WO2011010677A1 - Process for producing inorganic acid salt of 2-aminobutylamide - Google Patents

Process for producing inorganic acid salt of 2-aminobutylamide Download PDF

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WO2011010677A1
WO2011010677A1 PCT/JP2010/062274 JP2010062274W WO2011010677A1 WO 2011010677 A1 WO2011010677 A1 WO 2011010677A1 JP 2010062274 W JP2010062274 W JP 2010062274W WO 2011010677 A1 WO2011010677 A1 WO 2011010677A1
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aminobutyramide
inorganic acid
acid salt
inorganic
aminobutyronitrile
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PCT/JP2010/062274
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French (fr)
Japanese (ja)
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孝紀 佐藤
信也 才川
定夫 上村
昭宣 田中
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株式会社日本ファインケム
三菱瓦斯化学株式会社
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Priority to JP2011523679A priority Critical patent/JP5613162B2/en
Priority to CN2010800333762A priority patent/CN102471236A/en
Publication of WO2011010677A1 publication Critical patent/WO2011010677A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups

Definitions

  • the present invention relates to a method for producing a 2-aminobutyramide inorganic acid salt (5) having high purity and excellent quality from 2-hydroxybutyronitrile (1) economically and simply in a high yield.
  • Highly pure and excellent quality 2-aminobutyramide inorganic acid salt is very useful as a raw material for pharmaceutical synthesis.
  • X is an inorganic acid anion.
  • ⁇ -amino acid amide using cyanohydrin As a production method of ⁇ -amino acid amide using cyanohydrin as a starting material, a production method via ⁇ -amino nitrile is known, and ⁇ -amino nitrile is known to have a Strecker reaction synthesized from cyanohydrin and ammonia or ammonium salt. It has been.
  • a method for producing an ⁇ -amino acid amide using ⁇ -amino nitrile as a starting material an ⁇ -amino acid amide is produced by forming 5-oxazolidinone from ⁇ -amino nitrile as a reaction intermediate and then hydrolyzing the intermediate.
  • a synthesis method for obtaining see, for example, Patent Document 1). However, since these methods require the reaction to be carried out under anhydrous conditions, it is necessary to carry out the reaction by removing water produced as a by-product by the Strecker reaction, which requires a complicated process and apparatus.
  • ⁇ -amino nitrile is hydrated by reaction with a base and a ketone in an aqueous medium, an inorganic acid is mixed into the resulting ⁇ -amino acid amide-containing liquid, and then the resulting ⁇ -amino acid amide inorganic acid salt is formed.
  • a method for separating and recovering the liquid has been reported (see, for example, Patent Document 5). This method eliminates the need for distillation and concentration.
  • 2-aminobutyramide inorganic acid salt with high water solubility an ⁇ -amino acid amide inorganic acid is produced due to the influence of water contained in the reaction solution during crystal separation. A loss of salt to the filtrate occurs and causes a problem in yield.
  • the present invention is to provide an economical method capable of producing a 2-aminobutyramide inorganic acid salt (5) useful as a pharmaceutical raw material or the like in a high yield.
  • the present invention relates to a process for producing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1) through amination and Schiff basification.
  • the present inventors have a highly soluble 2-aminobutyramide inorganic acid salt (highly water-soluble) without performing a distillation concentration step that causes by-products.
  • the loss to the filtrate in the separation operation of 5) can be reduced, and the mixture of inorganic salts such as ammonia inorganic acid salt, which shows the same solvent solubility as 2-aminobutyramide inorganic acid salt, can also be reduced.
  • 2-hydroxybutyronitrile (1) is reacted with ammonia, and the reaction solution containing 2-aminobutyronitrile (2) is directly or directly added to the reaction solution.
  • a reaction solution containing 2-aminobutyronitrile (2) obtained by adding an inorganic strong base aqueous solution to separate two layers and dehydrating or degassing under reduced pressure to remove ammonia, In the presence of a strong inorganic base and a ketone solvent, the reaction is carried out under the condition that the amount of water with respect to 2-aminobutyronitrile (2) is 3 times mol or less, and 2-aminobutyronitrile (2) obtained in step (A) is obtained.
  • the water in the reaction solution is contained only in an equimolar amount by-produced in the aminonitrile formation. It is possible to further reduce the amount of water by performing the operation of adding two layers to separate the two layers. On the other hand, when ammonia water is used, the amount of water in the reaction solution increases. However, if the amount of water is too much, the amount of water can be reduced by adding an inorganic strong base to the reaction solution and separating the two layers. Can be reduced.
  • step (B) when synthesizing 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) from 2-aminobutyronitrile (2) in step (B), the amount of water in the reaction solution
  • step (C) a product containing 2-aminobutyramide Schiff base (3) as a main component is obtained, and further by using this product, in step (C), a small amount of water It has been found that it can be converted to the 2-aminobutyramide inorganic acid salt (5) at a high rate and in a high yield with an increase in the amount and, in some cases, a decrease in water accompanying the hydrolysis reaction of the Schiff base.
  • the solubility of the 2-aminobutyramide inorganic acid salt (5) in the ketone solvent is lower as the amount of water in the mother liquor is smaller. Therefore, by reducing the water content in the mother liquor, the loss of 2-aminobutyramide inorganic acid salt (5) to the filtrate in the crystal separation step can be reduced.
  • 2-aminobutyronitrile is hydrolyzed to 2-aminobutyramide under basic conditions in the presence of conventional water and ketone solvents, and then neutralized with acid to give 2-aminobutyramide salt.
  • a high-purity 2-aminoalkylamide inorganic acid salt that does not require a distillation and concentration step with side reactions, reduces loss to the filtrate during crystal separation, and further reduces the amount of inorganic salt contamination. has been found to be obtained in a high yield, and the present invention has been completed.
  • the present invention relates to a method for producing a 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1) described in the following 1) to 17).
  • the production method includes the following steps (A), (B) and ( A process for producing 2-aminobutyramide inorganic acid salt (5), which comprises C).
  • the reaction is carried out under conditions where the water content is 3 times mol or less, and the amount of 2-aminobutyramide Schiff base (3) is 0.6 times mol or more with respect to 2-aminobutyronitrile (2) contained in the reaction solution.
  • R is a methyl group or an ethyl group.
  • X is an inorganic acid anion.
  • step (A) ammonia is used in an amount of 1.0 to 1.5 times mol of 2-hydroxybutyronitrile (1).
  • step (A) The process for producing a 2-aminobutyramide inorganic acid salt (5) according to 1), wherein ammonia water is used as ammonia in step (A).
  • step (A) the concentration of aqueous ammonia is 35% by mass or more, and ammonia is used in an amount of 1.5 to 2.5 mol per mol of 2-hydroxybutyronitrile (1).
  • step (B) the reaction solution containing 2-aminobutyronitrile (2) was separated into two layers by adding an inorganic strong base or an inorganic strong base aqueous solution, and was contained in the upper organic phase.
  • the reaction solution containing 2-aminobutyronitrile (2) in the upper layer is separated from the aqueous inorganic strong base solution in the lower layer, and the separated reaction solution is used for the reaction.
  • step (B) the reaction solution containing 2-aminobutyronitrile (2) is degassed under a reduced pressure of 30 to 760 mmHg to distill off ammonia, and used in the reaction.
  • step (B) the inorganic strong base is used in an amount of 0.005 to 0.1-fold mol with respect to 2-aminobutyronitrile (2). 5) Production method.
  • step (B) The 2-aminobutyramide inorganic acid salt according to 1), wherein the ketone solvent is used in a molar amount of 1.0 to 12.0 times that of 2-aminobutyronitrile (2) in step (B). 5) Production method. 12) The process for producing a 2-aminobutyramide inorganic acid salt (5) according to 1), wherein in the step (B), the ketone solvent is acetone. 13) In step (C), the reaction solution obtained in step (B) is brought into contact with an inorganic acid or an aqueous solution of inorganic acid at an acid excess ratio such that the solution pH after contact mixing is 1 to 6. 2) A production method of 2-aminobutyramide inorganic acid salt (5).
  • step (C) The method for producing 2-aminobutyramide inorganic acid salt (5) according to 1), wherein in step (C), hydrogen chloride gas or an aqueous hydrochloric acid solution of 20% by mass or more is used as the inorganic acid or the inorganic acid aqueous solution. . 15) Further, the liquid containing the 2-aminobutyramide inorganic acid salt (5) obtained in the step (C) is crystallized directly or after being poured into a ketone solvent, and the precipitated crystals are separated into solid and liquid. A process for producing the 2-aminobutyramide inorganic acid salt (5) according to 1).
  • 2-aminobutyramide inorganic acid salt (5) is obtained from 2-hydroxybutyronitrile (1), 2-hydroxybutyronitrile (1) is reacted with ammonia to give 2-aminobutyronitrile (2 )
  • 2-aminobutyronitrile (2) is reacted with ammonia to give 2-aminobutyronitrile (2 )
  • the main component 2-aminobutyramide Schiff base (3) and the subsidiary component 2-aminobutyramide (4) 2-aminobutyramide having a low water content and a small amount of inorganic salts such as ammonia inorganic acid salt is obtained by contacting a reaction liquid containing a reaction product comprising an inorganic acid or an aqueous inorganic acid solution under acidic conditions.
  • a crystal slurry liquid containing the inorganic acid salt (5) can be obtained.
  • the mother liquor loss during the solid-liquid separation of the crystals is reduced, and the 2-aminobutyramide inorganic acid salt (5) with high yield and high purity can be produced.
  • the present invention comprises a step (A) for synthesizing 2-aminobutyronitrile (2) from 2-hydroxybutyronitrile (1), and a 2-aminobutyramide Schiff base (3) from 2-aminobutyronitrile (2).
  • 2-aminobutyramide (4) synthesis step (B) 2-aminobutyramide inorganic acid salt (5) is synthesized from 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4)
  • 2-Hydroxybutyronitrile (1) used in the step (A) of the present invention may be synthesized by a usual cyanohydrination reaction, for example, synthesized from propionaldehyde and hydrogen cyanide.
  • ammonia to be reacted with 2-hydroxybutyronitrile (1) any of ammonia gas, liquid ammonia, and aqueous ammonia solution can be used. However, it is possible to avoid mixing water into the reaction system and a complicated reaction apparatus. Ammonia gas is desirable in that it does not need to be used. In addition, although ammonia gas can be used as it is, it may be used after it is made dry ammonia gas by passing through a dehydration column using calcium chloride or the like.
  • the amount of ammonia used in the reaction must be equimolar or more stoichiometrically with respect to 2-hydroxybutyronitrile (1), but when ammonia gas and liquid ammonia are used, contamination of inorganic salts in the product Therefore, the amount is preferably as close to the theoretical amount as possible, and in that sense, the molar ratio is preferably 1.0 to 1.5 times the molar amount relative to 2-hydroxybutyronitrile (1). It is more preferably 1.0 to 1.2 times mole.
  • ammonia water When ammonia water is used, the reactivity is lower than when ammonia gas and liquid ammonia are used, and the amount of water in the subsequent process is reduced, so that ammonia water has a concentration of 35% by mass or more.
  • the amount of ammonia relative to 2-hydroxybutyronitrile (1) is preferably 1.5 times to 2.5 times mol, more preferably 1.8 times to 2.3 times mol. .
  • the reaction temperature is preferably in the range of ⁇ 5 to 25 ° C. so that 2-aminobutyronitrile (2) as a reaction product does not form a by-product such as a dimer, and is preferably 0 to 20 ° C. It is more preferable to carry out in the range.
  • the reaction solution obtained in the step (A) is used directly or after dehydration or deammonia treatment.
  • the step (B) Of course, it can be used as a reaction raw material.
  • the reaction solution is separated into two layers by adding an inorganic strong base or an inorganic strong base aqueous solution to the reaction solution.
  • the reaction solution containing the nitrile (2) and the inorganic strong base aqueous solution containing the removed water are separated.
  • an alkali metal such as sodium hydroxide, potassium hydroxide or calcium hydroxide, which is convenient for treatment after use, or Alkaline earth metal hydroxides are preferred, and sodium hydroxide is particularly preferred.
  • the amount of the inorganic strong base used is preferably such that the concentration of the inorganic base in the lower layer to be obtained is 15% by mass or more, and 30% by mass. It is more preferable to add so that it may become more than%.
  • the obtained lower layer can also be used in a step of obtaining a reaction solution containing 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) as an inorganic strong base.
  • the deammonia treatment after the synthesis of 2-aminobutyronitrile (2) is not particularly limited, but from the viewpoint of treatment time and operability, a reduced pressure of 30 to 760 mmHg is preferable, and a reduced pressure of 50 to 600 mmHg. Is more preferable.
  • the ammonia content in the reaction with the ketone solvent in the presence of the strong inorganic base is 2- It is preferable that it is 0.3 times mole or less with respect to aminobutyronitrile (2).
  • the purity of the 2-aminobutyramide inorganic acid salt (5) obtained in the step (C) is undesirably lowered.
  • the ammonia removal condition is 600 mmHg and 30 minutes, the ammonia content is reduced from 0.36 to 0.23 with respect to 2-aminobutyronitrile (2), and a product with a purity of 95% can be obtained (Table 1). 1).
  • the synthesis of 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) in the step (B) of the present invention is carried out in the presence of water, a strong inorganic base, and a ketone solvent.
  • the nitrile (2) is reacted by dropping.
  • an inorganic strong base is added dropwise to the ketone solvent, and then 2-aminobutyronitrile (2) is added. It is preferable to drop.
  • the inorganic strong base used in this reaction promotes activation of the amino group and reacts with a ketone solvent to form 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) via oxazolidine.
  • Working as a catalyst There are no restrictions on the type of inorganic strong base used, but hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide, which are readily available as industrial raw materials and are convenient for post-use treatment. In particular, sodium hydroxide is preferred.
  • the amount of the strong base to be used is preferably as small as possible, and in that sense, it is 0.005 to 0.1 times the molar ratio with respect to 2-aminobutyronitrile (2).
  • the amount is 0.02 to 0.07 times mol.
  • the amount is less than 0.005 mol, a decrease in the reaction rate to become a Schiff base is observed.
  • the amount exceeds 0.1 mol, the catalyst activity is not increased, and the inorganic content required for neutralization of the strong base used is simply not increased. This is not preferable because the acid amount increases and the amount of inorganic salt mixed in the product increases.
  • ketone solvent used in the step (B) of the present invention is not particularly limited.
  • ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and the like are preferable, and among these, methyl ethyl ketone, acetone Are preferred, and acetone is particularly preferred.
  • the amount of the ketone solvent used is stoichiometrically more than 1 equivalent to form the Schiff salt, but serves as a reaction solvent that maintains the solubility and dispersibility of the reaction raw materials and products,
  • it is preferably 1 to 12 times by mole, more preferably 3 to 6 times by mole, relative to the starting 2-aminobutyronitrile (2). preferable.
  • the weight ratio is preferably 4 times or more, and more preferably 7 times or more.
  • the reaction temperature is -20 to 30 ° C. in order to suppress hydrolysis reaction of 2-aminobutyramide Schiff base (3) to 2-aminobutyramide (4) and side reaction to 4-imidazolidinone.
  • a temperature range is preferable, and a temperature range of 0 to 20 ° C. is more preferable. If the temperature is higher than 30 ° C., side reactions become apparent, and if the temperature is lower than 0 ° C., the reaction time becomes longer and disadvantageous in terms of energy costs associated with cooling. Note that the extension of the reaction time leads to by-production of ⁇ -imidazolidinone after the 2-aminobutyramide Schiff base (3) is hydrolyzed to 2-aminobutyramide (4). It is desirable that the time be about 3 to 10 hours.
  • the amount of aminobutyramide (4) produced increases. For example, when the water content is 0.24 mol relative to 2-aminobutyronitrile (2), the production molar ratio of 2-aminobutyramide Schiff base (3) is 2-aminobutyronitrile (2). 0.85-fold mol of 2-aminobutyramide (4) is formed 0.08-fold mol of 2-aminobutyronitrile (2).
  • the loss of the target 2-aminobutyramide inorganic acid salt (5) to the filtrate increases.
  • the loss to the filtrate can also be reduced by increasing the amount of the ketone solvent used as the reaction solvent, but it is not preferable in view of production efficiency because the accompanying solvent recovery cost increases.
  • the water contained in the reaction solution of step (B) includes 2-aminobutyronitrile (2), including water by-produced during the synthesis of 2-aminobutyronitrile (2) and water derived from an aqueous inorganic strong base solution.
  • the Schiff base production rate is with respect to 2-aminobutyronitrile (2) obtained in step (A). It is preferable because it becomes 0.6 times mol or more.
  • inorganic acid used in the formation of the inorganic acid salt in step (C) there are no particular restrictions on the type of inorganic acid used in the formation of the inorganic acid salt in step (C), and examples include hydrochloric acid, hydrogen chloride gas, and nitric acid. From the viewpoint of the advantages, hydrochloric acid and hydrogen chloride gas are preferable, and hydrochloric acid is more preferable.
  • the inorganic acid used may be either a gaseous or liquid inorganic acid or an aqueous inorganic acid solution, but an inorganic acid aqueous solution having a concentration of 20% by mass or more or a gaseous or liquid inorganic acid is preferred.
  • the amount of inorganic acid used is such that 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) contained in the reaction solution obtained in step (B) are 2-aminobutyramide inorganic acid.
  • the amount is not particularly limited as long as it is converted into the salt (5), but usually 1.0 to 1.2 with respect to 2-aminobutyronitrile (2) charged as a raw material in the step (B). It is preferable to add so that the pH of the reaction mixture after contacting with an inorganic acid is 1 to 6, particularly preferably 3 to 5, using a double mole.
  • the pH of the reaction mixture is preferably maintained at pH 1-6 until the solid of the 2-aminobutyramide inorganic acid salt (5) is solid-liquid separated at the time of contact with the inorganic acid. 5 is preferably maintained.
  • the pH is maintained above 6, it is observed that a portion of the inorganic acid salt does not progress, stops with unstable 2-aminobutyramide, and the yield of 2-aminobutyramide inorganic acid salt decreases.
  • the pH is maintained at a pH of less than 1, the resulting 2-aminobutyramide inorganic acid salt has a yellowish coloring phenomenon.
  • the solvent composition is preferably as low as possible in order to reduce the solubility and improve the crystal yield.
  • a ketone solvent can be added after the synthesis, the water content in the mother liquor is preferably 15% or less from the viewpoint of industrial productivity.
  • the solid-liquid separation temperature of the crystals is preferably from ⁇ 10 to 20 ° C. and from 0 to 10 ° C. from the viewpoint of reducing the solubility of the 2-aminobutyramide inorganic acid salt (5) and reducing the mother liquor loss. More preferred.
  • the mother liquor containing the inorganic salt adhering to the crude crystals obtained by solid-liquid separation is washed away, it is also possible to wash with acetone or alcohol such as methanol or ethanol.
  • acetone or alcohol such as methanol or ethanol.
  • it is preferably washed with the solvent cooled to ⁇ 10 to 20 ° C., more preferably 0 to 10 ° C.
  • the amount of the washing solution used is 0.5 to 3 times the amount of the crude crystals separated by filtration.
  • the ketone solvent such as acetone contained in the mother liquor can be easily recovered by distillation operation and can be used for the next reaction.
  • step (A) the reaction between 2-hydroxybutyronitrile (1) and ammonia in the step (A) produces water in the same mole as 2-hydroxybutyronitrile (1) because this reaction is a dehydration substitution reaction. It will be.
  • the total amount of 2-aminobutyramide (4) Assuming the case of being converted into (), water equivalent to 2-aminobutyronitrile (2) is consumed. Therefore, when step (A) and step (B) are combined, step (A) The water generated in step (B) is consumed in step (B), and the amount of water is calculated as 0 mol.
  • the water accompanying the inorganic strong base aqueous solution used in the step (B) and the water accompanying the inorganic acid aqueous solution used in the step (C) are converted into the 2-aminobutyramide inorganic acid salt (5 ) The amount of water in the mother liquor when the crystals are separated into solid and liquid.
  • the amino group is protected because the Schiff base is the main component, side reactions such as dimerization are unlikely to occur, and a high-quality product with few impurities can be obtained.
  • ammonia is removed, the production amount of ammonium inorganic acid salt is reduced, and the mixing amount into the product is also reduced.
  • the amount of inorganic strong base used as a catalyst in the step (B) is also reduced, the amount of inorganic strong base salt mixed in is also reduced.
  • Example 1 Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, 24.0 g (0.27 mol) of 2-hydroxybutyronitrile was added, and ammonia was stirred while maintaining the liquid temperature at 8 ⁇ 2 ° C. After gas 6.0 g (0.35 mol [1.3 eq / 2-hydroxybutyronitrile]) was blown in, this was reacted at a reaction temperature of 20 ° C. for 8 hours to obtain a 2-aminobutyronitrile aqueous solution. 30.0 g (0.24 mol, [2-aminobutyronitrile purity 67.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
  • a reaction substrate solution 95.4 g having a charging ratio of [1.2 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 21.1%, acetone 68.1% was prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours to give 25.8 g of 2-aminobutylamide Schiff base (0.18 mol [0.76 times mol / 2-aminobutyronitrile]) and 2-aminobutyramide 3 95.4 g of a reaction solution containing 9.9 g (0.04 mol [0.16 mol / 2-aminobutyronitrile]) was obtained.
  • the 2-aminobutylamide Schiff base was identified by 1 H-NMR and 13 C-NMR.
  • Example 2 Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser was placed 83.1 g (0.93 mol) of 2-hydroxybutyronitrile, and ammonia was stirred while maintaining the liquid temperature at 8 ⁇ 2 ° C. After 20.7 g (1.22 mol [1.3 eq / 2-hydroxybutyronitrile]) of gas was blown in, this was reacted at a reaction temperature of 20 ° C. for 8 hours to obtain a 2-aminobutyronitrile aqueous solution. 103.8 g (0.84 mol [2-aminobutyronitrile purity 68.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
  • Example 3 Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser was placed 83.1 g (0.93 mol) of 2-hydroxybutyronitrile, and ammonia was stirred while maintaining the liquid temperature at 8 ⁇ 2 ° C. After 20.7 g (1.22 mol [1.3 eq / 2-hydroxybutyronitrile]) of gas was blown in, this was reacted at a reaction temperature of 20 ° C. for 8 hours to obtain a 2-aminobutyronitrile aqueous solution. 103.8 g (0.84 mol [2-aminobutyronitrile purity 68.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
  • Example 4 2-hydroxybutyronitrile (15.9 g, 0.18 mol) was placed in a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, and ammonia gas was maintained while maintaining the liquid temperature at about 10 ° C. with stirring. After blowing 3.9 g (0.23 mol [1.3 eq / 2-hydroxybutyronitrile]), this was reacted at a reaction temperature of 20 ° C. for 8 hours. As a result, an aqueous 2-aminobutyronitrile solution 19 0.8 g (0.17 mol [2-aminobutyronitrile purity 70.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
  • reaction substrate solution comprising 2%, water 1.3% [0.24 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 21.6%, acetone 72.3% Prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours, and 19.3 g of 2-aminobutylamide Schiff base (0.14 mol [0.85 times mol / 2-aminobutyronitrile]) and 2-aminobutyramide 1 60.4 g of a reaction solution containing 3 g (0.01 mol [0.08-fold mol / 2-aminobutyronitrile]) was obtained.
  • Example 5 Pure water 33.2 g (1.84 mol) was placed in a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, and ammonia gas 23.0 g (24.0 g) was maintained while maintaining the liquid temperature at about 10 ° C. with stirring. 1.35 mol [2.0 eq / 2-hydroxybutyronitrile]) was blown in, and 58.1 g (0.68 mol) of 2-hydroxybutyronitrile was stirred and the liquid temperature was kept at about 10 ° C. The solution was added dropwise over 5 hours. When this was reacted at a reaction temperature of 20 ° C.
  • Comparative Example 1 Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, 117.4 g (1.30 mol) of 2-hydroxybutyronitrile was placed, and ammonia was maintained while maintaining the liquid temperature at 8 ⁇ 2 ° C. with stirring. 27.4 g of gas (1.61 mol [1.2 eq / 2-hydroxybutyronitrile]) was added and reacted at a reaction temperature of 20 ° C. for 8 hours.

Abstract

Provided is a process for economically producing from 2-hydroxybutyronitrile a 2-aminobutylamide inorganic acid salt which is useful as a starting material for medicines, etc. 2-Hydroxybutyronitrile is reacted with ammonia to obtain a liquid reaction mixture containing 2-aminobutyronitrile. The mixture is reacted in the presence of a strong inorganic base and a ketone solvent to yield a liquid reaction mixture containing a 2-aminobutylamide Schiff base as a major component. This liquid reaction mixture is brought into contact with a solution of an inorganic acid. Thus, a high-quality 2-aminobutylamide inorganic acid salt having an excellent color tone and an excellent purity is produced in high yield.

Description

２－アミノブチルアミド無機酸塩の製造方法Method for producing 2-aminobutyramide inorganic acid salt
　本発明は２－ヒドロキシブチロニトリル（１）から、高純度で品質的に優れた２－アミノブチルアミド無機酸塩（５）を、経済的かつ簡便に、高収率で製造する方法に関する。高純度で品質的に優れた２－アミノブチルアミド無機酸塩は、医薬品の合成原料等として大変有用である。
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
 　（但し、Ｘは無機酸アニオンである。） The present invention relates to a method for producing a 2-aminobutyramide inorganic acid salt (5) having high purity and excellent quality from 2-hydroxybutyronitrile (1) economically and simply in a high yield. Highly pure and excellent quality 2-aminobutyramide inorganic acid salt is very useful as a raw material for pharmaceutical synthesis.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
 (However, X is an inorganic acid anion.)
　シアンヒドリンを出発物質としたα－アミノ酸アミドの製造方法としては、α－アミノニトリルを経由する製法が知られており、α－アミノニトリルはシアンヒドリンとアンモニア、またはアンモニウム塩から合成するストレッカー反応が知られている。α－アミノニトリルを出発原料としたα－アミノ酸アミドの製造方法としては、α－アミノニトリルから５－オキサゾリジノンを反応中間体として生成させた後、該中間体を加水分解することによってα－アミノ酸アミドを得る合成方法が報告されている（例えば、特許文献１参照）。しかしながら、これらの方法は反応を無水条件下で行う必要があるため、ストレッカー反応によって副生する水を除去して反応させる必要があり、煩雑なプロセスと装置を要する。 As a production method of α-amino acid amide using cyanohydrin as a starting material, a production method via α-amino nitrile is known, and α-amino nitrile is known to have a Strecker reaction synthesized from cyanohydrin and ammonia or ammonium salt. It has been. As a method for producing an α-amino acid amide using α-amino nitrile as a starting material, an α-amino acid amide is produced by forming 5-oxazolidinone from α-amino nitrile as a reaction intermediate and then hydrolyzing the intermediate. There has been reported a synthesis method for obtaining (see, for example, Patent Document 1). However, since these methods require the reaction to be carried out under anhydrous conditions, it is necessary to carry out the reaction by removing water produced as a by-product by the Strecker reaction, which requires a complicated process and apparatus.
　一方、α－アミノニトリルを水性媒体中で塩基およびケトンと反応させ、α－アミノ酸アミドを合成する方法が報告されている（例えば、特許文献２、３、４参照）。しかし、生成物であるα－アミノ酸アミドは極性が高く水易溶性であることから、収率を高めるためには結晶分離に先立って水を留去するか、結晶分離後の濾液を濃縮するかしてα－アミノ酸アミドの回収をはかる必要性がある。また、蒸留濃縮操作中にα－アミノ酸アミドとケトンが縮合して４－イミダゾリジノンが副生し、収率及び純度が低下してしまう問題もある。 On the other hand, a method has been reported in which α-amino nitrile is reacted with a base and a ketone in an aqueous medium to synthesize an α-amino acid amide (see, for example, Patent Documents 2, 3, and 4). However, since the product α-amino acid amide is highly polar and readily soluble in water, in order to increase the yield, water should be distilled off prior to crystal separation or the filtrate after crystal separation should be concentrated. Therefore, it is necessary to recover the α-amino acid amide. In addition, there is a problem that the α-amino acid amide and the ketone are condensed during the distillation and concentration operation to form 4-imidazolidinone as a by-product, resulting in a decrease in yield and purity.
　これに対して、α－アミノニトリルを水性媒体中で塩基およびケトンとの反応で水和させ、生成したα－アミノ酸アミド含有液に無機酸を混合し、次いで生成したα－アミノ酸アミド無機酸塩を分離回収する方法が報告されている（例えば、特許文献５参照）。この方法は蒸留濃縮操作が必要なくなるが、水溶性の高い２－アミノブチルアミド無機酸塩に適用した場合は、結晶分離時、反応液中に含まれる水分の影響により、α－アミノ酸アミド無機酸塩の濾液への損失が起こり収率的に問題となる。 On the other hand, α-amino nitrile is hydrated by reaction with a base and a ketone in an aqueous medium, an inorganic acid is mixed into the resulting α-amino acid amide-containing liquid, and then the resulting α-amino acid amide inorganic acid salt is formed. A method for separating and recovering the liquid has been reported (see, for example, Patent Document 5). This method eliminates the need for distillation and concentration. However, when it is applied to 2-aminobutyramide inorganic acid salt with high water solubility, an α-amino acid amide inorganic acid is produced due to the influence of water contained in the reaction solution during crystal separation. A loss of salt to the filtrate occurs and causes a problem in yield.
　このように、従来の方法は何れも製造方法としては不充分なものであり、製品収率、製品純度に優れ、かつ簡便に目的物が得られる工業的に実施可能な製造方法の提供が強く望まれて来た。 As described above, none of the conventional methods is sufficient as a production method, and there is a strong provision of an industrially feasible production method that is excellent in product yield and product purity and that can easily obtain a target product. It has been desired.
特公昭４３－１０６１５号公報Japanese Examined Patent Publication No. 43-10615 特開昭５２－２５７０１号公報JP-A-52-25701 特開昭５３－８２７０７号公報JP-A-53-82707 特開昭５７－１５８７４３号公報JP 57-158743 A 特開２００１－２４７５２９号公報JP 2001-247529 A
　原料の２－ヒドロキシブチロニトリル（１）から、高純度の２－アミノブチルアミド無機酸塩（５）を高収率かつ簡便に製造できる方法を提供する。すなわち、本発明は医薬品原料等として有用な２－アミノブチルアミド無機酸塩（５）を高い収率で製造できる、経済性に優れた方法を提供することにある。 Provided is a method by which a high-purity 2-aminobutyramide inorganic acid salt (5) can be easily produced from a raw material 2-hydroxybutyronitrile (1) with a high yield. That is, the present invention is to provide an economical method capable of producing a 2-aminobutyramide inorganic acid salt (5) useful as a pharmaceutical raw material or the like in a high yield.
　本発明は、２－ヒドロキシブチロニトリル（１）からアミノ化、シッフ塩基化を経て、２－アミノブチルアミド無機酸塩（５）を製造する方法に関する。 The present invention relates to a process for producing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1) through amination and Schiff basification.
　本発明者らは、反応系に混入する水とアンモニアの量を低減出来れば、副生物の生成原因となる蒸留濃縮工程を行わなくても、水溶性が高い２－アミノブチルアミド無機酸塩（５）の分離操作における濾液への損失が低減でき、しかも２－アミノブチルアミド無機酸塩と同様な溶媒溶解性を示すアンモニア無機酸塩等の無機塩類の製品への混入も低減できることから、この課題を解決すべく鋭意検討を重ねた。 If the amount of water and ammonia mixed in the reaction system can be reduced, the present inventors have a highly soluble 2-aminobutyramide inorganic acid salt (highly water-soluble) without performing a distillation concentration step that causes by-products. The loss to the filtrate in the separation operation of 5) can be reduced, and the mixture of inorganic salts such as ammonia inorganic acid salt, which shows the same solvent solubility as 2-aminobutyramide inorganic acid salt, can also be reduced. We intensively studied to solve the problem.
　その結果、以下に示すように、２－ヒドロキシブチロニトリル（１）をアンモニアと反応させ、２－アミノブチロニトリル（２）を含む反応液を、そのまま直接または、該反応液に無機強塩基或いは無機強塩基水溶液を添加して二層分離し脱水する方法や減圧下で脱気することによりアンモニアを除く方法を講じ、得られた２－アミノブチロニトリル（２）を含む反応液を、無機強塩基とケトン系溶媒の存在下、２－アミノブチロニトリル（２）に対する水の量が３倍モル以下の条件で反応させ、工程（Ａ）で得た２－アミノブチロニトリル（２）に対して、０．６倍モル以上の２－アミノブチルアミドシッフ塩基（３）と０．４倍モル以下の２－アミノブチルアミド（４）を含む反応液を生成させた後、該反応液と無機酸溶液を接触させ、２－アミノブチルアミド無機酸塩（５）を含む結晶スラリー液となし、そのまま直接、またはケトン系溶媒を追加した後に晶析させることにより、色調、純度ともに優れた高品質の２－アミノブチルアミド無機酸塩（５）を収率良く取得できることを見出した。
Figure JPOXMLDOC01-appb-C000008
 （Ｒはメチル基又はエチル基を、Ｘは無機酸アニオンを示す。） As a result, as shown below, 2-hydroxybutyronitrile (1) is reacted with ammonia, and the reaction solution containing 2-aminobutyronitrile (2) is directly or directly added to the reaction solution. Alternatively, a reaction solution containing 2-aminobutyronitrile (2) obtained by adding an inorganic strong base aqueous solution to separate two layers and dehydrating or degassing under reduced pressure to remove ammonia, In the presence of a strong inorganic base and a ketone solvent, the reaction is carried out under the condition that the amount of water with respect to 2-aminobutyronitrile (2) is 3 times mol or less, and 2-aminobutyronitrile (2) obtained in step (A) is obtained. ) In an amount of 0.6-fold mol of 2-aminobutyramide Schiff base (3) and 0.4-fold amount of 2-aminobutyramide (4). The liquid and the inorganic acid solution are contacted, -High quality 2-aminobutyramide inorganic material with excellent color tone and purity by crystallizing as a crystal slurry containing aminobutyramide inorganic acid salt (5) directly or after adding ketone solvent It was found that the acid salt (5) can be obtained with good yield.
Figure JPOXMLDOC01-appb-C000008
 (R represents a methyl group or an ethyl group, and X represents an inorganic acid anion.)
　つまり、アミノニトリル化の際に使用するアンモニアとしてアンモニアガスを用いると、反応液中の水分はアミノニトリル化の際に副生する等モル分のみ含まれることになるが、反応液へ無機強塩基を添加して二層分離する操作を行うことによって、水分量を更に低減することが可能になる。これに対し、アンモニア水を使用すると反応液中の水分量は増加するが、水分量が多すぎる場合は、同じく反応液へ無機強塩基を添加して二層分離する操作を行うことにより水分量の低減が可能となる。この様にして得られた２－アミノブチロニトリル（２）を、無機強塩基の存在下、ケトン系溶媒中で反応させると、反応系の水分が少ないことから２－アミノ基とケトン基との脱水縮合とそれに共役したニトリル基の酸アミド基への加水分解反応が起こるに止まり、シッフ塩基の加水分解がほとんど進行せず、その結果として、生成物である２－アミノブチルアミドシッフ塩基（３）と２－アミノブチルアミド（４）とのうち、２－アミノブチルアミドシッフ塩基（３）が主成分を占める生成物が得られることが明らかとなった。 In other words, when ammonia gas is used as the ammonia used in the aminonitrile formation, the water in the reaction solution is contained only in an equimolar amount by-produced in the aminonitrile formation. It is possible to further reduce the amount of water by performing the operation of adding two layers to separate the two layers. On the other hand, when ammonia water is used, the amount of water in the reaction solution increases. However, if the amount of water is too much, the amount of water can be reduced by adding an inorganic strong base to the reaction solution and separating the two layers. Can be reduced. When the 2-aminobutyronitrile (2) thus obtained is reacted in a ketone solvent in the presence of a strong inorganic base, the reaction system has little water, so that the 2-amino group and the ketone group Dehydration condensation and hydrolysis reaction of the nitrile group conjugated to the acid amide group only occurred, and the hydrolysis of the Schiff base hardly proceeded. As a result, the product 2-aminobutylamide Schiff base ( Of 3) and 2-aminobutyramide (4), it was revealed that a product in which 2-aminobutyramide Schiff base (3) occupies the main component was obtained.
　ところで、無機強塩基の存在下、ケトン系溶媒中で得られたシッフ塩基をα－アミノ酸アミドへ加水分解する為には、大過剰量の水の添加が必要となる。これに対して、無機酸酸性下でシッフ塩基の加水分解と塩形成とを同時に行った場合、ほぼ理論量の水でシッフ塩基の加水分解反応が起こり、実際上、反応系に水分を添加しなくても容易に加水分解反応が進行することが明らかとなった。また、シッフ塩基と等モルの水分が加水分解において消費されるため、更なる水分の低減も可能であることが明らかとなった。 Incidentally, in order to hydrolyze the Schiff base obtained in the ketone solvent in the presence of a strong inorganic base into α-amino acid amide, it is necessary to add a large excess amount of water. On the other hand, when the hydrolysis of the Schiff base and the salt formation are carried out at the same time under the acidic condition of the inorganic acid, the hydrolysis reaction of the Schiff base takes place with almost the theoretical amount of water. In practice, water is added to the reaction system. It became clear that the hydrolysis reaction proceeded easily without it. In addition, it has been clarified that the water can be further reduced because equimolar water is consumed in the hydrolysis with the Schiff base.
　このように、工程（Ｂ）において、２－アミノブチロニトリル（２）から２－アミノブチルアミドシッフ塩基（３）と２－アミノブチルアミド（４）を合成する際、反応液中の水分量を低く制限する操作法を採用することによって、２－アミノブチルアミドシッフ塩基（３）を主成分とする生成物が得られ、さらにこの生成物を用いることにより、工程（Ｃ）において、少ない水分増加量、場合によってはシッフ塩基の加水分解反応に伴う水分減少下に、高速度、高収率で２－アミノブチルアミド無機酸塩（５）に変換できることが判明した。
　２－アミノブチルアミド無機酸塩（５）のケトン系溶媒に対する溶解度は、母液中の水分量が少ないほど低い。よって、母液中の含水率を減らすことによって、結晶分離工程における２－アミノブチルアミド無機酸塩（５）の濾液への損失が低減可能となった。 Thus, when synthesizing 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) from 2-aminobutyronitrile (2) in step (B), the amount of water in the reaction solution By adopting an operation method that restricts the amount of water to a low level, a product containing 2-aminobutyramide Schiff base (3) as a main component is obtained, and further by using this product, in step (C), a small amount of water It has been found that it can be converted to the 2-aminobutyramide inorganic acid salt (5) at a high rate and in a high yield with an increase in the amount and, in some cases, a decrease in water accompanying the hydrolysis reaction of the Schiff base.
The solubility of the 2-aminobutyramide inorganic acid salt (5) in the ketone solvent is lower as the amount of water in the mother liquor is smaller. Therefore, by reducing the water content in the mother liquor, the loss of 2-aminobutyramide inorganic acid salt (5) to the filtrate in the crystal separation step can be reduced.
　この様に、反応液中の水分を低減すると、２－アミノブチルアミド無機酸塩（５）の濾液への損失が低減される。しかし同時に、アミノニトリル化の際に過剰に用いたアンモニアに由来するアンモニア無機酸塩の製品への混入が問題となるが、これについては、アミノニトリル化後にアンモニアの留去を行うことにより、製品中への無機塩類の混入量の低減が可能となった。また、α－アミノ酸アミドは塩基とケトンの存在下で加熱すると、イミダゾリジノンを与えることが知られているが、上記の２－アミノブチルアミドシッフ塩基（３）を、酸性条件下で加水分解と塩形成とを同時に行うと、加熱条件下においてもイミダゾリジノンを副生しないことも見出した。この様に、従来の水およびケトン系溶媒の共存下、塩基性条件下で２－アミノブチロニトリルを２－アミノブチルアミドまで加水分解した後、酸によって中和し２－アミノブチルアミド塩とする場合に比較して、副反応を伴う蒸留濃縮工程を要さず、結晶分離時の濾液への損失が少なく、さらには無機塩類の夾雑量が少ない高純度の２－アミノアルキルアミド無機酸塩を高収率で取得できることを見出し、本発明を完成するに至った。 Thus, when the moisture in the reaction solution is reduced, the loss of 2-aminobutyramide inorganic acid salt (5) to the filtrate is reduced. At the same time, however, the mixing of ammonia mineral acid salt derived from ammonia used in excess of the aminonitrile into the product becomes a problem. The amount of inorganic salts mixed in can be reduced. In addition, α-amino acid amide is known to give imidazolidinone when heated in the presence of a base and a ketone, but the above 2-aminobutyramide Schiff base (3) is hydrolyzed under acidic conditions. It has also been found that imidazolidinone is not by-produced even under heating conditions when the salt formation and salt formation are performed simultaneously. In this way, 2-aminobutyronitrile is hydrolyzed to 2-aminobutyramide under basic conditions in the presence of conventional water and ketone solvents, and then neutralized with acid to give 2-aminobutyramide salt. Compared with the case of the above, a high-purity 2-aminoalkylamide inorganic acid salt that does not require a distillation and concentration step with side reactions, reduces loss to the filtrate during crystal separation, and further reduces the amount of inorganic salt contamination. Has been found to be obtained in a high yield, and the present invention has been completed.
　即ち、本発明は、以下の１）～１７）に記載する、２－ヒドロキシブチロニトリル（１）から、２－アミノブチルアミド無機酸塩（５）を製造する方法に関する。
１）２－ヒドロキシブチロニトリル（１）から、２－アミノブチルアミド無機酸塩（５）を製造する方法において、該製造方法が以下に示す工程（Ａ）、工程（Ｂ）、および工程（Ｃ）を含むことを特徴とする、２－アミノブチルアミド無機酸塩（５）の製造方法。
　工程（Ａ）：２－ヒドロキシブチロニトリル（１）をアンモニアと反応させて、２－アミノブチロニトリル（２）を含む反応液を得る工程。
　工程（Ｂ）：工程（Ａ）で得た反応液を、無機強塩基と、アセトンおよびメチルエチルケトンから選ばれる１種類以上のケトン系溶媒の存在下、２－アミノブチロニトリル（２）に対して水分量が３倍モル以下の条件で反応させ、反応液中に含まれていた２－アミノブチロニトリル（２）に対し、０．６倍モル以上の２－アミノブチルアミドシッフ塩基（３）と０．４倍モル以下の２－アミノブチルアミド（４）を含む反応液を得る工程。
　工程（Ｃ）：工程（Ｂ）で得た反応液に、無機酸または無機酸水溶液を加えて、２－アミノブチルアミド無機酸塩（５）を得る工程。
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000011
 　（但し、Ｒはメチル基またはエチル基である。）
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000013
 　（但し、Ｘは無機酸アニオンである。）
２）工程（Ａ）において、アンモニアとしてアンモニアガスを使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
３）工程（Ａ）において、アンモニアを２－ヒドロキシブチロニトリル（１）に対して１．０～１．５倍モル使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
４）工程（Ａ）において、アンモニアとしてアンモニア水を使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
５）工程（Ａ）において、アンモニア水の濃度が３５質量％以上であり、アンモニアを２－ヒドロキシブチロニトリル（１）に対して１．５～２．５倍モル使用する、４）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
６）工程（Ｂ）において、２－アミノブチロニトリル（２）を含む反応液に無機強塩基または無機強塩基水溶液を加えることによって二層に分離させ、上層の有機相中に含まれていた水を下層の水相へ移行させた後に、上層の２－アミノブチロニトリル（２）を含む反応液を下層の無機強塩基水溶液より分取し、分取した反応液を反応に使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
７）２－アミノブチロニトリル（２）を含む反応液に対して、下層の無機強塩基水溶液中の無機強塩基濃度が１５質量％を下回らないように無機強塩基または無機強塩基水溶液を加える、６）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
８）工程（Ｂ）において、２－アミノブチロニトリル（２）を含む反応液を３０～７６０ｍｍＨｇの減圧下で脱気してアンモニアを留去したものを反応に使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
９）工程（Ｂ）において、無機強塩基を、２－アミノブチロニトリル（２）に対し０．００５～０．１倍モル使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１０）工程（Ｂ）において、無機強強塩基として、水酸化ナトリウム、水酸化カリウムおよび水酸化カルシウムから選ばれる一種以上の無機強塩基を使用する、１）記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１１）工程（Ｂ）において、ケトン系溶媒を、２－アミノブチロニトリル（２）に対し１．０～１２．０倍モル使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１２）工程（Ｂ）において、ケトン系溶媒がアセトンである、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１３）工程（Ｃ）において、工程（Ｂ）で得た反応液を、無機酸または無機酸水溶液と、接触混合後の液ｐＨが１～６になるような酸過剰な比率で接触させる、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１４）工程（Ｃ）において、無機酸または無機酸水溶液として、塩化水素ガスまたは２０質量％以上の塩酸水溶液を使用する、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１５）さらに、工程（Ｃ）で得られた２－アミノブチルアミド無機酸塩（５）を含む液をそのまま直接またはケトン系溶媒中に注加した後に晶析し、析出した結晶を固液分離する工程を含む、１）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１６）母液の含水率が１５質量％以下となる条件範囲下で、２－アミノブチルアミド無機酸塩（５）結晶の晶析と固液分離を行う、１５）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。
１７）ケトン系溶媒がアセトンである、１５）に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 That is, the present invention relates to a method for producing a 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1) described in the following 1) to 17).
1) In the method for producing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1), the production method includes the following steps (A), (B) and ( A process for producing 2-aminobutyramide inorganic acid salt (5), which comprises C).
Step (A): A step of reacting 2-hydroxybutyronitrile (1) with ammonia to obtain a reaction solution containing 2-aminobutyronitrile (2).
Step (B): The reaction solution obtained in Step (A) is added to 2-aminobutyronitrile (2) in the presence of a strong inorganic base and one or more ketone solvents selected from acetone and methyl ethyl ketone. The reaction is carried out under conditions where the water content is 3 times mol or less, and the amount of 2-aminobutyramide Schiff base (3) is 0.6 times mol or more with respect to 2-aminobutyronitrile (2) contained in the reaction solution. And a step of obtaining a reaction solution containing 0.4-fold mol or less of 2-aminobutyramide (4).
Step (C): A step of adding the inorganic acid or the aqueous inorganic acid solution to the reaction solution obtained in the step (B) to obtain the 2-aminobutyramide inorganic acid salt (5).
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000011
 (However, R is a methyl group or an ethyl group.)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000013
 (However, X is an inorganic acid anion.)
2) The process for producing 2-aminobutyramide inorganic acid salt (5) according to 1), wherein ammonia gas is used as ammonia in step (A).
3) In step (A), ammonia is used in an amount of 1.0 to 1.5 times mol of 2-hydroxybutyronitrile (1). 2-aminobutyramide inorganic acid salt (5) according to 1) Manufacturing method.
4) The process for producing a 2-aminobutyramide inorganic acid salt (5) according to 1), wherein ammonia water is used as ammonia in step (A).
5) In step (A), the concentration of aqueous ammonia is 35% by mass or more, and ammonia is used in an amount of 1.5 to 2.5 mol per mol of 2-hydroxybutyronitrile (1). Of 2-aminobutyramide inorganic acid salt (5).
6) In step (B), the reaction solution containing 2-aminobutyronitrile (2) was separated into two layers by adding an inorganic strong base or an inorganic strong base aqueous solution, and was contained in the upper organic phase. After transferring water to the lower aqueous phase, the reaction solution containing 2-aminobutyronitrile (2) in the upper layer is separated from the aqueous inorganic strong base solution in the lower layer, and the separated reaction solution is used for the reaction. A process for producing the 2-aminobutyramide inorganic acid salt (5) according to 1).
7) To the reaction solution containing 2-aminobutyronitrile (2), add an inorganic strong base or an inorganic strong base aqueous solution so that the concentration of the inorganic strong base in the lower inorganic strong base aqueous solution does not fall below 15% by mass. 6) The process for producing 2-aminobutyramide inorganic acid salt (5).
8) In step (B), the reaction solution containing 2-aminobutyronitrile (2) is degassed under a reduced pressure of 30 to 760 mmHg to distill off ammonia, and used in the reaction. A process for producing 2-aminobutyramide inorganic acid salt (5).
9) In step (B), the inorganic strong base is used in an amount of 0.005 to 0.1-fold mol with respect to 2-aminobutyronitrile (2). 5) Production method.
10) The 2-aminobutyramide inorganic acid salt according to 1), wherein at least one inorganic strong base selected from sodium hydroxide, potassium hydroxide and calcium hydroxide is used as the strong inorganic base in step (B) The manufacturing method of (5).
11) The 2-aminobutyramide inorganic acid salt according to 1), wherein the ketone solvent is used in a molar amount of 1.0 to 12.0 times that of 2-aminobutyronitrile (2) in step (B). 5) Production method.
12) The process for producing a 2-aminobutyramide inorganic acid salt (5) according to 1), wherein in the step (B), the ketone solvent is acetone.
13) In step (C), the reaction solution obtained in step (B) is brought into contact with an inorganic acid or an aqueous solution of inorganic acid at an acid excess ratio such that the solution pH after contact mixing is 1 to 6. 2) A production method of 2-aminobutyramide inorganic acid salt (5).
14) The method for producing 2-aminobutyramide inorganic acid salt (5) according to 1), wherein in step (C), hydrogen chloride gas or an aqueous hydrochloric acid solution of 20% by mass or more is used as the inorganic acid or the inorganic acid aqueous solution. .
15) Further, the liquid containing the 2-aminobutyramide inorganic acid salt (5) obtained in the step (C) is crystallized directly or after being poured into a ketone solvent, and the precipitated crystals are separated into solid and liquid. A process for producing the 2-aminobutyramide inorganic acid salt (5) according to 1).
16) 2-aminobutyramide inorganic acid salt (5) Crystallization and solid-liquid separation of the 2-aminobutyramide inorganic acid salt (5) are performed under a condition range in which the water content of the mother liquor is 15% by mass or less. Manufacturing method of inorganic acid salt (5).
17) The process for producing a 2-aminobutyramide inorganic acid salt (5) according to 15), wherein the ketone solvent is acetone.
　２－ヒドロキシブチロニトリル（１）から２－アミノブチルアミド無機酸塩（５）を製造する方法において、２－ヒドロキシブチロニトリル（１）をアンモニアと反応させ、２－アミノブチロニトリル（２）を含む反応液を無機強塩基およびケトン系溶媒の存在下に反応させることにより、主成分の２－アミノブチルアミドシッフ塩基（３）と副次的な成分の２－アミノブチルアミド（４）からなる反応生成物を含む反応液を得、これを無機酸または無機酸水溶液と酸性条件下に接触させることにより、含水率が低くアンモニア無機酸塩等の無機塩類が少ない、２－アミノブチルアミド無機酸塩（５）を含む結晶スラリー液を得ることができる。
　これによって結晶を固液分離する際の母液ロスが低減され、高収率で高純度の２－アミノブチルアミド無機酸塩（５）を製造することが可能となる。 In the process for producing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1), 2-hydroxybutyronitrile (1) is reacted with ammonia to give 2-aminobutyronitrile (2 ) In the presence of a strong inorganic base and a ketone solvent, the main component 2-aminobutyramide Schiff base (3) and the subsidiary component 2-aminobutyramide (4) 2-aminobutyramide having a low water content and a small amount of inorganic salts such as ammonia inorganic acid salt is obtained by contacting a reaction liquid containing a reaction product comprising an inorganic acid or an aqueous inorganic acid solution under acidic conditions. A crystal slurry liquid containing the inorganic acid salt (5) can be obtained.
As a result, the mother liquor loss during the solid-liquid separation of the crystals is reduced, and the 2-aminobutyramide inorganic acid salt (5) with high yield and high purity can be produced.
　本発明は２－ヒドロキシブチロニトリル（１）より２－アミノブチロニトリル（２）を合成する工程（Ａ）、２－アミノブチロニトリル（２）より２－アミノブチルアミドシッフ塩基（３）および２－アミノブチルアミド（４）を合成する工程（Ｂ）、２－アミノブチルアミドシッフ塩基（３）および２－アミノブチルアミド（４）より２－アミノブチルアミド無機酸塩（５）を合成する工程（Ｃ）からなる。
Figure JPOXMLDOC01-appb-C000014
 （Ｒはメチル基又はエチル基を、Ｘは無機酸アニオンを示す。） The present invention comprises a step (A) for synthesizing 2-aminobutyronitrile (2) from 2-hydroxybutyronitrile (1), and a 2-aminobutyramide Schiff base (3) from 2-aminobutyronitrile (2). And 2-aminobutyramide (4) synthesis step (B), 2-aminobutyramide inorganic acid salt (5) is synthesized from 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) Comprising the step (C) of
Figure JPOXMLDOC01-appb-C000014
 (R represents a methyl group or an ethyl group, and X represents an inorganic acid anion.)
　本発明の工程（Ａ）において使用する２－ヒドロキシブチロニトリル（１）は、通常のシアノヒドリン化反応で合成されたものでよく、例えば、プロピオンアルデヒドとシアン化水素から合成されたものが使用できる。 2-Hydroxybutyronitrile (1) used in the step (A) of the present invention may be synthesized by a usual cyanohydrination reaction, for example, synthesized from propionaldehyde and hydrogen cyanide.
　２－ヒドロキシブチロニトリル（１）と反応させるアンモニアとしては、アンモニアガス、液体アンモニアまたはアンモニア水溶液の何れでも使用可能であるが、反応系への水分混入を避けることができ、かつ複雑な反応装置を要さない点でアンモニアガスが望ましい。なお、アンモニアガスはそのままでも使用できるが、塩化カルシウム等を用いた脱水カラムを通過させることによって乾燥アンモニアガスとなした後に用いてもよい。反応に使用するアンモニア量としては、化学量論的に２－ヒドロキシブチロニトリル（１）に対し等モル以上必要であるが、アンモニアガスおよび液体アンモニアを使用する場合、製品中の無機塩の混入を避けるため、出来る限り理論量に近い量であることが好ましく、その意味で２－ヒドロキシブチロニトリル（１）に対し、モル比で１．０～１．５倍モルであることが好ましく、１．０～１．２倍モルであることがより好ましい。アンモニア水を使用する場合は、アンモニアガスおよび液体アンモニアを使用する場合より反応性が低くなること及び後の工程での水分量を少なくすることを考慮し、アンモニア水を３５質量％以上の濃度とすることが好ましく、２－ヒドロキシブチロニトリル（１）に対するアンモニア量は１．５倍～２．５倍モルとすることが好ましく、１．８倍～２．３倍モルとすることがより好ましい。反応温度としては、反応生成物である２－アミノブチロニトリル（２）が二量体等の副生成物を形成しないよう、－５～２５℃の範囲で行うことが好ましく、０～２０℃の範囲で行うことがより好ましい。 As ammonia to be reacted with 2-hydroxybutyronitrile (1), any of ammonia gas, liquid ammonia, and aqueous ammonia solution can be used. However, it is possible to avoid mixing water into the reaction system and a complicated reaction apparatus. Ammonia gas is desirable in that it does not need to be used. In addition, although ammonia gas can be used as it is, it may be used after it is made dry ammonia gas by passing through a dehydration column using calcium chloride or the like. The amount of ammonia used in the reaction must be equimolar or more stoichiometrically with respect to 2-hydroxybutyronitrile (1), but when ammonia gas and liquid ammonia are used, contamination of inorganic salts in the product Therefore, the amount is preferably as close to the theoretical amount as possible, and in that sense, the molar ratio is preferably 1.0 to 1.5 times the molar amount relative to 2-hydroxybutyronitrile (1). It is more preferably 1.0 to 1.2 times mole. When ammonia water is used, the reactivity is lower than when ammonia gas and liquid ammonia are used, and the amount of water in the subsequent process is reduced, so that ammonia water has a concentration of 35% by mass or more. The amount of ammonia relative to 2-hydroxybutyronitrile (1) is preferably 1.5 times to 2.5 times mol, more preferably 1.8 times to 2.3 times mol. . The reaction temperature is preferably in the range of −5 to 25 ° C. so that 2-aminobutyronitrile (2) as a reaction product does not form a by-product such as a dimer, and is preferably 0 to 20 ° C. It is more preferable to carry out in the range.
　本発明の工程（Ｂ）で用いる２－アミノブチロニトリル（２）は、工程（Ａ）で得られた反応液を、そのまま直接または脱水や脱アンモニア処理したものを使用する。なお、工程（Ａ）で得られたもの以外の市中より入手した２－アミノブチロニトリルであっても、本発明の目的に反しない範囲の性状を有するものであれば、工程（Ｂ）の反応原料として使用できるのは勿論のことである。 As the 2-aminobutyronitrile (2) used in the step (B) of the present invention, the reaction solution obtained in the step (A) is used directly or after dehydration or deammonia treatment. In addition, even 2-aminobutyronitrile obtained from the market other than the one obtained in the step (A), as long as it has properties in a range not violating the object of the present invention, the step (B) Of course, it can be used as a reaction raw material.
　２－アミノブチロニトリル（２）の合成後、反応液に無機強塩基または無機強塩基水溶液を加えることによって反応液を二層に分離させて、水が除かれた上層の２－アミノブチロニトリル（２）を含む反応液と、除かれた水を含む下層の無機強塩基水溶液を分取する。二層分離する際に使用する無機強塩基の種類に制限はないが、工業原料として入手し易く、使用後の処理においても便利な水酸化ナトリウム、水酸化カリウムまたは水酸化カルシウム等のアルカリ金属またはアルカリ土類金属の水酸化物が好ましく、特に水酸化ナトリウムが好ましい。無機強塩基の添加は上層中の水分低減が目的であるため、使用する無機強塩基の量としては、得られる下層中の無機塩基濃度が１５質量％以上になるよう加えるのが好ましく、３０質量％以上になるように加えるのがより好ましい。また、得られる下層は、無機強塩基として２－アミノブチルアミドシッフ塩基（３）と２－アミノブチルアミド（４）を含む反応液を得る工程に用いることも可能である。 After the synthesis of 2-aminobutyronitrile (2), the reaction solution is separated into two layers by adding an inorganic strong base or an inorganic strong base aqueous solution to the reaction solution. The reaction solution containing the nitrile (2) and the inorganic strong base aqueous solution containing the removed water are separated. There is no limitation on the type of inorganic strong base used for the two-layer separation, but it is easy to obtain as an industrial raw material, and an alkali metal such as sodium hydroxide, potassium hydroxide or calcium hydroxide, which is convenient for treatment after use, or Alkaline earth metal hydroxides are preferred, and sodium hydroxide is particularly preferred. Since the addition of the inorganic strong base is intended to reduce the water content in the upper layer, the amount of the inorganic strong base used is preferably such that the concentration of the inorganic base in the lower layer to be obtained is 15% by mass or more, and 30% by mass. It is more preferable to add so that it may become more than%. The obtained lower layer can also be used in a step of obtaining a reaction solution containing 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) as an inorganic strong base.
　一方、２－アミノブチロニトリル（２）合成後の脱アンモニア処理に特に制限はないが、処理時間および操作性の面から、圧力３０～７６０ｍｍＨｇの減圧下が好ましく、圧力５０～６００ｍｍＨｇの減圧下がより好ましい。また、無機強塩基の存在下にケトン系溶媒と反応させる際のアンモニア分、すなわち、工程（Ａ）で得た２－アミノブチロニトリル（２）を含む反応液中のアンモニア分は、２－アミノブチロニトリル（２）に対し０．３倍モル以下であることが好ましい。これを上回る場合は工程（Ｃ）で得られる２－アミノブチルアミド無機酸塩（５）の純度が低下するので好ましくない。例えば脱アンモニア条件６００ｍｍＨｇで３０分間とすると、アンモニア分は２－アミノブチロニトリル（２）に対しモル比０．３６から０．２３へ低減され、純度９５％の製品を得ることが出来る（表１参照）。 On the other hand, the deammonia treatment after the synthesis of 2-aminobutyronitrile (2) is not particularly limited, but from the viewpoint of treatment time and operability, a reduced pressure of 30 to 760 mmHg is preferable, and a reduced pressure of 50 to 600 mmHg. Is more preferable. Further, the ammonia content in the reaction with the ketone solvent in the presence of the strong inorganic base, that is, the ammonia content in the reaction solution containing 2-aminobutyronitrile (2) obtained in the step (A) is 2- It is preferable that it is 0.3 times mole or less with respect to aminobutyronitrile (2). If it exceeds the above range, the purity of the 2-aminobutyramide inorganic acid salt (5) obtained in the step (C) is undesirably lowered. For example, when the ammonia removal condition is 600 mmHg and 30 minutes, the ammonia content is reduced from 0.36 to 0.23 with respect to 2-aminobutyronitrile (2), and a product with a purity of 95% can be obtained (Table 1). 1).
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
　本発明の工程（Ｂ）における２－アミノブチルアミドシッフ塩基（３）および２－アミノブチルアミド（４）の合成は、水、無機強塩基、およびケトン系溶媒の存在下、２－アミノブチロニトリル（２）を滴下することによって反応させる。なお、これら反応を行う際の原料の滴下順序に特に制限はないが、反応を逐次的に進行させるため、ケトン系溶媒に無機強塩基を滴下した後、２－アミノブチロニトリル（２）を滴下するのが好ましい。 The synthesis of 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) in the step (B) of the present invention is carried out in the presence of water, a strong inorganic base, and a ketone solvent. The nitrile (2) is reacted by dropping. There are no particular restrictions on the order in which the raw materials are added during these reactions, but in order to allow the reactions to proceed sequentially, an inorganic strong base is added dropwise to the ketone solvent, and then 2-aminobutyronitrile (2) is added. It is preferable to drop.
　本反応で使用する無機強塩基は、アミノ基の活性化を促進し、ケトン系溶媒と反応させオキサゾリジンを経由し２－アミノブチルアミドシッフ塩基（３）および２－アミノブチルアミド（４）を形成する触媒として働いている。用いる無機強塩基の種類に制限はないが、工業原料として入手し易く、使用後の処理においても便利な水酸化ナトリウム、水酸化カリウムおよび水酸化カルシウム等のアルカリ金属またはアルカリ土類金属の水酸化物が好ましく、特に水酸化ナトリウムが好ましい。使用する強塩基の量としては、出来る限り少ない量であることが好ましく、その意味で２－アミノブチロニトリル（２）に対し、モル比で０.００５～０．１倍モルであることが好ましく、０．０２～０．０７倍モルであることがより好ましい。０．００５倍モルを下回るとシッフ塩基となる反応速度の低下が見られ、０．１倍モルを上回る場合は、触媒活性の増加には結びつかず、単に用いた強塩基の中和に要する無機酸量が増え、製品中に混入する無機塩量が多くなるだけで好ましくない。 The inorganic strong base used in this reaction promotes activation of the amino group and reacts with a ketone solvent to form 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) via oxazolidine. Working as a catalyst. There are no restrictions on the type of inorganic strong base used, but hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide, which are readily available as industrial raw materials and are convenient for post-use treatment. In particular, sodium hydroxide is preferred. The amount of the strong base to be used is preferably as small as possible, and in that sense, it is 0.005 to 0.1 times the molar ratio with respect to 2-aminobutyronitrile (2). Preferably, it is 0.02 to 0.07 times mol. When the amount is less than 0.005 mol, a decrease in the reaction rate to become a Schiff base is observed. When the amount exceeds 0.1 mol, the catalyst activity is not increased, and the inorganic content required for neutralization of the strong base used is simply not increased. This is not preferable because the acid amount increases and the amount of inorganic salt mixed in the product increases.
　本発明の工程（Ｂ）で使用するケトン系溶媒の種類に特に制限はないが、例えば、アセトンやメチルエチルケトン、メチルイソブチルケトン、シクロヘキサノンなどのようなケトン系溶媒が好適であり、このうちメチルエチルケトン、アセトンが好ましく、特にアセトンがより好ましい。ケトン系溶媒の使用量は、シッフ塩を形成する上で化学量論的に１当量以上を必要とするが、反応原料や生成物の溶解性や分散性を保つ反応溶媒としての役割を果たし、かつ結晶分離時の濾液への損失を低減できることが要求されることから、原料の２－アミノブチロニトリル（２）に対して１～１２倍モルが好ましく、３～６倍モルの範囲がより好ましい。一方、反応液中に含まれる水に対しては、重量比で４倍以上が好ましく、７倍以上の範囲がより好ましい。 The type of ketone solvent used in the step (B) of the present invention is not particularly limited. For example, ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and the like are preferable, and among these, methyl ethyl ketone, acetone Are preferred, and acetone is particularly preferred. The amount of the ketone solvent used is stoichiometrically more than 1 equivalent to form the Schiff salt, but serves as a reaction solvent that maintains the solubility and dispersibility of the reaction raw materials and products, In addition, since it is required to reduce loss to the filtrate at the time of crystal separation, it is preferably 1 to 12 times by mole, more preferably 3 to 6 times by mole, relative to the starting 2-aminobutyronitrile (2). preferable. On the other hand, with respect to the water contained in the reaction solution, the weight ratio is preferably 4 times or more, and more preferably 7 times or more.
　反応温度は２－アミノブチルアミドシッフ塩基（３）の２－アミノブチルアミド（４）への加水分解反応、および４－イミダゾリジノン体等への副反応を抑制するため－２０～３０℃の温度範囲とすることが好ましく、０～２０℃の温度範囲とすることがより好ましい。３０℃より温度が高いと副反応が顕在化し、０℃より温度が低いと反応時間が長くなり、かつ冷却に伴うエネルギーコストの面で不利となる。なお、反応時間の延長は、２－アミノブチルアミドシッフ塩基（３）が２－アミノブチルアミド（４）へ加水分解された後、α－イミダゾリジノン体の副生を招くことになるので、３～１０時間程度とすることが望ましい。 The reaction temperature is -20 to 30 ° C. in order to suppress hydrolysis reaction of 2-aminobutyramide Schiff base (3) to 2-aminobutyramide (4) and side reaction to 4-imidazolidinone. A temperature range is preferable, and a temperature range of 0 to 20 ° C. is more preferable. If the temperature is higher than 30 ° C., side reactions become apparent, and if the temperature is lower than 0 ° C., the reaction time becomes longer and disadvantageous in terms of energy costs associated with cooling. Note that the extension of the reaction time leads to by-production of α-imidazolidinone after the 2-aminobutyramide Schiff base (3) is hydrolyzed to 2-aminobutyramide (4). It is desirable that the time be about 3 to 10 hours.
　工程（Ｂ）の反応においては、前工程（Ａ）から混入する水および無機強塩基水溶液を添加することによって加わる水が多いほど、２－アミノブチルアミドシッフ塩基（３）が加水分解され、２－アミノブチルアミド（４）の生成量が増加する。例えば、２－アミノブチロニトリル（２）に対し、モル比０．２４の水分量の場合、２－アミノブチルアミドシッフ塩基（３）の生成モル比は、２－アミノブチロニトリル（２）に対し０．８５倍モル生成し、２－アミノブチルアミド（４）は２－アミノブチロニトリル（２）に対し０．０８倍モル生成する。又、２－アミノブチロニトリル（２）に対し、モル比１．１０の水分量の場合、２－アミノブチルアミドシッフ塩基（３）の生成モル比は、２－アミノブチロニトリル（２）に対し０．７６倍モル生成し、２－アミノブチルアミド（４）は２－アミノブチロニトリル（２）に対し０．１８倍モル生成する（表２参照）。 In the reaction of the step (B), the more the water added from the previous step (A) and the inorganic strong base aqueous solution are added, the more the 2-aminobutyramide Schiff base (3) is hydrolyzed. -The amount of aminobutyramide (4) produced increases. For example, when the water content is 0.24 mol relative to 2-aminobutyronitrile (2), the production molar ratio of 2-aminobutyramide Schiff base (3) is 2-aminobutyronitrile (2). 0.85-fold mol of 2-aminobutyramide (4) is formed 0.08-fold mol of 2-aminobutyronitrile (2). In addition, when the water content is 1.10 molar relative to 2-aminobutyronitrile (2), the molar ratio of 2-aminobutyramide Schiff base (3) is 2-aminobutyronitrile (2). 0.76-fold mol of 2-aminobutyramide (4) is formed 0.18-fold mol of 2-aminobutyronitrile (2) (see Table 2).
Figure JPOXMLDOC01-appb-T000016
 　２－アミノブチルアミドシッフ塩基（３）に対する２－アミノブチルアミド（４）の生成比率が高いほど、工程（Ｃ）の反応で消費される水分量が減り反応液中の含水率が高くなるので、目的物である２－アミノブチルアミド無機酸塩（５）の濾液への損失量が増加する。濾液への損失は反応溶媒であるケトン系溶媒の使用量を増やすことによっても低減可能であるが、それに伴う溶剤回収コストが増大するので生産効率を考慮すると好ましくない。その意味で、工程（Ｂ）の反応液に含まれる水分は、２－アミノブチロニトリル（２）合成時に副生した水や、無機強塩基水溶液に由来する水を含めて、２－アミノブチロニトリル（２）に対して３．０モル倍以下にすることが好ましく、その結果として、シッフ塩基の生成率は、工程（Ａ）で得た２－アミノブチロニトリル（２）に対して０．６倍モル以上のものとなることから好ましい。
Figure JPOXMLDOC01-appb-T000016
 The higher the production ratio of 2-aminobutyramide (4) to 2-aminobutyramide Schiff base (3), the lower the amount of water consumed in the reaction of step (C) and the higher the water content in the reaction solution. The loss of the target 2-aminobutyramide inorganic acid salt (5) to the filtrate increases. The loss to the filtrate can also be reduced by increasing the amount of the ketone solvent used as the reaction solvent, but it is not preferable in view of production efficiency because the accompanying solvent recovery cost increases. In that sense, the water contained in the reaction solution of step (B) includes 2-aminobutyronitrile (2), including water by-produced during the synthesis of 2-aminobutyronitrile (2) and water derived from an aqueous inorganic strong base solution. It is preferable to make it 3.0 mol times or less with respect to nitrile (2), and as a result, the Schiff base production rate is with respect to 2-aminobutyronitrile (2) obtained in step (A). It is preferable because it becomes 0.6 times mol or more.
　工程（Ｃ）の無機酸塩の形成において使用する無機酸の種類に特に制限はなく、塩酸、塩化水素ガス、硝酸が例示されるが、装置材質上の問題や廃棄物処理を含めた製法上の有利性の面から塩酸および塩化水素ガスが好ましく、塩酸がさらに好ましい。使用する無機酸はガス状もしくは液状の無機酸、または無機酸水溶液の何れでもよいが、２０質量％以上の濃度の無機酸水溶液またはガス状もしくは液状の無機酸が好ましい。より好ましくは、２－アミノブチルアミドシッフ塩基（３）を主成分とする反応液との接触時に生じる中和熱の発生をできる限り抑えるため、水によって予め希釈し徐熱した２０～６０質量％の濃度の無機酸水溶液である。２０質量％未満の濃度の無機酸水溶液を使用した場合は、中和した反応液中への水の混入量が増し結晶回収率の低下を招く。一方、６０質量％を越える濃度の無機酸水溶液またはガス状もしくは液状の無機酸を使用した場合は、中和した際に中和熱の発生を見る。 There are no particular restrictions on the type of inorganic acid used in the formation of the inorganic acid salt in step (C), and examples include hydrochloric acid, hydrogen chloride gas, and nitric acid. From the viewpoint of the advantages, hydrochloric acid and hydrogen chloride gas are preferable, and hydrochloric acid is more preferable. The inorganic acid used may be either a gaseous or liquid inorganic acid or an aqueous inorganic acid solution, but an inorganic acid aqueous solution having a concentration of 20% by mass or more or a gaseous or liquid inorganic acid is preferred. More preferably, in order to suppress as much as possible the generation of heat of neutralization that occurs upon contact with the reaction solution containing 2-aminobutyramide Schiff base (3) as a main component, 20-60 mass% diluted with water in advance and gradually heated. An aqueous inorganic acid solution having a concentration of When an aqueous inorganic acid solution having a concentration of less than 20% by mass is used, the amount of water mixed into the neutralized reaction solution increases, leading to a decrease in crystal recovery. On the other hand, when an inorganic acid aqueous solution having a concentration exceeding 60% by mass or a gaseous or liquid inorganic acid is used, generation of heat of neutralization is observed upon neutralization.
　無機酸の使用量は、工程（Ｂ）で得られた反応液中に含まれる２－アミノブチルアミドシッフ塩基（３）と２－アミノブチルアミド（４）とが、２－アミノブチルアミド無機酸塩（５）に変換される量であれば特に制限はないが、通常は、工程（Ｂ）において原料として仕込まれた２－アミノブチロニトリル（２）に対して１．０～１．２倍モルを用い、無機酸と接触させた後の反応混合液のｐＨが１～６になるよう添加するのが好ましく、特にｐＨが３～５になるように添加するのが好ましい。なお、反応混合液のｐＨは、無機酸との接触時、２－アミノブチルアミド無機酸塩（５）の結晶を固液分離する段階まで、ｐＨ１～６に維持することが好ましく、特にｐＨ３～５に維持することが好ましい。６を上回るｐＨで維持すると、一部無機酸塩まで進行せず、不安定な２－アミノブチルアミドで止まり、２－アミノブチルアミド無機酸塩の収率が低下する現象が認められる。又１を下回るｐＨで維持すると得られた２－アミノブチルアミド無機酸塩が黄色味を帯びる着色現象が認められる。 The amount of inorganic acid used is such that 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) contained in the reaction solution obtained in step (B) are 2-aminobutyramide inorganic acid. The amount is not particularly limited as long as it is converted into the salt (5), but usually 1.0 to 1.2 with respect to 2-aminobutyronitrile (2) charged as a raw material in the step (B). It is preferable to add so that the pH of the reaction mixture after contacting with an inorganic acid is 1 to 6, particularly preferably 3 to 5, using a double mole. The pH of the reaction mixture is preferably maintained at pH 1-6 until the solid of the 2-aminobutyramide inorganic acid salt (5) is solid-liquid separated at the time of contact with the inorganic acid. 5 is preferably maintained. When the pH is maintained above 6, it is observed that a portion of the inorganic acid salt does not progress, stops with unstable 2-aminobutyramide, and the yield of 2-aminobutyramide inorganic acid salt decreases. Further, when the pH is maintained at a pH of less than 1, the resulting 2-aminobutyramide inorganic acid salt has a yellowish coloring phenomenon.
　２－アミノブチルアミド無機酸塩（５）の合成において、無機酸と２－アミノブチルアミドシッフ塩基（３）の接触後、瞬時に２－アミノブチルアミド無機酸塩（５）の微小な結晶が形成されるため、結晶粒径を大きくして固液分離時の分離性を向上させるため、好ましくは２０～５０℃、より好ましくは３０～４０℃で熟成させることが望ましい。２０℃を下回ると結晶形成が早く進むので、粒径が大きく濾過性に優れた結晶が得られず、５０℃を上回ると溶解度の面から結晶形成が阻害される。熟成時間は熟成温度によって異なるが、例えば４０℃で熟成を行った場合、２～１０時間が好ましい。溶媒組成としては、溶解度を低下させ結晶収率を向上させるため、水分含量は低いほどよい。合成後ケトン系溶媒の追加も可能であるが、工業的生産性の観点から母液中の水分含量は１５％以下が好ましい。
　結晶の固液分離温度は２－アミノブチルアミド無機酸塩（５）の溶解度を下げ、母液ロスを低減させる意味から、－１０から２０℃で行うことが好ましく、０から１０℃で行うことがより好ましい。また、固液分離によって得られた粗結晶に付着した無機塩を含む母液を洗い流すため、アセトン或いはメタノール、エタノール等のアルコールで洗浄することも可能である。その時の結晶の溶解損失を減らすため好ましくは－１０から２０℃、より好ましくは０～１０℃に冷却した前記溶媒で洗浄する。使用される洗浄液量は濾別された粗結晶量の０．５～３倍容を目安とする。なお、母液中に含まれるアセトン等のケトン系溶媒は蒸留操作で容易に回収でき、次反応への利用も可能である。 In the synthesis of 2-aminobutyramide inorganic acid salt (5), after contacting the inorganic acid with 2-aminobutyramide Schiff base (3), minute crystals of 2-aminobutyramide inorganic acid salt (5) are instantaneously formed. In order to increase the crystal grain size and improve the separability at the time of solid-liquid separation, it is preferable to age at 20 to 50 ° C., more preferably 30 to 40 ° C. When the temperature is lower than 20 ° C., crystal formation proceeds rapidly, so that a crystal having a large particle size and excellent filterability cannot be obtained. When the temperature is higher than 50 ° C., crystal formation is hindered from the viewpoint of solubility. Although the aging time varies depending on the aging temperature, for example, when aging is performed at 40 ° C., 2 to 10 hours are preferable. The solvent composition is preferably as low as possible in order to reduce the solubility and improve the crystal yield. Although a ketone solvent can be added after the synthesis, the water content in the mother liquor is preferably 15% or less from the viewpoint of industrial productivity.
The solid-liquid separation temperature of the crystals is preferably from −10 to 20 ° C. and from 0 to 10 ° C. from the viewpoint of reducing the solubility of the 2-aminobutyramide inorganic acid salt (5) and reducing the mother liquor loss. More preferred. Moreover, since the mother liquor containing the inorganic salt adhering to the crude crystals obtained by solid-liquid separation is washed away, it is also possible to wash with acetone or alcohol such as methanol or ethanol. In order to reduce the dissolution loss of the crystal at that time, it is preferably washed with the solvent cooled to −10 to 20 ° C., more preferably 0 to 10 ° C. The amount of the washing solution used is 0.5 to 3 times the amount of the crude crystals separated by filtration. The ketone solvent such as acetone contained in the mother liquor can be easily recovered by distillation operation and can be used for the next reaction.
　ところで、工程（Ａ）における２－ヒドロキシブチロニトリル（１）とアンモニアとの反応は、本反応が脱水置換反応であることより２－ヒドロキシブチロニトリル（１）と同等モルの水が生成することになる。次の２－アミノブチロニトリル（２）より、２－アミノブチルアミドシッフ塩基（３）と２－アミノブチルアミド（４）とを合成する反応では、仮にその全量が２－アミノブチルアミド（４）に変換された場合を想定すると、２－アミノブチロニトリル（２）と同等モルの水が消費されるので、工程（Ａ）と工程（Ｂ）を合わせた場合には、工程（Ａ）で生成した水が工程（Ｂ）で消費され、水の出納としては出入り０モルと計算される。つまり、この場合、工程（Ｂ）で用いた無機強塩基水溶液に伴う水および工程（Ｃ）で用いた無機酸水溶液に伴う水が、工程（Ｃ）で２－アミノブチルアミド無機酸塩（５）結晶を固液分離する際の母液中の水分量となる。 By the way, the reaction between 2-hydroxybutyronitrile (1) and ammonia in the step (A) produces water in the same mole as 2-hydroxybutyronitrile (1) because this reaction is a dehydration substitution reaction. It will be. In the following reaction for synthesizing 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) from 2-aminobutyronitrile (2), the total amount of 2-aminobutyramide (4) Assuming the case of being converted into (), water equivalent to 2-aminobutyronitrile (2) is consumed. Therefore, when step (A) and step (B) are combined, step (A) The water generated in step (B) is consumed in step (B), and the amount of water is calculated as 0 mol. That is, in this case, the water accompanying the inorganic strong base aqueous solution used in the step (B) and the water accompanying the inorganic acid aqueous solution used in the step (C) are converted into the 2-aminobutyramide inorganic acid salt (5 ) The amount of water in the mother liquor when the crystals are separated into solid and liquid.
　つまり、２－アミノブチルアミドシッフ塩基（３）が加水分解され２－アミノブチルアミド無機酸塩（５）となる過程で同等モルの水が消費されるので、シッフ塩基の組成比が高いほど、工程（Ｃ）の無機酸塩形成後の水分量が低減されることになる。即ち、工程（Ａ）で生成した水をできる限り除いて置くことにより、工程（Ｂ）で２－アミノブチルアミドシッフ塩基（３）の組成比率が高い反応生性物が得られる。これによって、工程（Ｃ）の無機酸中和工程で加わる水の一部がシッフ塩基の加水分解に使用され、母液中の水分量は低下する。また、シッフ塩基が主成分であることより、アミノ基が保護される形になるので二量化等の副反応が起こり難くなり、不純物の少ない高品質の製品が得られる。なお、アンモニアが除かれていれば、アンモニウム無機酸塩の生成量も減り、製品中への混入量も低減する。また、工程（Ｂ）で触媒として使用される無機強塩基量も低減されているので、無機強塩基塩の混入量も低減される。 That is, in the process where 2-aminobutyramide Schiff base (3) is hydrolyzed to become 2-aminobutyramide inorganic acid salt (5), an equivalent mole of water is consumed. Therefore, the higher the composition ratio of Schiff base, The amount of water after the formation of the inorganic acid salt in the step (C) is reduced. That is, by removing the water produced in step (A) as much as possible, a reaction product having a high composition ratio of 2-aminobutyramide Schiff base (3) can be obtained in step (B). As a result, part of the water added in the inorganic acid neutralization step of step (C) is used for the hydrolysis of the Schiff base, and the amount of water in the mother liquor decreases. Further, since the amino group is protected because the Schiff base is the main component, side reactions such as dimerization are unlikely to occur, and a high-quality product with few impurities can be obtained. In addition, if ammonia is removed, the production amount of ammonium inorganic acid salt is reduced, and the mixing amount into the product is also reduced. Moreover, since the amount of inorganic strong base used as a catalyst in the step (B) is also reduced, the amount of inorganic strong base salt mixed in is also reduced.
　以下、実施例および比較例をもって本発明をより具体的に説明するが、本発明はこれらの例にのみ限定されるものではない。
　なお、２－ヒドロキシブチロニトリル、２－アミノブチロニトリル及び２－アミノブチルアミド塩酸塩は高速液体クロマトグラフィーを用いて下記ＨＰＬＣ分析条件にて測定し、アンモニア分、水分、２－アミノブチルアミドシッフ塩基及び２－アミノブチルアミドはガスクロマトグラフィーを用いて下記ＧＣ分析条件にて測定した。また、同定などに用いた核磁気共鳴スペクトル（1Ｈ－ＮＭＲ、13Ｃ－ＮＭＲ）は、下記の条件にて測定した。
［ＨＰＬＣ分析条件］
カラム：ＣＡＰＣＥＬＬ　ＰＡＫ　ＣＲ　１：４　φ４．６ｍｍ×２５０ｍｍ　（資生堂）
移動層：水／メタノール＝４９／１（２．３ｍＭ過塩素酸及び５ｍＭペンタンスルホン酸ナトリウム含有）
流速：１ｍｌ／分
検出：ＲＩ
［ＧＣ分析条件］
カラム：ＴＥＮＡＸ　ＴＡ６０／８０　φ２．６ｍｍ×２Ｍ　（ジーエルサイエンス）
温度：８０℃（０分）→１０℃／分→２３０℃（３０分）
キャリアガス：ヘリウム
流速：１０ｍｌ／分
検出：ＴＣＤ
［核磁気共鳴スペクトル測定条件（1Ｈ－ＮＭＲ、13Ｃ－ＮＭＲ）］
測定周波数：５００ＭＨｚ（1Ｈ－ＮＭＲ）、１２５ＭＨｚ（13Ｃ－ＮＭＲ）
溶媒：重クロロホルム
化学シフト基準物質：テトラメチルシラン Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these examples.
In addition, 2-hydroxybutyronitrile, 2-aminobutyronitrile and 2-aminobutyramide hydrochloride were measured under the following HPLC analysis conditions using high performance liquid chromatography, and the ammonia content, moisture, 2-aminobutyramide were measured. The Schiff base and 2-aminobutyramide were measured using gas chromatography under the following GC analysis conditions. Further, nuclear magnetic resonance spectra ( 1 H-NMR, 13 C-NMR) used for identification and the like were measured under the following conditions.
[HPLC analysis conditions]
Column: CAPCELL PAK CR 1: 4 φ4.6 mm × 250 mm (Shiseido)
Moving layer: water / methanol = 49/1 (containing 2.3 mM perchloric acid and 5 mM sodium pentanesulfonate)
Flow rate: 1 ml / min Detection: RI
[GC analysis conditions]
Column: TENAX TA60 / 80 φ2.6mm × 2M (GL Science)
Temperature: 80 ° C (0 minutes) → 10 ° C / minute → 230 ° C (30 minutes)
Carrier gas: Helium Flow rate: 10 ml / min Detection: TCD
[Nuclear magnetic resonance spectrum measurement conditions ( 1 H-NMR, 13 C-NMR)]
Measurement frequency: 500 MHz ( 1 H-NMR), 125 MHz ( 13 C-NMR)
Solvent: Deuterated chloroform chemical shift Reference material: Tetramethylsilane
実施例１
　攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコに２－ヒドロキシブチロニトリル２４．０ｇ（０．２７モル）を入れ、攪拌下、液温を８±２℃に保ちながらアンモニアガス６．０ｇ（０．３５モル[１．３当量／２－ヒドロキシブチロニトリル]）を吹き込んだ後、これを反応温度２０℃にて８時間反応させたところ、２－アミノブチロニトリル水溶液３０．０ｇ（０．２４モル、[２－アミノブチロニトリル純度６７．０％、水分１７．０％、アンモニア分５．０％]）を得た。
　続いて、攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコにアセトン６５．０ｇ（１．１２モル）、４８％水酸化ナトリウム水溶液０．４０ｇ（０．００５モル[０．０２当量／２－アミノブチロニトリル]）を入れ、攪拌下、２－アミノブチロニトリル水溶液３０．０ｇ（０．２４モル）を滴下して、水酸化ナトリウム０．２％、水５．５％[１．２当量／２－アミノブチロニトリル]、２－アミノブチロニトリル２１．１％、アセトン６８．１％の仕込み比率よりなる反応基質液９５．４ｇを調製した。これを反応温度２０℃にて７時間反応させ、２－アミノブチルアミドシッフ塩基２５．８ｇ（０．１８モル[０．７６倍モル／２－アミノブチロニトリル]）および２－アミノブチルアミド３．９ｇ（０．０４モル[０．１６倍モル／２－アミノブチロニトリル]）を含む反応液９５．４ｇを得た。なお、２－アミノブチルアミドシッフ塩基は、1Ｈ－ＮＭＲおよび13Ｃ－ＮＭＲにより同定した。
1Ｈ－ＮＭＲ　δ［ｐｐｍ］：０．８９（ＣＨ 3 －ＣＨ2－ＣＨ＜）；　１．７５，１．８６（ＣＨ3－ＣＨ 2 －ＣＨ＜）；　１．８６，２．０７（（ＣＨ 3 ）2Ｃ＝Ｎ－）；　３．８９（ＣＨ3－ＣＨ2－ＣＨ＜）；　５．６９，６．９１（－ＮＨ 2 ）
13Ｃ－ＮＭＲ　δ［ｐｐｍ］：１０．２（ＣＨ3－ＣＨ2－ＣＨ＜）；　１８．９（ＣＨ3－ＣＨ2－ＣＨ＜）；　２７．８、２９．６（（ＣＨ3）2Ｃ＝Ｎ－）；　６５．２，６５．４（ＣＨ3－ＣＨ2－ＣＨ＜）；１６８．３（（ＣＨ3）2 Ｃ＝Ｎ－）；１７６．５（＞Ｃ＝Ｏ）
　次いで、この反応液と３６％塩酸水溶液３０．７ｇ（０．３０モル）を液温４０℃液ｐＨ４になるように保持しながら少量ずつ接触させて、２－アミノブチルアミド塩酸塩２９．５ｇ（０．２１モル）を得た（収率８０．１％／２－ヒドロキシブチロニトリル基準）。
　滴下後、０℃まで冷却してさらに晶析を図った後、濾過によって２－アミノブチルアミド塩酸塩の白色結晶２８．１ｇ（０．１９モル、純度９１．５％、塩化アンモニウム８．５％、塩化ナトリウム０．０２％）の結晶を取得した。出発原料の２－ヒドロキシブチロニトリルに対する取得収率６９．９％、母液ロス１０．２％であり、不純物のイミダゾリジノンは検出されなかった。また母液の含水率は１５．０％だった。 Example 1
Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, 24.0 g (0.27 mol) of 2-hydroxybutyronitrile was added, and ammonia was stirred while maintaining the liquid temperature at 8 ± 2 ° C. After gas 6.0 g (0.35 mol [1.3 eq / 2-hydroxybutyronitrile]) was blown in, this was reacted at a reaction temperature of 20 ° C. for 8 hours to obtain a 2-aminobutyronitrile aqueous solution. 30.0 g (0.24 mol, [2-aminobutyronitrile purity 67.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
Subsequently, 65.0 g (1.12 mol) of acetone and 0.40 g (0.005 mol [0.02 mol] of 48% sodium hydroxide aqueous solution were added to a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser. Equivalent / 2-aminobutyronitrile]), and 30.0 g (0.24 mol) of 2-aminobutyronitrile aqueous solution was added dropwise with stirring to give 0.2% sodium hydroxide and 5.5% water. A reaction substrate solution 95.4 g having a charging ratio of [1.2 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 21.1%, acetone 68.1% was prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours to give 25.8 g of 2-aminobutylamide Schiff base (0.18 mol [0.76 times mol / 2-aminobutyronitrile]) and 2-aminobutyramide 3 95.4 g of a reaction solution containing 9.9 g (0.04 mol [0.16 mol / 2-aminobutyronitrile]) was obtained. The 2-aminobutylamide Schiff base was identified by 1 H-NMR and 13 C-NMR.
1 H-NMR δ [ppm] : 0.89 (C H 3 -CH 2 -CH <); 1.75,1.86 (CH 3 -C H 2 -CH <); 1.86,2.07 ((C H 3 ) 2 C═N—); 3.89 (CH 3 —CH 2 —C H <); 5.69, 6.91 (—N H 2 )
13 C-NMR δ [ppm] : 10.2 (C H 3 -CH 2 -CH <); 18.9 (CH 3 - C H 2 -CH <); 27.8,29.6 ((C H 3) 2 C = N-); 65.2,65.4 (CH 3 -CH 2 - C H <); 168.3 ((CH 3) 2 C = N -); 176.5 (> C = O)
Next, the reaction solution and 30.7 g (0.30 mol) of 36% hydrochloric acid aqueous solution were contacted little by little while maintaining the solution temperature at 40 ° C. and pH 4 to give 29.5 g of 2-aminobutyramide hydrochloride ( 0.21 mol) was obtained (yield 80.1% / 2-hydroxybutyronitrile basis).
After the dropwise addition, the mixture was cooled to 0 ° C. and further crystallized, and then filtered, 28.1 g of white crystals of 2-aminobutyramide hydrochloride (0.19 mol, purity 91.5%, ammonium chloride 8.5%) , Sodium chloride 0.02%) was obtained. The obtained yield was 69.9% with respect to 2-hydroxybutyronitrile as the starting material, and the mother liquor loss was 10.2%. The impurity imidazolidinone was not detected. The water content of the mother liquor was 15.0%.
実施例２
　攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコに２－ヒドロキシブチロニトリル８３．１ｇ（０．９３モル）を入れ、攪拌下、液温を８±２℃に保ちながらアンモニアガス２０．７ｇ（１．２２モル[１．３当量／２－ヒドロキシブチロニトリル]）を吹き込んだ後、これを反応温度２０℃にて８時間反応させたところ、２－アミノブチロニトリル水溶液１０３．８ｇ（０．８４モル[２－アミノブチロニトリル純度６８．０％、水分１７．０％、アンモニア分５．０％]）を得た。
　この反応液を、内圧６００ｍｍＨｇの減圧下で３０分攪拌し、常圧に戻したところ、２－アミノブチロニトリル水溶液１００．２ｇ（０．８４モル、[２－アミノブチロニトリル純度７０．０％、水分１７．６％、アンモニア分１．５％]を得た。
　続いて、攪拌機、温度計および凝縮器を備えた５００ｍＬ容の四つ口フラスコにアセトン２２８.０ｇ（３．９３モル）、４８％水酸化ナトリウム水溶液１．６ｇ（０．０２モル[０．０２当量／２－アミノブチロニトリル]）を入れ、攪拌下、取得した２－アミノブチロニトリルを１００．２ｇ（０．８４モル）を滴下して、水酸化ナトリウム０．２％、水５．６％[１．１当量／２－アミノブチロニトリル]、２－アミノブチロニトリル２１．２％、アセトン６９．１％の仕込み比率よりなる反応基質液３２９．８ｇを調製した。これを反応温度２０℃にて７時間反応させ、２－アミノブチルアミドシッフ塩基９２．０ｇ（０．６５モル[０．７７倍モル／２－アミノブチロニトリル]）および２－アミノブチルアミド１１．１ｇ（０．１１モル[０．１５倍モル／２－アミノブチロニトリル]）を含む反応液３２９．８ｇを得た。
　次いで、この反応液と３６％塩酸水溶液９１．２ｇ（０．９０モル）を液温４０℃液ｐＨ４になるように保持しながら少量ずつ接触させて、２－アミノブチルアミド塩酸塩１０２．７ｇ（０．７４モル）を得た（収率８０．０％／２－ヒドロキシブチロニトリル基準）。
　滴下後、０℃まで冷却してさらに晶析を図った後、濾過によって２－アミノブチルアミド塩酸塩の白色結晶９７．３ｇ（０．６７モル、純度９５．０％、塩化アンモニウム５．０％、塩化ナトリウム０．０２％）の結晶を取得した。出発原料の２－ヒドロキシブチロニトリルに対する取得収率７１．７％、母液ロス９．０％であり、不純物のイミダゾリジノンは検出されなかった。また母液の含水率は１４．６％だった。 Example 2
Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser was placed 83.1 g (0.93 mol) of 2-hydroxybutyronitrile, and ammonia was stirred while maintaining the liquid temperature at 8 ± 2 ° C. After 20.7 g (1.22 mol [1.3 eq / 2-hydroxybutyronitrile]) of gas was blown in, this was reacted at a reaction temperature of 20 ° C. for 8 hours to obtain a 2-aminobutyronitrile aqueous solution. 103.8 g (0.84 mol [2-aminobutyronitrile purity 68.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
This reaction solution was stirred for 30 minutes under a reduced pressure of 600 mmHg and returned to normal pressure. As a result, 100.2 g (0.84 mol, [2-aminobutyronitrile purity 70.0 mol) of an aqueous 2-aminobutyronitrile solution was obtained. %, Moisture 17.6%, ammonia content 1.5%].
Subsequently, 228.0 g (3.93 mol) of acetone and 1.6 g of 48% aqueous sodium hydroxide solution (0.02 mol [0.02 mol) were added to a 500 mL four-necked flask equipped with a stirrer, a thermometer and a condenser. Equivalent / 2-aminobutyronitrile]), and 100.2 g (0.84 mol) of the obtained 2-aminobutyronitrile was added dropwise with stirring to give 0.2% sodium hydroxide, water 5. A reaction substrate solution (329.8 g) comprising 6% [1.1 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 21.2% and acetone 69.1% was prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours, and 92.0 g of 2-aminobutylamide Schiff base (0.65 mol [0.77-fold mol / 2-aminobutyronitrile]) and 2-aminobutyramide 11 329.8 g of a reaction solution containing 0.1 g (0.11 mol [0.15 mol / 2-aminobutyronitrile]) was obtained.
Next, the reaction solution and 91.2 g (0.90 mol) of 36% hydrochloric acid aqueous solution were brought into contact with each other while maintaining the solution temperature at 40 ° C. and pH 4 to give 102.7 g of 2-aminobutyramide hydrochloride ( 0.74 mol) was obtained (yield 80.0% / 2-hydroxybutyronitrile basis).
After the dropwise addition, the mixture was cooled to 0 ° C. and further crystallized, and then, 97.3 g (0.67 mol, purity 95.0%, ammonium chloride 5.0%) of 2-aminobutyramide hydrochloride was obtained by filtration. , Sodium chloride 0.02%) was obtained. The obtained yield based on 2-hydroxybutyronitrile as a starting material was 71.7%, and the mother liquor loss was 9.0%. The impurity imidazolidinone was not detected. The water content of the mother liquor was 14.6%.
実施例３
　攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコに２－ヒドロキシブチロニトリル８３．１ｇ（０．９３モル）を入れ、攪拌下、液温を８±２℃に保ちながらアンモニアガス２０．７ｇ（１．２２モル[１．３当量／２－ヒドロキシブチロニトリル]）を吹き込んだ後、これを反応温度２０℃にて８時間反応させたところ、２－アミノブチロニトリル水溶液１０３．８ｇ（０．８４モル[２－アミノブチロニトリル純度６８．０％、水分１７．０％、アンモニア分５．０％]）を得た。
　この反応液に４８％水酸化ナトリウム水溶液４０．２ｇ（０．４８モル）を滴下した後、常圧下で３０分攪拌した。３０分静置後、分液により上層液８４．４ｇ（０．８３モル[２－アミノブチロニトリル純度８３．４％、水分４．１％、アンモニア分４．０％]）と下層液５９．６ｇ（水酸化ナトリウム濃度３０．０％）に分取した。
　続いて、攪拌機、温度計および凝縮器を備えた５００ｍＬ容の四つ口フラスコにアセトン２２８．０ｇ（３．９３モル）、４８％水酸化ナトリウム水溶液１．６ｇ（０．０２モル[０．０２当量／２－アミノブチロニトリル]）を入れ、攪拌下、分取した２－アミノブチロニトリルを含む上層液８４．４ｇ（０．８３モル）を滴下して、水酸化ナトリウム０．２％、水１．４％[０．２６当量／２－アミノブチロニトリル]、２－アミノブチロニトリル２１．７％、アセトン７２．７％の仕込み比率よりなる反応基質液３１４．０ｇを調製した。これを反応温度２０℃にて７時間反応させ、２－アミノブチルアミドシッフ塩基１００．３ｇ（０．７１モル[０．８４倍モル／２－アミノブチロニトリル]）および２－アミノブチルアミド７．７ｇ（０．０８モル[０．０９倍モル／２－アミノブチロニトリル]）を含む反応液３１４．０ｇを得た。
　続いて、この反応液と３６％塩酸水溶液９３．３ｇ（０．９２モル）を液温４０℃、液ｐＨ４になるように保持しながら少量ずつ接触させて、２－アミノブチルアミド塩酸塩１０１．５ｇ（０．７３モル）を得た（収率７８．５％／２－ヒドロキシブチロニトリル基準）。
　滴下後、０℃まで冷却してさらに晶析を図った後、濾過によって２－アミノブチルアミド塩酸塩の白色結晶９８．３ｇ（０．６８モル、純度９５．７％、塩化アンモニウム４．３％、塩化ナトリウム０．００％）の結晶を取得した。出発原料の２－ヒドロキシブチロニトリルに対する取得収率７３．０％、母液ロス５．５％であり、不純物のイミダゾリジノンは検出されなかった。また母液の含水率は１３．２％だった。 Example 3
Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser was placed 83.1 g (0.93 mol) of 2-hydroxybutyronitrile, and ammonia was stirred while maintaining the liquid temperature at 8 ± 2 ° C. After 20.7 g (1.22 mol [1.3 eq / 2-hydroxybutyronitrile]) of gas was blown in, this was reacted at a reaction temperature of 20 ° C. for 8 hours to obtain a 2-aminobutyronitrile aqueous solution. 103.8 g (0.84 mol [2-aminobutyronitrile purity 68.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
To this reaction solution, 40.2 g (0.48 mol) of a 48% sodium hydroxide aqueous solution was added dropwise, followed by stirring under normal pressure for 30 minutes. After standing for 30 minutes, 84.4 g (0.83 mol [2-aminobutyronitrile purity 83.4%, moisture 4.1%, ammonia content 4.0%]) and lower layer liquid 59 were separated by liquid separation. It was fractionated to 0.6 g (sodium hydroxide concentration 30.0%).
Subsequently, 228.0 g (3.93 mol) of acetone and 1.6 g of 48% aqueous sodium hydroxide solution (0.02 mol [0.02 mol) were added to a 500 mL four-necked flask equipped with a stirrer, a thermometer and a condenser. Equivalent amount / 2-aminobutyronitrile]), 84.4 g (0.83 mol) of the upper layer solution containing 2-aminobutyronitrile was added dropwise with stirring, and sodium hydroxide 0.2% 314.0 g of a reaction substrate solution having a charge ratio of 1.4% water [0.26 equivalent / 2-aminobutyronitrile], 21.7% 2-aminobutyronitrile, 72.7% acetone was prepared. . This was reacted at a reaction temperature of 20 ° C. for 7 hours, and 100.3 g (0.71 mol [0.84 times mol / 2-aminobutyronitrile]) 2-aminobutyramide Schiff base and 7-aminobutyramide 7 314.0 g of a reaction solution containing 0.77 g (0.08 mol [0.09 mol / 2-aminobutyronitrile]) was obtained.
Subsequently, this reaction solution and 93.3 g (0.92 mol) of 36% hydrochloric acid aqueous solution were contacted little by little while maintaining the solution temperature at 40 ° C. and the solution pH 4 to give 2-aminobutyramide hydrochloride 101. 5 g (0.73 mol) was obtained (yield 78.5% / 2-hydroxybutyronitrile basis).
After the dropwise addition, the mixture was cooled to 0 ° C. for further crystallization, and was then filtered to give 98.3 g (0.68 mol, purity 95.7%, ammonium chloride 4.3%) of 2-aminobutyramide hydrochloride. , Sodium chloride 0.00%) was obtained. The acquisition yield based on 2-hydroxybutyronitrile as a starting material was 73.0%, and the mother liquor loss was 5.5%. The impurity imidazolidinone was not detected. The water content of the mother liquor was 13.2%.
実施例４
　攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコに２－ヒドロキシブチロニトリル１５．９ｇ（０．１８モル）を入れ、攪拌下、液温を約１０℃に保ちながらアンモニアガス３．９ｇ（０．２３モル［１．３当量／２－ヒドロキシブチロニトリル］）を吹き込んだ後、これを反応温度２０℃にて８時間反応させたところ、２－アミノブチロニトリル水溶液１９．８ｇ（０．１７モル[２－アミノブチロニトリル純度７０．０％、水分１７．０％、アンモニア分５．０％]）が得られた。
　この反応液に４８％水酸化ナトリウム水溶液７．９ｇ（０．１０モル）を滴下し、常圧下で３０分攪拌した。３０分静置後、分液により上層液１７．２ｇ（０．１７モル[２－アミノブチロニトリル純度８０．６％、水分４．０％、アンモニア分４．０％]）と下層液１０．５ｇ（水酸化ナトリウム濃度３１．９％）に分取した。
　続いて、分取した２－アミノブチロニトリルを含む上層液を、内圧６００ｍｍＨｇの減圧下で３０分攪拌した後、常圧に戻したところ、２－アミノブチロニトリル水溶液１６．７ｇ（０．１７モル、[２－アミノブチロニトリル純度８３．０％、水分４．２％、アンモニア分１．０％]）を得た。
　続いて、攪拌機、温度計および凝縮器を備えた５００ｍＬ容の四つ口フラスコに、アセトン４３．４ｇ（０．７５モル）、４８％水酸化ナトリウム水溶液０．３ｇ（０．００４モル[０．０２当量／２－アミノブチロニトリル]）を入れ、攪拌下、減圧処理をした２－アミノブチロニトリルを含む上層液１６．７ｇ（０．１６モル）を滴下して、水酸化ナトリウム０．２％、水１．３％[０．２４当量／２－アミノブチロニトリル]、２－アミノブチロニトリル２１．６％、アセトン７２．３％の仕込み比率よりなる反応基質液６０．４ｇを調製した。これを反応温度２０℃にて７時間反応させ、２－アミノブチルアミドシッフ塩基１９．３ｇ（０．１４モル[０．８５倍モル／２－アミノブチロニトリル]）および２－アミノブチルアミド１．３ｇ（０．０１モル[０．０８倍モル／２－アミノブチロニトリル]）を含む反応液６０．４ｇを得た。
　次いで、この反応液と３６％塩酸水溶液１６．０ｇ（０．１６モル）を液温が４０℃、液ｐＨが４になるように保持しながら少量ずつ接触させて、２－アミノブチルアミド塩酸塩１９．３ｇ（０．１４モル）を得た（収率７８．５％／２－ヒドロキシブチロニトリル基準）。
　滴下後、０℃まで冷却してさらに晶析を図った後、濾過によって２－アミノブチルアミド塩酸塩の白色結晶１８．４ｇ（０．１３モル、純度９９．２％、塩化アンモニウム０．８％、塩化ナトリウム０．００％）を得た。出発原料の２－ヒドロキシブチロニトリルに対する取得収率は７３．９％、母液ロス４．６％であり、不純物のイミダゾリジノンは検出されなかった。また母液の含水率は１２．８％だった。 Example 4
2-hydroxybutyronitrile (15.9 g, 0.18 mol) was placed in a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, and ammonia gas was maintained while maintaining the liquid temperature at about 10 ° C. with stirring. After blowing 3.9 g (0.23 mol [1.3 eq / 2-hydroxybutyronitrile]), this was reacted at a reaction temperature of 20 ° C. for 8 hours. As a result, an aqueous 2-aminobutyronitrile solution 19 0.8 g (0.17 mol [2-aminobutyronitrile purity 70.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
To this reaction solution, 7.9 g (0.10 mol) of a 48% aqueous sodium hydroxide solution was added dropwise and stirred for 30 minutes under normal pressure. After standing for 30 minutes, 17.2 g (0.17 mol [2-aminobutyronitrile purity: 80.6%, moisture: 4.0%, ammonia content: 4.0%]) and lower layer liquid 10 were separated by liquid separation. It was fractionated to 0.5 g (sodium hydroxide concentration 31.9%).
Subsequently, the separated upper layer liquid containing 2-aminobutyronitrile was stirred for 30 minutes under a reduced pressure of 600 mmHg and then returned to normal pressure. As a result, 16.7 g (0. 17 mol, [2-aminobutyronitrile purity: 83.0%, water content: 4.2%, ammonia content: 1.0%].
Subsequently, in a 500 mL four-necked flask equipped with a stirrer, a thermometer, and a condenser, 43.4 g (0.75 mol) of acetone and 0.3 g of a 48% sodium hydroxide aqueous solution (0.004 mol [.0. 02 equivalent / 2-aminobutyronitrile]) was added, and 16.7 g (0.16 mol) of an upper layer solution containing 2-aminobutyronitrile treated under reduced pressure was added dropwise with stirring. 60.4 g of a reaction substrate solution comprising 2%, water 1.3% [0.24 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 21.6%, acetone 72.3% Prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours, and 19.3 g of 2-aminobutylamide Schiff base (0.14 mol [0.85 times mol / 2-aminobutyronitrile]) and 2-aminobutyramide 1 60.4 g of a reaction solution containing 3 g (0.01 mol [0.08-fold mol / 2-aminobutyronitrile]) was obtained.
Then, this reaction solution and 16.0 g (0.16 mol) of 36% hydrochloric acid aqueous solution were contacted little by little while maintaining the solution temperature at 40 ° C. and the solution pH at 4, to give 2-aminobutyramide hydrochloride. 19.3 g (0.14 mol) was obtained (yield 78.5% / 2-hydroxybutyronitrile basis).
After the dropwise addition, the mixture was cooled to 0 ° C. for further crystallization, followed by filtration to 18.4 g (0.13 mol, purity 99.2%, ammonium chloride 0.8%) of 2-aminobutyramide hydrochloride. , Sodium chloride 0.00%). The acquisition yield based on 2-hydroxybutyronitrile as a starting material was 73.9%, and the mother liquor loss was 4.6%. The impurity imidazolidinone was not detected. The water content of the mother liquor was 12.8%.
実施例５
　攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコに純水３３．２ｇ（１．８４モル）を入れ、攪拌下、液温を約１０℃に保ちながらアンモニアガス２３．０ｇ（１．３５モル［２．０当量／２－ヒドロキシブチロニトリル］）を吹き込んだ後、２－ヒドロキシブチロニトリル５８．１ｇ（０．６８モル）を攪拌下、液温を約１０℃に保ちながら、５時間で滴下した。これを反応温度２０℃にて３時間反応させたところ、２－アミノブチロニトリル水溶液１１４．３ｇ（０．６０モル[２－アミノブチロニトリル純度４４．７％、水分３９．７％、アンモニア分１０．３％]）が得られた。
　この反応液に４８％水酸化ナトリウム水溶液６２．５ｇ（０．５８モル）を滴下し、常圧下で３０分攪拌した。３０分静置後、分液により上層液７１．３ｇ（０．６０モル[２－アミノブチロニトリル純度７０．３％、水分１２．８％、アンモニア分１０．０％]）と下層液１０５．５g（水酸化ナトリウム濃度２８．４％）に分取した。
　続いて、分取した２－アミノブチロニトリルを含む上層液を、内圧６００ｍｍＨｇの減圧下で３０分攪拌した後、常圧に戻したところ、２－アミノブチロニトリル水溶液６４．９ｇ（０．６０モル、[２－アミノブチロニトリル純度７７．２％、水分１４．０％、アンモニア分１．１％]）を得た。
　続いて、攪拌機、温度計および凝縮器を備えた５００ｍＬ容の四つ口フラスコに、アセトン１６１．５ｇ（２．７８モル）、４８％水酸化ナトリウム水溶液１．２ｇ（０．０１４モル[０．０２当量／２－アミノブチロニトリル]）を入れ、攪拌下、減圧処理をした２－アミノブチロニトリルを含む上層液６４．９ｇ（０．６０モル）を滴下して、水酸化ナトリウム０．２％、水４．０％[０．８３当量／２－アミノブチロニトリル]、２－アミノブチロニトリル２２．０％、アセトン７１．０％の仕込み比率よりなる反応基質液２２７．６ｇを調製した。これを反応温度２０℃にて７時間反応させ、２－アミノブチルアミドシッフ塩基６８．３ｇ（０．４８モル[０．８０倍モル／２－アミノブチロニトリル]）および２－アミノブチルアミド８．０ｇ（０．０８モル[０．１３倍モル／２－アミノブチロニトリル]）を含む反応液２２７．６ｇを得た。
　次いで、この反応液と３６％塩酸水溶液６０．０ｇ（０．６０モル）を液温が４０℃、液ｐＨが４になるように保持しながら少量ずつ接触させて、２－アミノブチルアミド塩酸塩７４．０ｇ（０．５３モル）を得た（収率７８．５％／２－ヒドロキシブチロニトリル基準）。
　滴下後、０℃まで冷却してさらに晶析を図った後、濾過によって２－アミノブチルアミド塩酸塩の白色結晶６７．９ｇ（０．４８モル、純度９９．０％、塩化アンモニウム１．０％、塩化ナトリウム０．００％）を得た。出発原料の２－ヒドロキシブチロニトリルに対する取得収率は７１．３％、母液ロス７．２％であり、不純物のイミダゾリジノンは検出されなかった。また母液の含水率は１４．０％だった。 Example 5
Pure water 33.2 g (1.84 mol) was placed in a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, and ammonia gas 23.0 g (24.0 g) was maintained while maintaining the liquid temperature at about 10 ° C. with stirring. 1.35 mol [2.0 eq / 2-hydroxybutyronitrile]) was blown in, and 58.1 g (0.68 mol) of 2-hydroxybutyronitrile was stirred and the liquid temperature was kept at about 10 ° C. The solution was added dropwise over 5 hours. When this was reacted at a reaction temperature of 20 ° C. for 3 hours, 114.3 g of an aqueous 2-aminobutyronitrile solution (0.60 mol [purity of 2-aminobutyronitrile 44.7%, moisture 39.7%, ammonia Min 10.3%]) was obtained.
To this reaction solution, 62.5 g (0.58 mol) of 48% aqueous sodium hydroxide solution was added dropwise and stirred for 30 minutes under normal pressure. After standing for 30 minutes, 71.3 g (0.60 mol [2-aminobutyronitrile purity 70.3%, moisture 12.8%, ammonia content 10.0%]) and lower layer liquid 105 were separated by liquid separation. To 0.5 g (sodium hydroxide concentration 28.4%).
Subsequently, the separated upper layer liquid containing 2-aminobutyronitrile was stirred for 30 minutes under a reduced pressure of 600 mmHg and then returned to normal pressure. As a result, 64.9 g (0. 60 mol, [2-aminobutyronitrile purity 77.2%, moisture 14.0%, ammonia content 1.1%]).
Subsequently, 16500 g (2.78 mol) of acetone and 1.2 g of a 48% aqueous sodium hydroxide solution (0.014 mol [0. 14 mol [0. 0]) were added to a 500 mL four-necked flask equipped with a stirrer, a thermometer and a condenser. 02 equivalent / 2-aminobutyronitrile]) was added, and 64.9 g (0.60 mol) of an upper layer solution containing 2-aminobutyronitrile treated under reduced pressure was added dropwise with stirring. 227.6 g of a reaction substrate solution comprising 2%, water 4.0% [0.83 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 22.0% and acetone 71.0% were charged. Prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours to give 68.3 g (0.48 mol [0.80-fold mol / 2-aminobutyronitrile]) of 2-aminobutyramide Schiff base and 2-aminobutyramide 8 The reaction liquid 227.6g containing 0.0g (0.08 mol [0.13 times mole / 2-aminobutyronitrile]) was obtained.
Then, this reaction solution and 60.0 g (0.60 mol) of 36% hydrochloric acid aqueous solution were contacted little by little while maintaining the solution temperature at 40 ° C. and the solution pH at 4, to give 2-aminobutyramide hydrochloride. 74.0 g (0.53 mol) was obtained (yield 78.5% / 2-hydroxybutyronitrile basis).
After the dropwise addition, the mixture was cooled to 0 ° C. and further crystallized, and then filtered, 67.9 g of white crystals of 2-aminobutyramide hydrochloride (0.48 mol, purity 99.0%, ammonium chloride 1.0%) , Sodium chloride 0.00%). The yield of the starting material 2-hydroxybutyronitrile was 71.3% and the mother liquor loss was 7.2%, and no impurity imidazolidinone was detected. The water content of the mother liquor was 14.0%.
比較例１
　攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコに２－ヒドロキシブチロニトリル１１７．４ｇ（１．３０モル）を入れ、攪拌下、液温を８±２℃に保ちながらアンモニアガス２７．４ｇ（１．６１モル[１．２当量／２－ヒドロキシブチロニトリル]）を添加し、これを反応温度２０℃にて８時間反応させたところ、６７．８％の２－アミノブチロニトリル水溶液１４４．８ｇ（１．１６モル[２－アミノブチロニトリル純度６７．８％、水分１７.０％、アンモニア分４．５％]）が得られた。
　次いで、攪拌機、温度計および凝縮器を備えた２００ｍＬ容の四つ口フラスコにアセトン１５．８ｇ(０．２７モル[０．２３当量／２－アミノブチロニトリル])、２５％水酸化ナトリウム水溶液１０．７ｇ（０．０７モル[０．０６当量／２－アミノブチロニトリル]）及び水４０．８ｇ（２．２７モル）を入れ、攪拌下、２－アミノブチロニトリル水溶液１４４．８ｇ（１．１６モル）を滴下して、水酸化ナトリウム１．３％、水３４．１％[３．５当量／２－アミノブチロニトリル]、２－アミノブチロニトリル４６．１％、アセトン７．５％の仕込み比率よりなる反応基質液２１２．１ｇを調製した。
　これを反応温度２０℃にて７時間反応させ、２－アミノブチルアミドシッフ塩基１３．８ｇ（０．１０モル[０．０８倍モル／２－アミノブチロニトリル]）および２－アミノブチルアミド８９．０ｇ（０．８７モル[０．７５倍モル／２－アミノブチロニトリル]）を含む反応液２１２．１ｇを得た。
　その後３６％塩酸１３７．０ｇ（１．３５モル）を８±２℃に保持しながら加え、２－アミノブチルアミド塩酸塩を１３０．０ｇ（０．９４モル）合成した（収率７２．３％／２－ヒドロキシブチロニトリル基準）。その後、８４℃、２００ｍｍＨｇで減圧濃縮を行い水分の除去をした後、アセトン２４３．６ｇ（４．２０モル）を滴下した。滴下後０℃まで冷却してさらに晶析を図った後、濾過によって２－アミノブチルアミド塩酸塩の薄黄色結晶１１５．６ｇ（０．７３モル、純度８８．０％、塩化アンモニウム１１．０％、塩化ナトリウム０．９％）の結晶を取得した。取得収率５６．７％／２－ヒドロキシブチロニトリル基準、母液ロス１１．３％／２－ヒドロキシブチロニトリル基準、不純物のイミダゾリジノンは検出されなかった。しかし、上記の濃縮操作により、イミダゾリジノン等の不純物が副生し、２－アミノブチルアミド塩酸塩の量は４．６％減少した。また母液の含水率は１３．１％だった。
Figure JPOXMLDOC01-appb-T000017
 Comparative Example 1
Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, 117.4 g (1.30 mol) of 2-hydroxybutyronitrile was placed, and ammonia was maintained while maintaining the liquid temperature at 8 ± 2 ° C. with stirring. 27.4 g of gas (1.61 mol [1.2 eq / 2-hydroxybutyronitrile]) was added and reacted at a reaction temperature of 20 ° C. for 8 hours. As a result, 67.8% 2-amino 144.8 g (1.16 mol [2-aminobutyronitrile purity 67.8%, moisture 17.0%, ammonia content 4.5%]) of an aqueous solution of butyronitrile was obtained.
Next, 15.8 g of acetone (0.27 mol [0.23 equivalent / 2-aminobutyronitrile]), 25% aqueous sodium hydroxide solution was added to a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser. 10.7 g (0.07 mol [0.06 equivalent / 2-aminobutyronitrile]) and 40.8 g (2.27 mol) of water were added, and 144.8 g of a 2-aminobutyronitrile aqueous solution was added with stirring. 1.16 mol) was added dropwise, sodium hydroxide 1.3%, water 34.1% [3.5 equivalents / 2-aminobutyronitrile], 2-aminobutyronitrile 46.1%, acetone 7 A reaction substrate solution 212.1 g having a charging ratio of 5% was prepared.
This was reacted at a reaction temperature of 20 ° C. for 7 hours, and 13.8 g of 2-aminobutyramide Schiff base (0.10 mol [0.08-fold mol / 2-aminobutyronitrile]) and 2-aminobutyramide 89 212.1 g of a reaction solution containing 0.0 g (0.87 mol [0.75 mol / 2-aminobutyronitrile]) was obtained.
Thereafter, 137.0 g (1.35 mol) of 36% hydrochloric acid was added while maintaining the temperature at 8 ± 2 ° C. to synthesize 130.0 g (0.94 mol) of 2-aminobutyramide hydrochloride (yield 72.3%). / 2-hydroxybutyronitrile standard). Then, after concentration under reduced pressure at 84 ° C. and 200 mmHg to remove moisture, 243.6 g (4.20 mol) of acetone was added dropwise. After dropwise addition, the mixture was cooled to 0 ° C. and further crystallized, and then filtered to give 115.6 g (0.73 mol, purity 88.0%, ammonium chloride 11.0%) of 2-aminobutyramide hydrochloride. , Sodium chloride 0.9%) was obtained. Acquisition yield 56.7% / 2-hydroxybutyronitrile standard, mother liquor loss 11.3% / 2-hydroxybutyronitrile standard, no impurity imidazolidinone was detected. However, impurities such as imidazolidinone were by-produced by the above concentration operation, and the amount of 2-aminobutyramide hydrochloride was reduced by 4.6%. The water content of the mother liquor was 13.1%.
Figure JPOXMLDOC01-appb-T000017

Claims (17)

  1. 　２－ヒドロキシブチロニトリル（１）から、２－アミノブチルアミド無機酸塩（５）を製造する方法において、該製造方法が以下に示す工程（Ａ）、工程（Ｂ）、および工程（Ｃ）を含むことを特徴とする、２－アミノブチルアミド無機酸塩（５）の製造方法。
    　工程（Ａ）：２－ヒドロキシブチロニトリル（１）をアンモニアと反応させて、２－アミノブチロニトリル（２）を含む反応液を得る工程。
    　工程（Ｂ）：工程（Ａ）で得た反応液を、無機強塩基と、アセトンおよびメチルエチルケトンから選ばれる１種類以上のケトン系溶媒の存在下、２－アミノブチロニトリル（２）に対して水分量が３倍モル以下の条件で反応させ、反応液中に含まれていた２－アミノブチロニトリル（２）に対し、０．６倍モル以上の２－アミノブチルアミドシッフ塩基（３）と０．４倍モル以下の２－アミノブチルアミド（４）を含む反応液を得る工程。
    　工程（Ｃ）：工程（Ｂ）で得た反応液に、無機酸または無機酸水溶液を加えて、２－アミノブチルアミド無機酸塩（５）を得る工程。
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
     　（但し、Ｒはメチル基またはエチル基である。）
    Figure JPOXMLDOC01-appb-C000004
     　（但し、Ｘは無機酸アニオンである。）     In the method for producing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1), the production method includes the following steps (A), (B), and (C): A process for producing a 2-aminobutyramide inorganic acid salt (5), comprising:
    Step (A): A step of reacting 2-hydroxybutyronitrile (1) with ammonia to obtain a reaction solution containing 2-aminobutyronitrile (2).
    Step (B): The reaction solution obtained in Step (A) is added to 2-aminobutyronitrile (2) in the presence of a strong inorganic base and one or more ketone solvents selected from acetone and methyl ethyl ketone. The reaction is carried out under conditions where the water content is 3 times mol or less, and the amount of 2-aminobutyramide Schiff base (3) is 0.6 times mol or more with respect to 2-aminobutyronitrile (2) contained in the reaction solution. And a step of obtaining a reaction solution containing 0.4-fold mol or less of 2-aminobutyramide (4).
    Step (C): A step of adding the inorganic acid or the aqueous inorganic acid solution to the reaction solution obtained in the step (B) to obtain the 2-aminobutyramide inorganic acid salt (5).
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
     (However, R is a methyl group or an ethyl group.)
    Figure JPOXMLDOC01-appb-C000004
     (However, X is an inorganic acid anion.)
  2. 　工程（Ａ）において、アンモニアとしてアンモニアガスを使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein ammonia gas is used as ammonia in the step (A).
  3. 　工程（Ａ）において、アンモニアを２－ヒドロキシブチロニトリル（１）に対して１．０～１．５倍モル使用する、請求項２に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The 2-aminobutyramide inorganic acid salt (5) according to claim 2, wherein ammonia is used in the step (A) in an amount of 1.0 to 1.5 times mol with respect to 2-hydroxybutyronitrile (1). Production method.
  4. 　工程（Ａ）において、アンモニアとしてアンモニア水を使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein ammonia water is used as ammonia in step (A).
  5. 　工程（Ａ）において、アンモニア水の濃度が３５質量％以上であり、アンモニアを２－ヒドロキシブチロニトリル（１）に対して１．５～２．５倍モル使用する、請求項４に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 5. The step (A) according to claim 4, wherein the ammonia water has a concentration of 35% by mass or more, and ammonia is used in an amount of 1.5 to 2.5 times mol with respect to 2-hydroxybutyronitrile (1). A process for producing 2-aminobutyramide inorganic acid salt (5).
  6. 　工程（Ｂ）において、２－アミノブチロニトリル（２）を含む反応液に無機強塩基または無機強塩基水溶液を加えることによって二層に分離させ、上層の有機相中に含まれていた水を下層の水相へ移行させた後に、上層の２－アミノブチロニトリル（２）を含む反応液を下層の無機強塩基水溶液より分取し、分取した反応液を反応に使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 In the step (B), the reaction solution containing 2-aminobutyronitrile (2) is separated into two layers by adding an inorganic strong base or an aqueous solution of strong inorganic base, and water contained in the upper organic phase is removed. The reaction liquid containing 2-aminobutyronitrile (2) in the upper layer is separated from the lower aqueous strong inorganic base solution after being transferred to the lower aqueous phase, and the separated reaction liquid is used for the reaction. 2. The process for producing a 2-aminobutyramide inorganic acid salt (5) according to 1.
  7. 　２－アミノブチロニトリル（２）を含む反応液に対して、下層の無機強塩基水溶液中の無機強塩基濃度が１５質量％を下回らないように無機強塩基または無機強塩基水溶液を加える、請求項６に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 An inorganic strong base or an inorganic strong base aqueous solution is added to the reaction solution containing 2-aminobutyronitrile (2) so that the concentration of the inorganic strong base in the lower inorganic strong base aqueous solution does not fall below 15% by mass. Item 7. A process for producing a 2-aminobutyramide inorganic acid salt (5) according to Item 6.
  8. 　工程（Ｂ）において、２－アミノブチロニトリル（２）を含む反応液を３０～７６０ｍｍＨｇの減圧下で脱気してアンモニアを留去したものを反応に使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 2. The process according to claim 1, wherein in the step (B), the reaction liquid containing 2-aminobutyronitrile (2) is degassed under a reduced pressure of 30 to 760 mmHg to distill off ammonia, and used in the reaction. -Method for producing aminobutyramide inorganic acid salt (5).
  9. 　工程（Ｂ）において、無機強塩基を、２－アミノブチロニトリル（２）に対し０．００５～０．１倍モル使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein in step (B), the inorganic strong base is used in an amount of 0.005 to 0.1 mol per mol of 2-aminobutyronitrile (2). ) Manufacturing method.
  10. 　工程（Ｂ）において、無機強塩基として、水酸化ナトリウム、水酸化カリウムおよび水酸化カルシウムから選ばれる一種以上の無機強塩基を使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The 2-aminobutyramide inorganic acid salt according to claim 1, wherein in the step (B), at least one inorganic strong base selected from sodium hydroxide, potassium hydroxide and calcium hydroxide is used as the inorganic strong base. 5) Production method.
  11. 　工程（Ｂ）において、ケトン系溶媒を、２－アミノブチロニトリル（２）に対し１．０～１２．０倍モル使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein in step (B), the ketone solvent is used in an amount of 1.0 to 12.0 times moles relative to 2-aminobutyronitrile (2). ) Manufacturing method.
  12. 　工程（Ｂ）において、ケトン系溶媒がアセトンである、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein in the step (B), the ketone solvent is acetone.
  13. 　工程（Ｃ）において、工程（Ｂ）で得た反応液を、無機酸または無機酸水溶液と、接触混合後の液ｐＨが１～６になるような酸過剰な比率で接触させる、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 In the step (C), the reaction solution obtained in the step (B) is brought into contact with an inorganic acid or an inorganic acid aqueous solution at an acid excess ratio such that the solution pH after contact mixing is 1 to 6. A process for producing the 2-aminobutyramide inorganic acid salt (5) described in 1.
  14. 　工程（Ｃ）において、無機酸または無機酸水溶液として、塩化水素ガスまたは２０質量％以上の塩酸水溶液を使用する、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein, in step (C), hydrogen chloride gas or a 20% by mass or more hydrochloric acid aqueous solution is used as the inorganic acid or the inorganic acid aqueous solution.
  15. 　さらに、工程（Ｃ）で得られた２－アミノブチルアミド無機酸塩（５）を含む液をそのまま直接またはケトン系溶媒中に注加した後に晶析し、析出した結晶を固液分離する工程を含む、請求項１に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 Further, the step of crystallizing the liquid containing the 2-aminobutyramide inorganic acid salt (5) obtained in step (C) directly or after pouring into a ketone solvent, and separating the precipitated crystals into a solid-liquid separation The process for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, comprising
  16. 　母液の含水率が１５質量％以下となる条件範囲下で、２－アミノブチルアミド無機酸塩（５）結晶の晶析と固液分離を行う、請求項１５に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The 2-aminobutyramide inorganic substance according to claim 15, wherein the 2-aminobutyramide inorganic acid salt (5) crystals are crystallized and solid-liquid separated under a condition range in which the water content of the mother liquor is 15% by mass or less. Manufacturing method of acid salt (5).
  17. 　ケトン系溶媒がアセトンである、請求項１５に記載の２－アミノブチルアミド無機酸塩（５）の製造方法。 The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 15, wherein the ketone solvent is acetone.
PCT/JP2010/062274 2009-07-22 2010-07-21 Process for producing inorganic acid salt of 2-aminobutylamide WO2011010677A1 (en)

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