVM, a pH of 7, and a temperature of 30°C, and a small amount of the culture solution was sampled midway. The sample was appropriately diluted with a buffer solution, added to an acrylonitrile aqueous solution, allowed to react, filtered with a disk filter, and the amount of acrylamide (AAM) produced was measured with a gas chromatograph (Porapak column, column temperature 210°C, FID detector), whereby the activity of the nitrile hydratase (reaction rate per unit of the culture solution per unit time) was determined. The culturing was ended at a time when the activity of the nitrile hydratase no longer increased.

[0203] Then, the cells were washed with 50 mM of a phosphate buffer (pH 7.7) to obtain a cell suspension having a dry cell weight of 15%. Hereinafter, the cells obtained here will be referred to as "Jl cells".

[0204] (2) Comparison of the hydration reaction rates in the absence / presence of an amide compound

[0205] A reaction solution 100 mL containing an initial AN concentration of 2%, an initial AAM concentration of 0% or 47%, a phosphate-based pH buffer, and water (initial pH 7.0) was prepared and set at 20°C. The hydration reaction of AN was started (20°C) by adding 0.5 mL of the cell suspension described below to the reaction solution and stirring. The reaction solution was sampled after 10 minutes of the reaction, and the amount of AAM produced was measured.

[0206] As the cell suspension, a Jl cell suspension (cell concentration (as dry cells): 4.11 g / L) was used.

[0207] (The cell concentration was calculated by dividing the weight of the residue after drying at 125°C for 3 hours by the sample amount.)

[0208] The reaction rate ratio of the hydration reaction rate S1 of AN in the reaction solution A prepared above, which had an initial AAM concentration of 47%, to the hydration reaction rate S2 of AN in the reaction solution B prepared above, which had an initial AAM concentration of 0%, is represented by S1 / S2 and was 0.60.

[0209] Note that the hydration reaction rates S1 and S2 were calculated from the amount of AAM produced 10 minutes after the time when the cell suspension was added to the reaction solutions A and B and stirred.

[0210] <Example 1>

[0211] The production of acrylamide was carried out by a semi-batch reaction according to the following procedure.

[0212] Into a 3L reactor, 300 mL of water and 100 mg (1.25 g as slurry) of Jl bacteria as a biological catalyst were put as a dry bacterial body. The amount of the dry bacterial body was 0.38 g per 1 kg of acrylamide produced. Then, 194 g of acrylonitrile (hereinafter, sometimes written as "AN"; containing methoxyhydroquinone 45 ppm) was slowly put over 3.23 hours. In the reaction liquid, the temperature was set to 35°C, and the reaction was carried out in such a manner that the pH was adjusted to 7 with 1% sodium hydroxide aqueous solution.

[0213] The reaction which started immediately after the start of the feed was initially continued with the circulation of nitrogen gas in the reactor in an amount equivalent to the air volume of the gas phase portion, so that the oxygen concentration of the gas phase portion was 10 vol% relative to the total volume of the gas phase portion, and the ignition of AN in the gas phase portion was prevented. The concentration transition of AN is shown in Table 1.

[0214] As for the AN concentration of the liquid phase and the acrylamide (AAM) concentration of the liquid phase, the reaction liquid was collected and appropriately diluted, and then measured with a gas chromatograph (column PoraPack-PS (Waters) 1 m, column temperature 210°C, carrier gas: helium, FID detector) respectively.

[0215] The gas phase AN concentration was calculated from the liquid phase composition by Wilson RK method using ASPEN Plus of ASPEN Tech Co. Further, the low concentration of 300 ppm or less was actually measured using an AN detection tube, and it was confirmed that there was no large deviation. Based on this, the gas phase flash point was found based on whether the AN concentration in the gas phase fell within the lower limit of the explosion range (3%).

[0216] The gas phase oxygen concentration was calculated from the amount of nitrogen flowing in.

[0217] [Table 1]

[0218]

[0219] In the AN feed, the gas phase portion was filled with a mixed gas of nitrogen and air, and the oxygen concentration thereof was maintained at 10 vol%. The relationship of the formula (Y < 50X - 35) was satisfied in the AN feed. At the time of reaction 2.90 hours and reaction 3.23 hours, the reaction liquid temperature was higher than the gas phase flash point, and it was a dangerous region, but by carrying out the reaction with the oxygen concentration of the gas phase portion being 10%, it was possible to safely operate.

[0220] The AN concentration of the reaction liquid (liquid phase) was reduced to about 1 / 4 from 3.19% at the time of completion of the feed to 0.80% after about 30 minutes after the completion of the feed. The flash point of the gas phase at the time of 30 minutes was 63°C, and the AN concentration in the gas phase was about 9.8 hPa.

[0221] The nitrogen gas introduction was stopped when the AN concentration of the liquid phase reached 0.80%, the gas phase portion was filled with air, and the reaction was continued.

[0222] The AN concentration of the liquid phase decreased to 0.39% or less about 0.77 hours after the completion of the feed, the flash point of the gas phase also rose to 95°C or more, and the AN concentration in the gas phase became 4.9 hPa.

[0223] The AN concentration of the liquid phase decreased to 0.10% or less about 1.27 hours after the completion of the feed.

[0224] The reaction of Example 1 was repeated 5 times, and all of them could be operated stably and safely.

[0225] [Example 2]

[0226] The oxygen concentration of the gas phase portion was changed as described below, and otherwise, the AN was hydrated to produce AAM as in Example 1. That is, the reaction started immediately after the start of the feed initially caused nitrogen gas to continuously flow in the reactor at 3 times the air volume of the gas phase portion, so that the oxygen concentration of the gas phase portion was 5% by volume relative to the total volume of the reaction tank, and the ignition of AN in the gas phase portion was prevented.

[0227] The results of the concentration transition of AN and the like are shown in Table 2.

[0228] [Table 2]

[0229]

[0230] In the AN feed, the gas phase portion was filled with a mixed gas of nitrogen gas and air, and the oxygen concentration thereof was maintained at 5% by volume. The relationship of the formula (Y < 50X - 35) was satisfied in the AN feed. At 2.90 hours of the reaction and 3.23 hours of the reaction, the reaction liquid temperature was higher than the gas phase flash point, and it was a dangerous region, but by causing the oxygen concentration of the gas phase portion to be 10%, the reaction could be operated safely.

[0231] The AN concentration of the reaction liquid (liquid phase) decreased to 0.83% or less about 30 minutes after the completion of the feed from 3.15% at the time of the completion of the feed. The flash point of the gas phase at the time of 30 minutes was 63°C, and the AN concentration in the gas phase was about 10.2 hPa. The nitrogen gas introduction was stopped when the AN concentration of the liquid phase reached 0.83%, the gas phase portion was filled with air, and the reaction was continued.

[0232] The AN concentration of the liquid phase decreased to 0.42% about 0.77 hours after the completion of the feed, the flash point of the gas phase also rose to 95°C or more, and the AN concentration in the gas phase became 5.3 hPa.

[0233] The AN concentration of the liquid phase decreased to 0.1% or less about 1.27 hours after the completion of the feed. The reaction of Example 2 above was repeated 5 times, and all of them were able to operate stably and safely.

[0234] The results of Examples 1 and 2 are summarized as follows: In the stage where the AN concentration of the reaction liquid is relatively high, there is a tendency that the AN concentration of the gas phase portion of the reaction tank becomes high and the flash point becomes low, so nitrogen is made to flow into the gas phase portion so that the oxygen concentration becomes 10 vol% or less, more preferably 5 vol% or less. Thereby, it is confirmed that the flash point of the gas phase portion is raised and the safety is improved.

[0235] [Example 3]

[0236] The production of AAM was carried out by a continuous reaction according to the following procedure.

[0237] As the reactor, 6 stirred tanks (2 L) with jacket cooling were connected in series so that the reaction liquid flowed from the first tank to the sixth tank in order. The connection of each reactor was carried out at a portion 1 cm from the bottom with a SUS pipe of 15 mm in inner diameter, and the flow rate was adjusted with a control valve. A 4-blade stirrer was installed in each tank. In addition, a pH controller was installed for each tank.

[0238] The connection valves of each reactor were adjusted so that the final concentration of the AAM aqueous solution (1.5 L) of each tank was 25%, 38%, 45%, 50%, 50% and 50% in order from the first tank to the sixth tank. In addition, the biocatalyst as Jl bacteria was added at a rate of 10.1 g / hr (converted to the weight of the dried bacteria) in the first tank, and the raw material water was added at a rate of 2050 ml / hr in the first tank. Furthermore, AN was fed for 30 minutes at a rate of 548 g / hr in the first tank, 443 g / hr in the second tank and 242 g / hr in the third tank. Each tank was maintained with a liquid level, and adjusted so that the temperature became 25 to 40°C and the pH became 7 with 1% sodium hydroxide aqueous solution.

[0239] After 24 hours of operation, the AN concentration of each tank was measured after stabilization, and the results are shown in Table 3.

[0240] [Table 3]

[0241]

[0242] The residence time of each tank was 30 minutes, and the AN concentration decreased sharply after the fourth tank where no AN was fed. Along with this, there was no dispersion of AN after the fourth tank, and the flash point after the fourth tank was sufficiently higher than the reaction temperature, so no nitrogen was circulated. On the other hand, the first to third tanks were ensured to be safe by mixing an equivalent amount of nitrogen in the air in the gas phase portion.

[0243] In the case of performing a continuous reaction by connecting a plurality of reaction tanks as in Example 3 above, as in the case of Example 1 in which a semi-batch reaction is performed using a single reaction tank, the biological catalyst (bacterial cell) showing a specific reaction rate ratio is used, the AN concentration of the feed to the reaction solution is rapidly reduced in at least one reaction tank, thereby raising the flash point thereof, the nitrogen dilution of the gas phase portion is stopped, and air circulation can be performed. In addition, in the first to third tanks, the hydration reaction can be performed at a temperature higher than the flash point of the liquid phase under atmospheric composition (maximum 40°C).

[0244] Industrial applicability

[0245] The present application is useful in the industrial production of acrylamide, methacrylamide, and the like amide compounds.

Claims

1. A method for producing an amide compound, which is a method for producing an amide compound from a nitrile compound in the presence of a biological catalyst having nitrile hydratase activity, characterized by, at least in the case where the concentration of the nitrile compound in the gas phase portion of a reaction tank containing the reaction liquid in the presence of air is within the explosive range, the hydrating reaction is carried out under conditions where the oxygen concentration in the gas phase portion of the reaction tank is 10% by volume or less.

2. A method for producing an amide compound, which is a method for producing an amide compound from a nitrile compound in the presence of a biological catalyst having nitrile hydratase activity, the concentration of the nitrile compound in a reaction liquid for producing an amide compound from a nitrile compound by hydrating reaction is a concentration satisfying the following formula (1), Y≤50X-35, Y is in mass% wherein X represents the concentration of the nitrile compound relative to the total mass of the reaction liquid, in mass%, and Y represents the concentration of the amide compound relative to the total mass of the reaction liquid, in mass%.

3. The method of producing an amide compound according to claim 1 or 2, wherein, the concentration of the nitrile compound in the reaction liquid is (1) or (2) below, (1) when the concentration of the nitrile compound relative to the total mass of the reaction liquid is 1.7 mass% or more, (2) when the concentration X of the nitrile compound relative to the total mass of the reaction liquid is 0.7 to less than 1.7 mass% and Y≤50X-35 is satisfied, Y is in mass%, where Y represents the concentration of the amide compound relative to the total mass of the reaction liquid, in mass%.

4. The method of producing an amide compound according to any one of claims 1 to 3, characterized by, the biological catalyst used in the reaction is a biological catalyst in which the ratio of the hydrating reaction rate in the following reaction liquid A to the hydrating reaction rate in the following reaction liquid B, represented by S1 / S2, is 0.2 or more, reaction liquid A: a reaction liquid at 20°C containing an amide compound at 47 mass% relative to the total mass of the reaction liquid, a nitrile compound at 2 mass%, and the remainder water, reaction liquid B: a reaction liquid at 20°C containing an amide compound at 0 mass% relative to the total mass of the reaction liquid, a nitrile compound at 2 mass%, and the remainder water.

5. The method of producing an amide compound according to any one of claims 1 to 4, wherein the time required for the mass of the nitrile compound added to the reaction liquid to be halved by the hydrating reaction is 1.5 hours or less, or the time required for the concentration of the nitrile compound contained in the reaction liquid to be halved by the hydrating reaction is 1.5 hours or less.

6. The method of producing an amide compound according to any one of claims 1 to 5, wherein the nitrile compound is a compound having a double bond, and the nitrile compound is stored in a storage container having an oxygen concentration of 1 to 10% by volume in the presence of a quinone-based polymerization inhibitor.

7. The method of producing an amide compound according to any one of claims 1 to 6, wherein the nitrile compound is acrylonitrile or methacrylonitrile.

8. The method of producing an amide compound according to any one of claims 1 to 7, wherein the amide compound is acrylamide or methacrylamide.

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