Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P13/00—Preparation of nitrogen-containing organic compounds
  • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/88—Lyases (4.)
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y402/00—Carbon-oxygen lyases (4.2)
  • C12Y402/01—Hydro-lyases (4.2.1)
  • C12Y402/01084—Nitrile hydratase (4.2.1.84)

Definitions

• the present invention relates to a method for producing an amide compound from a nitrile compound using a biocatalyst having nitrile hydratase activity.
• Patent Document 5 discloses a method for producing acrylamide using a multi-tank continuous reaction apparatus, in which acrylonitrile is supplied to a plurality of tanks on the upstream side of the reaction, and acrylonitrile is not supplied to a plurality of tanks on the downstream side, and the reaction liquid is aged.
• Patent Document 6 discloses a method for producing acrylamide by controlling the change in acrylonitrile concentration during the reaction. In this method, acrylonitrile is reacted over a long period of time in order to reduce the generation of acrylic acid.
• Patent Document 7 discloses a method for producing an amide compound using dried cells.
• acrylonitrile is highly toxic, highly flammable, has low solubility in water, is relatively low in polarity, and is easily dispersed.
• highly flammable raw materials such as acrylonitrile
• some measures are required to prevent the reaction liquid containing the raw materials from catching fire and ensure safety. For example, if the raw materials in the reaction liquid are made low in concentration, it is possible to react outside the explosive range, but this slows down the reaction rate and reduces productivity.
• the desired product an amide compound such as acrylamide, is prone to polymerization, and in order to suppress this polymerization, it is effective not only to add a polymerization inhibitor but also to have a certain amount of oxygen present.
• the oxygen concentration In order to prevent the polymerization of the resulting acrylamide, it is desirable for the oxygen concentration to be relatively high. However, in an environment with a high oxygen concentration, there is an increased risk of the raw material acrylonitrile dispersing in the gas phase catching fire. Therefore, in order to achieve safety and high productivity, it is important to control the gas composition in the gas phase in the reaction vessel. However, the appropriate oxygen concentration range for avoiding such a situation has not been known until now.
• the objective of the present invention is to provide a method for safely producing amide compounds while maintaining high productivity.
• the present invention relates to the following [1] to [8].
• a method for producing an amide compound from a nitrile compound in the presence of a biocatalyst having nitrile hydratase activity comprising the steps of: At least in the case where the concentration of the nitrile compound in the gas phase of a reaction vessel containing a reaction liquid in the presence of air is such that the liquid composition of the reaction liquid is within the explosion range, The hydration reaction is carried out under conditions in which the oxygen concentration in the gas phase of the reaction tank is 10% by volume or less.
• a method for producing an amide compound from a nitrile compound in the presence of a biocatalyst having nitrile hydratase activity comprising the steps of: The method for producing an amide compound according to [1], wherein the concentration of the nitrile compound in a reaction solution for producing an amide compound from a nitrile compound by a hydration reaction satisfies the following formula (1): Y ⁇ 50X-35 (mass%) ...
• reaction liquid A A reaction liquid at 20° C. containing 47% by mass of an amide compound, 2% by mass of a nitrile compound, and the remainder water, based on the total mass of the reaction liquid.
• reaction liquid B A reaction liquid at 20° C.
• the time required for the mass of the nitrile compound added to the reaction solution to be reduced by half through a hydration reaction is within 1.5 hours, or The method for producing an amide compound according to any one of [1] to [4], wherein the time required for the concentration of the nitrile compound contained in the reaction solution to be reduced by half due to the hydration reaction is within 1.5 hours.
• [6] The method for producing 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 in the gas phase of 1 to 10% by volume in the presence of a quinone-based polymerization inhibitor.
• [7] The method for producing an amide compound according to any one of [1] to [6], wherein the nitrile compound is acrylonitrile or methacrylonitrile.
• [8] The method for producing an amide compound according to any one of [1] to [7], wherein the amide compound is acrylamide or methacrylamide.
• the present invention relates to the following [A1] to [A5].
• [A1] 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 biocatalyst having nitrile hydratase activity, the method comprising adjusting the oxygen concentration in a gas phase of at least one reaction vessel containing the reaction solution to 1 to 10% by volume.
• 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 biocatalyst having nitrile hydratase activity comprising the steps of: adjusting the oxygen concentration in a gas phase of at least one reaction vessel containing the reaction solution to 1 to 10% by volume when the following condition (1) or (2) is satisfied: (1) When the concentration of the nitrile compound relative to the total mass of the reaction solution is 1.7% by mass or more, (2) When the concentration X of the nitrile compound relative 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 (wherein X represents the concentration X, and Y represents the concentration (unit: mass%) of the amide compound relative to the total mass of the reaction solution).
• [A3] The method for producing an amide compound according to [A1] 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 a gas phase of the storage container is 1 to 10% by volume.
• [A4] The method for producing an amide compound according to any one of [A1] to [A3], wherein the nitrile compound is acrylonitrile or methacrylonitrile.
• [A5] The method for producing an amide compound according to any one of [A1] to [A4], wherein the amide compound is acrylamide or methacrylamide.
• the present invention relates to the following [B1] to [B5].
• [B1] A method for producing an amide compound by subjecting a nitrile compound to a hydration reaction in a reaction solution Z in the presence of a biocatalyst having nitrile hydratase activity, the biocatalyst exhibiting a hydration reaction rate S1 in the following reaction solution A and exhibiting a hydration reaction rate S2 in the following reaction solution B, the reaction rate ratio represented by S1/S2 being 0.2 or more, and the hydration reaction being carried out in at least one reaction tank containing the reaction solution Z at a temperature higher than the flash point of the reaction solution Z under atmospheric composition.
• reaction liquid A A reaction liquid at 20° C. containing, based on the total mass, 47% by mass of the amide compound, 2% by mass of the nitrile compound, and the remainder water.
• reaction liquid B A reaction liquid at 20° C. containing, relative to the total mass, 0 mass % of the amide compound, 2 mass % of the nitrile compound, and the remainder water.
• [B2] The method for producing an amide compound according to [B1], wherein the time required for the mass of the nitrile compound added to the reaction solution Z to be reduced by half through the hydration reaction is within 1.5 hours, or the time required for the concentration of the nitrile compound contained in the reaction solution Z to be reduced by half through the hydration reaction is within 1.5 hours.
• [B3] The method for producing an amide compound according to [B1] or [B2], wherein the biocatalyst is added to the reaction solution Z as bacterial cells, and the amount of the bacterial cells added is 0.4 g or less, calculated as the dry weight of the bacterial cells, per 1 kg of the amide compound produced in the reaction solution Z.
• [B4] The method for producing an amide compound according to any one of [B1] to [B3], wherein the nitrile compound is acrylonitrile or methacrylonitrile.
• [B5] The method for producing an amide compound according to any one of [B1] to [B4], wherein the amide compound is acrylamide or methacrylamide.
• the method of the present invention makes it possible to safely produce amide compounds from nitrile compounds while maintaining high productivity (without reducing productivity).
• a first aspect of the present invention 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 biocatalyst having nitrile hydratase activity.
• an amide compound is produced from a nitrile compound in the presence of a biocatalyst having nitrile hydratase activity.
• the raw material nitrile compound may be present in a high concentration in a reaction solution in at least one reaction vessel.
• the nitrile compound volatilizes, and the nitrile compound is present in a high concentration in the gas phase of the reaction vessel, which increases the risk of the nitrile compound catching fire or exploding due to the influence of oxygen present in the gas phase.
• the catalyst is preferably one that has a high reaction rate, and more preferably a biocatalyst that causes only a small decrease in the hydration reaction rate of the nitrile compounds even in a situation where the hydration reaction progresses and amide compounds accumulate.
• a catalyst having a high reaction rate means that the rate of conversion of a nitrile compound to an amide compound per unit time is high.
• the time required for the concentration of the nitrile compound in the reaction solution to decrease by 50% at the time when the addition of the nitrile compound is completed or interrupted, or the time required for the concentration of the nitrile compound in the reaction solution to decrease by 50% at the time when the reaction is started can be preferably within 1.5 hours, more preferably within 1.2 hours, more preferably within 1 hour, more preferably within 45 minutes, and even more preferably within 30 minutes.
• a biocatalyst that reduces the hydration reaction rate of a nitrile compound only slightly even when the hydration reaction progresses and an amide compound accumulates is preferably, for example, a biocatalyst in which the hydration reaction rate of a nitrile compound in an aqueous solution containing 47% by mass of an amide compound is 0.2 times or more the hydration reaction rate of a nitrile compound in an aqueous solution containing 0% by mass of an amide compound. More preferably, a biocatalyst in which the hydration reaction rate is 0.25 times or more, and even more preferably, 0.3 times or more can be used.
• a biocatalyst whose nitrile hydratase activity has been adjusted using genetic modification techniques, as described below, can be used, or it can be achieved by adjusting the amount (or concentration) of the catalyst used.
• nitrile hydratase refers to an enzyme capable of hydrating a nitrile compound to produce the corresponding amide compound.
• a biocatalyst having nitrile hydratase activity may be the nitrile hydratase protein itself, but may also be an animal cell, a plant cell, a cell organelle, or a microbial cell that contains nitrile hydratase, or a processed product thereof.
• the treated material examples include disrupted animal cells, plant cells, cell organelles, or microbial cells, or enzymes extracted from microbial cells (raw enzymes or purified enzymes); animal cells, plant cells, cell organelles, microbial cells, or enzymes themselves immobilized on a carrier; and the like.
• the treated material also includes animal cells, plant cells, cell organelles, or microbial cells (sometimes called "killed cells") that have been treated with a drug to lose their proliferation ability.
• Immobilization methods include the entrapment method, cross-linking method, and carrier binding method.
• the entrapment method is a method in which the enzyme is coated with a polymer film.
• the cross-linking method is a method in which the enzyme is cross-linked with a reagent that has two or more functional groups (a multifunctional cross-linking agent).
• the carrier binding method is a method in which the enzyme is bound to a water-insoluble carrier.
• substances (immobilization carriers) used for immobilization include glass beads, silica gel, polyurethane, polyacrylamide, polyvinyl alcohol, carrageenan, alginic acid, agar, and gelatin.
• microorganisms include those with nitrile hydratase activity, such as the genera Rhodococcus, Gordona, Pseudomonas, Pseudonocardia, Geobacillus, Bacillus, Bacteridium, Micrococcus, Brevibacterium, Corynebacterium, Nocardia, Microbacterium, Fuza, and others.
• nitrile hydratase activity such as the genera Rhodococcus, Gordona, Pseudomonas, Pseudonocardia, Geobacillus, Bacillus, Bacteridium, Micrococcus, Brevibacterium, Corynebacterium, Nocardia, Microbacterium, Fuza, and others.
• microorganisms that may be useful include those belonging to the genera Fusarium, Agrobacterium, Acinetobacter, Xanthobacter, Streptomyces, Rhizobium, Klebsiella, Enterobacter, Erwinia, Pantoea, Candida
• Rhodococcus rhodochrous J-1 strain described in JP-B-06-55148 was deposited on September 18, 1987 under the accession number "FERM BP-1478" at the National Institute of Technology and Evaluation, Patent Organism Depositary (1-1-1 Central 6, Higashi, Tsukuba, Ibaraki Prefecture, Japan (hereinafter the same in this specification)).
• Rhodococcus rhodochrous NCIMB41164 strain described in International Publication WO2005/054456 was deposited on March 5, 2003 at the National Collection of Industrial, Food and Marine Bacteria, Ltd. (NCIMB) (NCIMB Ltd Ferguson Building Craibstone Estate Buksburn Aberdeen AB21 9YA) under the accession number NCIMB41164.
• one type having desirable characteristics selected from the above microorganisms can be used alone or two or more types can be used in combination.
• the gene encoding the nitrile hydratase can be introduced and expressed in the microbial cells by conventional molecular biology techniques (for details of these molecular techniques, see Sambrook, Fritsch and Maniatis, "Molecular Cloning: A Laboratory Manual," 2nd Edition (1989), Cold Spring Harbor Laboratory Press).
• an enzyme obtained by expressing a nucleic acid encoding a natural nitrile hydratase (wild type) or a mutant (improved type) thereof in the microbial cells can also be used.
• one type selected from the above enzymes can be used alone, or two or more types can be used in combination.
• accession number of wild-type nitrile hydratase is published in NCBI databases such as GenBank (http://www.ncbi.nlm.nih.gov/).
• accession number of the ⁇ subunit derived from Rhodococcus rhodochrous J1 is "P21219”
• the accession number of the ⁇ subunit is "P21220”
• the accession number of the ⁇ subunit derived from Rhodococcus rhodochrous M8 (SU1731814) is "ATT79340”
• accession number of the ⁇ subunit is "AAT79339”.
• accession number of the ⁇ subunit derived from Pseudomonas thermophila JCM3095 is “1IREA”
• accession number of the ⁇ subunit is "1IREB”.
• transformants into which a wild-type nitrile hydratase gene has been introduced include, but are not limited to, Escherichia coli MT10770 (FERM P-14756) transformed with nitrile hydratase from the genus Achromobacter (JP Patent Publication No. 8-266277), Escherichia coli MT10822 (FERM BP-5785) transformed with nitrile hydratase from the genus Pseudonocardia (JP Patent Publication No. 9-275978), or a microorganism transformed with nitrile hydratase from the species Rhodococcus rhodochrous (JP Patent Publication No. 4-211379).
• Improved (mutated) nitrile hydratases in which amino acid substitutions have been made in wild-type nitrile hydratases are known (JP 2010-172295 A, JP 2007-143409 A, JP 2007-043910 A, JP 2008-253182 A, JP 2019-088326 A, JP 2019-088327 A, WO 05/116206 pamphlet, WO 12/164933 pamphlet, WO 12/169203 pamphlet, WO 15/186298 pamphlet, etc.).
• a microorganism into which such an improved nitrile hydratase has been introduced can also be used.
• microorganisms having nitrile hydratase activity or processed products thereof can be used for amide synthesis reaction immediately after preparation of the bacterial cells, or can be stored after preparation of the bacterial cells and used for amide synthesis reaction as necessary.
• the method of culturing the microorganism for preparing the bacterial cells can be appropriately selected depending on the type of the microorganism. Seed culture may be performed before main culture.
• the cells of the microorganism having nitrile hydratase activity or a processed product thereof can be used for a batch reaction or a continuous reaction.
• the reaction system can be appropriately selected from a fluidized bed, a fixed bed, a suspension bed, and the like. In this case, the catalyst temperature in the reaction liquid is not particularly limited as long as it does not interfere with the mixing of the aqueous medium and the nitrile compound.
• a method for measuring the reaction rate of a biocatalyst that shows whether the biocatalyst reduces the hydration rate of a nitrile compound only slightly even in the presence of an amide compound is described below.
• acrylonitrile is used as the nitrile compound
• acrylamide is used as the amide compound.
• 100 mL of an aqueous solution containing 2% by mass of acrylonitrile and 0% by mass of acrylamide and 100 mL of an aqueous solution containing 2% by mass of acrylonitrile and 47% by mass of acrylamide are prepared.
• a catalyst solution containing a predetermined amount of catalyst is added thereto to initiate the reaction. After the reaction starts, sampling is performed multiple times at regular intervals.
• the sampling time can be, for example, 1 to 40 minutes, preferably 2 to 30 minutes, and more preferably 3 to 20 minutes.
• the sample liquid is filtered through a filter, and phosphoric acid is added to stop the reaction. Thereafter, the concentrations of acrylonitrile and acrylamide present in the reaction liquid are measured using gas chromatography or liquid chromatography. From the obtained values, the conversion rate from the nitrile compound to the amide compound can be calculated, and the rate ratio can be obtained.
• the nitrile compound used as a raw material in the production method of this embodiment is not particularly limited as long as it is a compound that can be converted to an amide compound by a catalyst having nitrile hydratase activity.
• the nitrile compound include aliphatic saturated nitriles such as acetonitrile, propionitrile, succinonitrile, and adiponitrile, aliphatic unsaturated nitriles such as acrylonitrile and methacrylonitrile, aromatic nitriles such as benzonitrile and phthalodinitrile, and heterocyclic nitriles such as nicotinonitrile.
• the nitrile compound in this embodiment is preferably a C2 to C4 nitrile compound such as acetonitrile, propionitrile, acrylonitrile, methacrylonitrile, n-butyronitrile, and isobutyronitrile, and the nitrile compounds that this embodiment is particularly effective for are acrylonitrile, methacrylonitrile, and acetonitrile.
• a polymerizable nitrile compound such as (meth)acrylonitrile
• a polymerization inhibitor examples include stable radicals such as catechols, quinones, benzoquinones, diphenylpicrylhydrazyl, hindered amines, and phenothiazine. Among these, quinones are preferred, hydroquinones are more preferred, and methoxyhydroquinone is even more preferred.
• the amount of the polymerization inhibitor to be added is not particularly limited, and can be appropriately selected depending on the types of the nitrile compound and polymerization inhibitor, storage conditions, etc. For example, when a quinone is used, the amount can be 1 to 1000 ppm, preferably 10 to 100 ppm, based on acrylonitrile.
• nitrile compound stored in the presence of dissolved oxygen and a quinone-based polymerization inhibitor as the nitrile compound used in the present invention.
• a nitrile compound stored in the presence of dissolved oxygen and a quinone-based polymerization inhibitor as the nitrile compound used in the present invention.
• Raw Water The water used as a raw material (raw water) is used in the hydration reaction with acrylonitrile when producing acrylamide.
• water include pure water; aqueous solutions of acids, salts, etc. dissolved in water; and the like.
• acids include phosphoric acid, acetic acid, citric acid, boric acid, acrylic acid, formic acid, etc.
• salts include sodium salts, potassium salts, ammonium salts, etc. of the above acids.
• Specific examples of water are not particularly limited, but include water such as pure water, ultrapure water, and city water; and buffer solutions such as Tris buffer, phosphate buffer, acetate buffer, citrate buffer, and borate buffer.
• the pH (20° C.) of the raw water is preferably 5 to 9.
• the raw water may contain dissolved oxygen. Since dissolved oxygen has the effect of suppressing the polymerization of the nitrile compound, which is the raw material, and the amide compound, which is the product, it is not necessary to remove the dissolved oxygen by means of aeration or the like.
• the method for producing an amide compound from a nitrile compound using a biocatalyst having nitrile hydratase activity may be any method, such as a batch reaction, a semi-batch reaction, a multi-vessel continuous reaction, or a reaction using a pipe reactor.
• a batch reaction or semi-batch reaction there is an advantage that the period during which the risk is high can be limited to the early stage of the reaction due to a marked decrease in the gas phase concentration of the nitrile compound, particularly in the latter half of the reaction.
• the multi-tank continuous reaction is a reaction carried out by using an apparatus having a plurality of continuous reaction tanks, continuously or intermittently supplying raw materials (including a nitrile compound, water (raw water), and a biocatalyst) to the reaction tanks, and continuously or intermittently removing the reaction mixture (hereinafter also referred to as "reaction liquid") from the reactor without extracting the entire amount, and transferring it to the next reaction tank.
• reaction liquid reaction mixture
• the apparatus used in the multi-vessel continuous reaction is equipped with two or more reactors connected in series, and produces amide compounds from nitrile compounds and water through continuous reactions using a biocatalyst in each reactor. More specifically, in a continuous reaction apparatus, the raw materials to be reacted are added to the most upstream reactor and the reactor connected to it to start the reaction, and the reaction liquid is moved successively to the reactors located downstream to allow the reaction to proceed. The reaction liquid containing the produced acrylamide can then be collected from the most downstream reactor.
• the number of reactors is not particularly limited and can be appropriately selected depending on the reaction conditions, etc. For example, 2 to 20 reactors are preferable, 2 to 12 reactors are more preferable, 2 to 10 reactors are even more preferable, and 2 to 8 reactors are even more preferable. Some reactors may be connected in parallel as necessary. Each reactor may be independent, or a large reactor may be divided into multiple reactors by partitions. In the case of a reactor divided by partitions, each space divided by the partitions is considered to be one reactor.
• the tank for supplying the nitrile compound, biocatalyst, raw water, other auxiliary agents, etc. is not limited to the most upstream tank, but may be one tank or two or more tanks.
• the latter (downstream) tanks are used for reaction cut-off and maturation, and the reaction liquid containing the product can be extracted from the most downstream tank (final tank) or a tank located upstream of it.
• the number of tanks for supplying raw materials and the number of tanks for aging or the like can be appropriately selected depending on the reaction conditions, reaction scale, etc.
• the type of reactor is not particularly limited, and various types of reactors can be used, such as stirred type, fixed bed type, fluidized bed type, moving bed type, tower type, and tubular type. Among these, stirred type reactors are preferred because they can promote dispersion and mixing of the raw materials. Reactors of different types can also be combined and linked.
• the stirring device is preferably a stirring blade.
• the shape of the stirring blade is not particularly limited, and examples include a paddle, a disk turbine, a propeller, a helical ribbon, an anchor, and a paddler.
• both acrylonitrile and acrylamide are compounds that are easily polymerized. Polymerization is an exothermic reaction, and once polymerization begins, it is difficult to stop, which may cause serious damage.
• the oxygen concentration in the gas phase of a reaction vessel containing a reaction liquid is a liquid composition of the reaction liquid that is included in the explosion range, it is necessary to carry out the reaction under conditions in which the oxygen concentration in the gas phase of the reaction vessel is 10% by volume or less.
• the total volume of the gas phase of the reaction vessel is the volume obtained by subtracting the volume of the reaction liquid (liquid phase) from the total volume of the reaction vessel.
• the oxygen concentration in the gas phase of the reaction vessel is preferably 1 to 10% by volume, and more preferably 1 to 5% by volume.
• volume % means a concentration range between the upper explosion limit, which is the upper limit of the concentration of a nitrile compound that causes an explosion, and the lower explosion limit, which is the lower limit of the concentration.
• the “explosion range” is 3.0 to 17.0 volume %.
• the concentration of the nitrile compound in the reaction liquid satisfies the following formula (1).
• Y ⁇ 50X-35 (mass%) ... (1) (wherein X represents the concentration (mass%) of the nitrile compound relative to the total mass of the reaction solution, and Y represents the concentration (mass%) of the amide compound relative to the total mass of the reaction solution.)
• the oxygen concentration in the gas phase of the reaction vessel can be adjusted to 10% by volume or less, thereby more reliably suppressing ignition or explosion of the raw material nitrile compound.
• the concentration of the nitrile compound relative to the total mass of the reaction liquid is 1.7 mass% or more.
• a concentration X of the nitrile compound relative to the total mass of the reaction solution is 0.7 mass% or more and less than 1.7 mass%, and Y ⁇ 50X ⁇ 35 (mass%) is satisfied (wherein X represents the concentration X, and Y represents the concentration (unit: mass%) of the amide compound relative to the total mass of the reaction solution).
• the above formula (2) was created from the concentration transitions obtained by determining the concentrations of nitrile compounds and amide compounds that have a flash point of 40° C. or less. Flash points are measured by known methods such as the Cleveland open-type, Tag-closed-type, and Seta-type. However, since it takes a lot of work to actually measure a wide range of compositions, it is also possible to change the temperature and measure the concentration of the nitrile compound in the gas phase using a detector tube or gas chromatography, and determine whether the composition is explosive based on the composition, or to estimate the gas-liquid equilibrium using the Wilson formula or the like, and estimate the flash point based on that.
• the flash point of acrylonitrile will be higher than 40° C. That is, if the concentration of acrylonitrile contained in the reaction liquid is less than 0.7% by mass, the amide compound can be produced safely even if the temperature of the reaction liquid is set to less than 40° C., for example, 20 to 30° C.
• the flash point is calculated by measuring the acrylonitrile vapor pressure of the mixed liquid by the Wilson-RK method using ASPENTEC's ASPEN Plus in the high concentration range.
• the acrylonitrile concentration in the gas phase can be measured using a detector tube. It is preferable to confirm that there is no contradiction between these. Furthermore, the flash point was estimated based on the lower limit of the explosion range of known acrylonitrile explosion range data.
• the concentration of acrylonitrile is 1.7% by mass or more, the flash point of acrylonitrile will be 40°C or less regardless of the concentration of acrylamide, increasing the risk of acrylonitrile igniting or exploding. Therefore, it is preferable to adjust the oxygen concentration in the gas phase to 10% by volume or less based on the total volume percent of the gas phase of the reaction vessel. This allows the amide compound to be produced safely.
• the method for adjusting the oxygen concentration in the gas phase of the reaction vessel is not particularly limited.
• the oxygen concentration can be adjusted by flowing an inert gas into the gas phase of the reaction vessel.
• the type of inert gas to be introduced is not particularly limited, and for example, nitrogen, argon, neon, helium, krypton, xenon, radon, etc. can be used. These inert gases can be used alone or in combination of two or more.
• the device and method for introducing the inert gas are not particularly limited, and can be appropriately selected depending on the reaction device, reaction scale, etc.
• reaction for which the oxygen concentration in the gas phase is adjusted there are no particular limitations on the reaction for which the oxygen concentration in the gas phase is adjusted, and the method can be applied to any of the following: batch reactions, semi-batch reactions, multi-tank continuous reactions, and reactions using pipe reactors.
• the reaction vessel for which the oxygen concentration in the gas phase is adjusted is not particularly limited, and the adjustment may be made for all reaction vessels used, or for some of the reaction vessels used.
• a plurality of reaction tanks are used.
• the oxygen concentration in the gas phase may be adjusted in all reaction tanks, or the oxygen concentration in the gas phase may be adjusted in a reaction tank where the volatilization amount of the nitrile compound is large, such as a reaction tank to which a nitrile compound is added.
• a water-soluble monocarboxylate having two or more carbon atoms can be added to the reaction liquid.
• timing of adding the water-soluble monocarboxylate can be added to the reactor located at the most upstream side, and the water-soluble monocarboxylate contained in the reaction liquid moves downstream together with the reaction liquid, so that it is contained in the reaction liquid in each reactor. It may also be added to each reactor before or after the reaction is started.
• the water-soluble monocarboxylate may be either a saturated monocarboxylate or an unsaturated monocarboxylate.
• the saturated carboxylic acid include acetic acid, propionic acid, and n-caproic acid.
• the unsaturated carboxylic acid include acrylic acid and methacrylic acid.
• the salt include the sodium salt, potassium salt, and ammonium salt of the saturated monocarboxylate or unsaturated monocarboxylate.
• the amount of the water-soluble monocarboxylate to be added is preferably 20 to 5,000 mg/kg in terms of acid relative to the amount of acrylamide produced.
• the pH of the reaction in which acrylonitrile is hydrated to produce acrylamide is preferably 6 to 9, and more preferably 7 to 8.5.
• Methods for measuring pH include the indicator method, metal electrode method, glass electrode method, and semiconductor sensor method, but the glass electrode method, which is widely used industrially, is preferred.
• the reaction temperature (temperature of the reaction liquid) when hydrating acrylonitrile is not particularly limited, but is preferably 10 to 50°C, more preferably 15 to 45°C, and even more preferably 20 to 40°C.
• the reaction temperature is preferably 10 to 50°C, more preferably 15 to 45°C, and even more preferably 20 to 40°C.
• the time required for the concentration of the nitrile compound in the reaction liquid to decrease to 50% or less from the start of the reaction is preferably within 1.5 hours, more preferably within 1.2 hours, more preferably within 1 hour, more preferably within 45 minutes, and even more preferably within 30 minutes.
• the time required for the concentration of the nitrile compound in the reaction solution to decrease to 50% or less at the time when the addition of the nitrile compound is completed or interrupted, or the time required for the concentration of the nitrile compound in the reaction solution to decrease to 50% at the time when the reaction is started is preferably within 1.5 hours, more preferably within 1.2 hours, more preferably within 1 hour, more preferably within 45 minutes, and even more preferably within 30 minutes. In either case, the reaction proceeds and the amide compound accumulates in the reaction liquid.
• the time required for the concentration of the nitrile compound in the reaction liquid to decrease to 50% or less at the time when the addition of the nitrile compound is completed or interrupted, or the time required for the concentration of the nitrile compound in the reaction liquid to decrease to 50% at the time when the reaction was started is preferably within 1.5 hours, more preferably within 1.2 hours, more preferably within 1 hour, more preferably within 45 minutes, and even more preferably within 30 minutes.
• the activity of a catalyst is actually compared by unit weight rather than by actual weight of the catalyst.
• a smaller amount of catalyst added is advantageous in terms of catalyst removal after the reaction is completed. Therefore, it is preferable to use a catalyst that is highly active and has little inhibition of the amide compound. More specifically, it is preferable to produce the amide compound in an amount of catalyst 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, and even more preferably 0.30 g or less per 1 kg of the amide compound.
• the addition of the nitrile compound is interrupted, it is preferable to wait at least 1.5 hours, preferably at least 1 hour, and more preferably at least 45 minutes before resuming the addition of the nitrile compound. This is because the concentration of the nitrile compound in the reaction solution can be sufficiently reduced.
• the reaction solution After the addition of the nitrile compound is completed, it is preferable to continue the reaction for 1.5 hours or more, preferably 1 hour or more, and more preferably 45 minutes or more. This is because the concentration of the nitrile compound in the reaction solution can be sufficiently reduced in this manner.
• the total amount of acrylonitrile added depends on the final acrylamide concentration, 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.
• the reaction can be carried out in a homogeneous system, but the reaction is not limited to this.
• the concentration of acrylonitrile in the water will decrease. If the decrease is rapid, the diffusion of acrylonitrile is suppressed and the risk of ignition and explosion of acrylonitrile in the gas phase is reduced. The effect is obtained in the aging time in the latter half of the reaction in a batch reaction or semi-batch reaction, and in the reaction aging part in the rear stage of the reactor in a continuous reaction. The more rapid the decrease in acrylonitrile concentration is, the more limited the dangerous region or dangerous time is.
• the flash point of an aqueous solution containing 48% acrylamide and 2% acrylonitrile in air is 37°C, but the flash point of water containing 49% acrylamide and 1% acrylonitrile rises sharply to 56°C, and safety is also improved.
• the partial pressure of acrylonitrile is also a value in 25° C. water, but it is halved from 3.8 hectopascals at 2% acrylonitrile to 1.9 hectopascals at 1% acrylonitrile, so losses etc. are also reduced.
• the atmosphere refers to the Earth's atmosphere of standard composition, which contains approximately 21% oxygen.
• reaction liquid Z a reaction liquid
• the biocatalyst contains, for example, an enzyme having nitrile hydratase activity, and can be added to reaction liquid Z as live bacteria or as resting bacteria that have been treated with a drug so as not to lose enzyme activity.
• the biocatalyst When the biocatalyst is added in a given amount to the following reaction solution A and the following reaction solution B, the biocatalyst preferably exhibits the following properties: That is, it is preferable that 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, 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, and 0.6 or more, in that order.
• a specific example of such a biocatalyst is the J1 strain used in the Examples described below.
• reaction liquid A A reaction liquid at 20° C. (or 19 to 21° C.) containing 47% by mass (or may be 46 to 48% by mass) of the amide compound, 2.0% by mass (or may be 1.9 to 2.1% by mass) of the nitrile compound, and the remainder water, relative to the total mass of the reaction liquid.
• reaction solution B A reaction solution at 20° C. (or 19 to 21° C.) containing 0 mass % of the amide compound, 2.0 mass % (or 1.9 to 2.1 mass %) of the nitrile compound, and the remainder water, relative to the total mass of the reaction solution.
• the hydration reaction rates S1 and S2 in reaction solutions A and B are determined by adding a predetermined amount of biocatalyst to reaction solutions A and B and stirring them, setting the reaction start time as the time point, and sampling a portion of reaction solutions A and B after 10 minutes to measure the amount of amide compound produced over the 10-minute reaction time.
• reaction liquids A and B The mass of water contained in reaction liquids A and B is the remaining mass obtained by subtracting the mass of components other than water from the total mass of the reaction liquid.
• Reaction liquids A and B may or may not contain optional components other than the nitrile compound and the amide compound.
• a pH buffer is preferable as the optional component.
• the concentration of the pH buffer is, for example, 0.1 mM to 200 mM.
• the nitrile compound in the reaction solution Z can be quickly consumed and the flash point of the reaction solution Z can be quickly raised.
• the temperature can be quickly raised to a temperature higher than the flash point of the reaction solution Z under atmospheric composition, and the hydration reaction can be carried out.
• the suitable nitrile compound to be fed to the reaction liquid Z in this embodiment is as described above, and may be one type or two or more types, and is preferably at least one of acrylonitrile and methacrylonitrile.
• the amide compound produced in the reaction solution Z of this embodiment preferably has an unsaturated bond, and is preferably at least one of acrylamide and methacrylamide.
• the amount of the nitrile compound fed (added) to the reaction solution Z can be, for example, 0.10 to 50 mass %, preferably 1.0 to 45 mass %, more preferably 2.0 to 40 mass %, and even more preferably 2.0 to 37 mass %, based on the total mass of the reaction solution Z placed in a given reaction vessel.
• the total mass of the reaction solution Z includes the mass of the fed nitrile compound.
• the content of the nitrile compound contained in the reaction liquid Z decreases as the reaction progresses, but 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 relative to the total mass of the reaction liquid Z placed in a specified reaction vessel.
• the amount of water contained in the reaction solution Z can be, for example, 10.0 to 99.9 mass% relative to the total mass of the reaction solution Z contained in a specified reaction tank, preferably 20.0 to 99.5 mass%, more preferably 30.0 to 80.0 mass%, and even more preferably 40.0 to 70.0 mass%.
• the amount is equal to or more than the lower limit of the above range, the handleability of the resulting amide compound is good.
• the content is equal to or less than the upper limit of the above range, the efficiency of the hydration reaction of the nitrile compound and the efficiency of the distribution of the product amide compound are improved.
• the reaction temperature of the reaction solution Z can be higher than the flash point of the reaction solution Z under atmospheric composition.
• the flash point of the reaction liquid Z increases.
• the concentration of the nitrile compound tends to be high and the flash point low during the initial to middle stages of the reaction.
• the reaction temperature can be made higher than the flash point.
• the reaction temperature during this period may be lower than the increased flash point.
• the reaction when a non-batch (continuous) reaction is carried out in which the nitrile compound is fed to reaction liquid Z continuously or in multiple batches, the reaction can be carried out at a temperature higher than the flash point of reaction liquid Z during a stable period in which the supply and consumption of the nitrile compound (production of the amide compound) are balanced and the reaction is stable.
• the concentration of the nitrile compound in each reaction tank can be independently controlled, managed, and measured. In at least one of the multiple reaction tanks, the reaction can be carried out at a temperature higher than the flash point of reaction liquid Z.
• the flash point of the reaction liquid Z is measured by a known method such as the Cleveland open-type, Tag-closed type, Seta type, etc.
• the flash point may be estimated based on a method in which the temperature is changed and the concentration of the nitrile compound in the gas phase is measured using a detector tube or gas chromatography, and whether or not the composition is explosive is determined from the composition, or the gas-liquid equilibrium is estimated using the Wilson equation or the like.
• reaction liquid Z Of the entire reaction period (for example, 10 minutes to 100 hours) in reaction liquid Z, the period during which the reaction is carried out at a temperature higher than the flash point of reaction liquid Z may be 0.1% or more, 1% or more, 5% or more, 10% or more, 20% or more, or 30% or more. There is no particular upper limit to this period, and the shorter the period, the higher the safety, but as a guideline, it is 90% or less.
• the temperature of reaction liquid Z i.e., the reaction temperature
• a temperature control device attached to the reaction vessel containing reaction liquid Z.
• temperature control devices include a heater, a Peltier element, a thermostat, etc.
• the time required for the mass (content) or concentration of the nitrile compound at any given time point to subsequently be reduced by half is preferably within 1.5 hours, more preferably within 1.2 hours, more preferably within 1.0 hour, more preferably within 45 minutes, and even more preferably within 30 minutes.
• the shorter the time required for the reduction by half the more quickly the flash point of the reaction solution Z can be increased, and the greater the safety.
• the arbitrary time point is not particularly limited, but examples thereof include the time point when the feeding (addition) of the entire amount of the nitrile compound is completed in a batch system, and the time point when the reaction is stabilized in a continuous system.
• the mass or concentration of the nitrile compound decreases due to the production of an amide compound by the reaction of nitrile hydratase.
• the mass or concentration can be measured, for example, by sampling a small amount of the reaction solution Z and subjecting it to a conventional method such as gas chromatography or liquid chromatography.
• the amount of the bacterial cell added can be understood by converting it to per kg of the amide compound produced in the reaction solution Z.
• the amount of the bacterial cells as the biocatalyst to be added to the reaction solution 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 even more preferably 0.30 g or less, per 1 kg of the amide compound produced in the reaction solution Z.
• the amount of the amide compound produced in the reaction solution Z can be calculated by measuring the amount of the amide compound contained in the reaction solution Z at the end of the batch-type reaction by a conventional method such as gas chromatography or liquid chromatography.
• the sample was appropriately diluted with a buffer solution, added to an aqueous acrylonitrile solution, reacted, and filtered with a disk filter or the like, and the amount of acrylamide (AAM) produced was measured by gas chromatography (Porapak column, column temperature 210 ° C, FID detector) to measure the activity of nitrile hydratase (reaction rate per unit time and unit culture solution).
• the culture was terminated when the nitrile hydratase enzyme activity no longer increased. Thereafter, the mixture was washed with 50 mM phosphate buffer (pH 7.7) to obtain a cell suspension containing 15% of the dried cell weight.
• the cell suspension thus obtained may be hereinafter referred to as "J1 cell.”
• the bacterial cell concentration was determined by taking a small amount of the suspension, drying it at 125°C for 3 hours, and dividing the weight of the residue by the sample volume.
• the reaction rate ratio, expressed as S1/S2, of the hydration reaction rate S1 of AN in reaction solution A having an initial AAM concentration of 47% prepared above and the hydration reaction rate S2 of AN in reaction solution B having an initial AAM concentration of 0% prepared above was 0.60.
• the hydration reaction rates S1 and S2 were calculated from the amount of AAM produced within 10 minutes of reaction time from the time when the bacterial cell suspension was added to the reaction solutions A and B and stirred.
• Example 1 Acrylamide was produced by a semi-batch reaction according to the following procedure. 300 mL of water and 100 mg of dried J1 bacteria (1.25 g as slurry) were added to a 3 L reactor. The amount of dried bacteria added was 0.38 g per kg of acrylamide produced. Then, 194 g of acrylonitrile (hereinafter sometimes referred to as "AN"; containing 45 ppm of methoxyhydroquinone) was slowly fed over 3.23 hours. In this reaction solution, the temperature was set to 35°C, and the pH was adjusted to 7 with a 1% aqueous sodium hydroxide solution to carry out the reaction.
• AN acrylonitrile
• liquid phase AN concentration and liquid phase acrylamide (AAM) concentration were measured by collecting the reaction solution, diluting it appropriately, and then using gas chromatography (column PoraPack-PS (Waters) 1 m, column temperature 210°C, carrier gas: helium, FID detector).
• the gas-phase AN concentration was estimated from the liquid-phase composition by the Wilson RK method using an ASPEN Plus from ASPEN Tec. Furthermore, low concentrations below 300 ppm were measured using an AN detector tube to confirm that the measurements were not significantly off. Based on this, the gas-phase flash point was calculated based on whether the AN concentration in the gas phase was within the lower limit of the explosive range (3%). The gas phase oxygen concentration was calculated from the amount of inflowing nitrogen.
• the gas phase was filled with a mixed gas of nitrogen and air, and the oxygen concentration was maintained at 10% by volume.
• the relationship of the above formula (Y ⁇ 50X-35) was satisfied.
• the reaction liquid temperature was higher than the gas phase flash point, which was in a dangerous range, but the reaction was carried out with the oxygen concentration in the gas phase at 10%, allowing safe operation.
• the AN concentration in the reaction liquid (liquid phase) was 3.19% at the time of completion of the feed, but was reduced to 0.80% about 30 minutes after the completion of the feed, which was about a quarter of the original amount.
• the flash point of the gas phase was 63°C, and the AN concentration in the gas phase was about 9.8 hPa.
• the AN concentration in the liquid phase reached 0.80%, the introduction of nitrogen was stopped and the gas phase was filled with air to continue the reaction.
• the AN concentration in 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 increased to 95° C. or more, and the AN concentration in the gas phase became 4.9 hPa.
• the AN concentration in the liquid phase decreased to below 0.10% approximately 1.27 hours after the feed was completed.
• the reaction of Example 1 was repeated five times, and all operations were stable and safe.
• Example 2 Except for changing the oxygen concentration in the gas phase as described below, AN was hydrated and AAM was produced in the same manner as in Example 1. That is, at the beginning of the reaction that began immediately after the start of feeding, nitrogen gas was continuously flowed into the reactor in an amount three times the volume of the air in the gas phase, and the oxygen concentration in the gas phase was set to 5 volume % relative to the total volume of the reaction vessel, thereby preventing ignition of AN in the gas phase.
• the results, including the transition of AN concentration, are as shown in Table 2.
• the gas phase was filled with a mixed gas of nitrogen and air, and the oxygen concentration was maintained at 5% by volume.
• the relationship of the above formula (Y ⁇ 50X-35) was satisfied.
• the reaction liquid temperature was higher than the gas phase flash point, which was a dangerous range, but the reaction was carried out safely by setting the oxygen concentration in the gas phase to 10%.
• the AN concentration in the reaction liquid (liquid phase) was 3.15% at the time of completion of the feed, and 0.83% about 30 minutes after the completion of the feed, decreasing to about 1/4.
• the flash point of the gas phase at this 30-minute point was 63° C., and the AN concentration in the gas phase was about 10.2 hPa.
• the AN concentration in the liquid phase reached 0.83%
• the introduction of nitrogen was stopped, and the gas phase was filled with air to continue the reaction.
• the AN concentration in 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 increased to 95° C. or higher, and the AN concentration in the gas phase became 5.3 hPa.
• the AN concentration in the liquid phase decreased to 0.1% or less about 1.27 hours after the completion of the feed.
• the reaction of Example 2 was repeated five times, and all the reactions were stable and safe.
• Example 3 The production of AAM was carried out by continuous reactions according to the following procedure. Six reactors (2 L) with jacket cooling and stirrers were connected in series so that the reaction liquid flowed from the first to sixth tanks in order. Each reactor was connected with a SUS pipe with an inner diameter of 15 mm at a height of 1 cm from the bottom, and the flow rate was adjusted with a control valve. A four-paddle stirrer was attached to each tank. In addition, a pH controller was attached to each tank. The connecting valves of the individual reactors were adjusted so that the final concentration of the AAM aqueous solution (1.5 L) in each tank was 25%, 38%, 45%, 50%, 50%, and 50% from the first tank to the sixth tank in order.
• a biocatalyst, J1 bacteria was added to the first tank at a rate of 10.1 g/hr (calculated as the weight of the dry cells), and raw water was added to the first tank at a rate of 2050 ml/hr.
• AN was fed to the first tank at a rate of 548 g/hr, 443 g/hr to the second tank, and 242 g/hr to the third tank over 30 minutes.
• Each tank was adjusted to maintain the liquid level, temperature of 25 to 40 ° C, and pH of 7 using a 1% aqueous sodium hydroxide solution. After 24 hours of operation, the AN concentration in each tank was measured at a stable state, and the results are shown in Table 3.
• the residence time in each tank was 30 minutes, and the AN concentration dropped sharply from the fourth tank onwards, where AN was not fed. At the same time, there was no diffusion of AN from the fourth tank onwards, and as the flash point from the fourth tank onwards was sufficiently higher than the reaction temperature, nitrogen gas was not fed. Meanwhile, safety was ensured in the first through third tanks by mixing the same amount of nitrogen gas into the air in the gas phase.
• Example 3 when multiple reaction tanks were connected to perform a continuous reaction, similar to Example 1, in which a semi-batch reaction was performed using a single reaction tank, a biocatalyst (bacterial cells) exhibiting a specific reaction rate ratio was used, and the AN concentration fed into the reaction liquid was quickly lowered in at least one reaction tank, thereby raising the flash point, stopping nitrogen dilution in the gas phase, and allowing air to circulate. Furthermore, in the first to third tanks, the hydration reaction was performed at a temperature (maximum 40°C) higher than the flash point of the liquid phase under atmospheric composition.
• the present invention is useful in the industrial production of amide compounds such as acrylamide and methacrylamide.

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