JP5613162B2 - Method for producing 2-aminobutyramide inorganic acid salt - Google Patents

Description

（但し、Ｘは無機酸アニオンである。）The present invention relates to a method for producing 2-aminobutyramide inorganic acid salt (5) having high purity and excellent quality from 2-hydroxybutyronitrile (1) economically and simply at a high yield. A 2-aminobutyramide inorganic acid salt having high purity and excellent quality is very useful as a raw material for synthesizing pharmaceuticals.

(However, X is an inorganic acid anion.)

  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 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.

  On the other hand, a method for synthesizing an α-amino acid amide by reacting α-amino nitrile with a base and a ketone in an aqueous medium has been reported (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, whether 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 in that the α-amino acid amide and the ketone are condensed during the distillation and concentration operation to produce 4-imidazolidinone as a by-product, resulting in a decrease in yield and purity.

  In contrast, 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, but when applied to a highly water-soluble 2-aminobutyramide inorganic acid salt, 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.

  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.

Japanese Patent Publication No.43-10615 JP-A-52-25701 JP-A-53-82707 JP-A-57-158743 JP 2001-247529 A

  Provided is a method for easily producing a high-purity 2-aminobutyramide inorganic acid salt (5) from a raw material 2-hydroxybutyronitrile (1) with a high yield. That is, this invention is providing the method excellent in economical efficiency which can manufacture 2-aminobutyramide inorganic acid salt (5) useful as a pharmaceutical raw material etc. with a high yield.

  The present invention relates to a method for producing a 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1) through amination and Schiff basification.

  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. Since 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 showing the same solvent solubility as 2-aminobutyramide inorganic acid salt can be reduced. We intensively studied to solve the problem.

（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 a strong inorganic 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. ), A reaction solution containing 0.6-fold mol or more of 2-aminobutyramide Schiff base (3) and 0.4-fold mol or less of 2-aminobutyramide (4) is produced. The liquid and the inorganic acid solution are contacted, -A high-quality 2-aminobutyramide inorganic compound that is excellent in color tone and purity by being crystallized as a crystal slurry liquid containing aminobutyramide inorganic acid salt (5), directly or after adding a ketonic solvent. It was found that the acid salt (5) can be obtained with good yield.

(R represents a methyl group or an ethyl group, and X represents an inorganic acid anion.)

  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 an inorganic strong base, the reaction system has little water, and therefore the 2-amino group and the ketone group Dehydration condensation and hydrolysis reaction of the nitrile group conjugated to the acid amide group occurs, and the hydrolysis of the Schiff base hardly proceeds. As a result, the product 2-aminobutylamide Schiff base ( It became clear that the product in which 2-aminobutyramide Schiff base (3) occupies the main component was obtained among 3) and 2-aminobutyramide (4).

  By the way, in order to hydrolyze the Schiff base obtained in a ketone solvent into an α-amino acid amide in the presence of a strong inorganic base, 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.

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-aminobutylamide Schiff base (3) as a main component can be obtained, and by using this product, in step (C), a small amount of moisture is obtained. 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 of water 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, loss of 2-aminobutyramide inorganic acid salt (5) to the filtrate in the crystal separation step can be reduced.

  Thus, if the water | moisture content in a reaction liquid is reduced, the loss to the filtrate of 2-aminobutyramide inorganic acid salt (5) will be 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-mentioned 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. High purity 2-aminoalkylamide inorganic acid salt that does not require a distillation and concentration step with side reaction, less loss to the filtrate at the time of crystal separation, and less contaminated inorganic salts Has been found to be obtained in a high yield, and the present invention has been completed.

（但し、Ｒはメチル基またはエチル基である。）

（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, this invention relates to the method of manufacturing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1) described in the following 1) -17).
1) In the method for producing 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1), the production method shows the following steps (A), (B), and ( A process for producing a 2-aminobutyramide inorganic acid salt (5), comprising 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 the condition that 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 times 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).

(However, R is a methyl group or an ethyl group.)

(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) The 2-aminobutyramide inorganic acid salt (5) according to 1), wherein ammonia is used in the step (A) in an amount of 1.0 to 1.5 moles relative to 2-hydroxybutyronitrile (1) Manufacturing method.
4) The method for producing 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). The manufacturing method 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 the water is transferred 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. The manufacturing method of 2-aminobutyramide inorganic acid salt (5) as described in 1).
7) To the reaction solution containing 2-aminobutyronitrile (2), an inorganic strong base or an inorganic strong base aqueous solution is added 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 production method of 2-aminobutyramide inorganic acid salt (5) according to 6).
8) In the step (B), the reaction solution containing 2-aminobutyronitrile (2) is degassed under a reduced pressure of 30 to 760 mmHg, and the ammonia is distilled off. The manufacturing method of 2-aminobutyramide inorganic acid salt (5).
9) In step (B), an inorganic strong base is used in an amount of 0.005 to 0.1 times mol of 2-aminobutyronitrile (2). 5) Production method.
10) In step (B), at least one inorganic strong base selected from sodium hydroxide, potassium hydroxide and calcium hydroxide is used as the inorganic strong base, 2-aminobutyramide inorganic acid salt according to 1) The manufacturing method of (5).
11) The 2-aminobutyramide inorganic acid salt according to 1), wherein the ketone solvent is used in an amount of 1.0 to 12.0 times mol to 2-aminobutyronitrile (2) in step (B). 5) Production method.
12) The method 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 inorganic acid solution at an acid-excess ratio such that the solution pH after contact mixing is 1 to 6. ) 2-aminobutyramide inorganic acid salt (5).
14) The method for producing 2-aminobutyramide inorganic acid salt (5) according to 1), wherein 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 in the step (C). .
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 subjected to solid-liquid separation. The manufacturing method of 2-aminobutyramide inorganic acid salt (5) as described in 1) including the process to carry out.
16) 2-aminobutyramide according to 15), wherein crystallization and solid-liquid separation of 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 method for producing a 2-aminobutyramide inorganic acid salt (5) according to 15), wherein the ketone solvent is acetone.

In the method 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 an inorganic strong 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 by contacting a reaction liquid containing a reaction product comprising an inorganic acid or an aqueous acid solution under acidic conditions. A crystal slurry liquid containing the inorganic acid salt (5) can be obtained.
As a result, mother liquor loss during solid-liquid separation of crystals is reduced, and it becomes possible to produce 2-aminobutyramide inorganic acid salt (5) with high yield and high purity.

（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 includes a step (A) for synthesizing 2-aminobutyronitrile (2) from 2-hydroxybutyronitrile (1), and a 2-aminobutyramide Schiff base (3) from 2-aminobutyronitrile (2). Step (B) for synthesizing 2-aminobutyramide (4), 2-aminobutyramide inorganic acid salt (5) is synthesized from 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) Comprising the step (C) of

(R represents a methyl group or an ethyl group, and X represents an inorganic acid anion.)

  The 2-hydroxybutyronitrile (1) used in the step (A) of the present invention may be one synthesized by a normal cyanohydrination reaction, and for example, one synthesized from propionaldehyde and hydrogen cyanide can be used.

  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 is stoichiometrically more than equimolar 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 mole of 2-hydroxybutyronitrile (1). It is more preferable that it is 1.0-1.2 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 with respect to 2-hydroxybutyronitrile (1) is preferably 1.5 times to 2.5 times mol, more preferably 1.8 times to 2.3 times mol. . As reaction temperature, it is preferable to carry out in the range of -5-25 degreeC so that 2-aminobutyronitrile (2) which is a reaction product may not form by-products, such as a dimer, 0-20 degreeC. It is more preferable to carry out in the range.

  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 deammonification treatment. In addition, even if it is 2-aminobutyronitrile obtained from the market other than what was obtained at the process (A), if it has the property of the range which is not contrary to the objective of this invention, a process (B) Of course, it can be used as a reaction raw material.

  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, and the upper layer of 2-aminobutyronitrile from which water has been removed is removed. 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%. Moreover, the lower layer obtained can also be used for the process of obtaining the reaction liquid containing 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) as an inorganic strong base.

  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. In addition, the ammonia content in the reaction with the ketone solvent in the presence of an inorganic strong 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). When exceeding this, since the purity of 2-aminobutyramide inorganic acid salt (5) obtained at a process (C) falls, it is not preferable. 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).

  The synthesis of 2-aminobutyramide Schiff base (3) and 2-aminobutyramide (4) in 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. In addition, although there is no restriction | limiting in particular in the dripping order of the raw material at the time of performing these reaction, in order to advance reaction sequentially, after dripping an inorganic strong base to a ketone solvent, 2-aminobutyronitrile (2) is added. It is preferable to drop.

  The inorganic strong base used in this reaction promotes the 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 strong base to be used is preferably as small as possible, and in that sense, it is 0.005 to 0.1-fold moles with respect to 2-aminobutyronitrile (2). Preferably, it is 0.02-0.07 times mole. 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.

  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 that the loss to the filtrate at the time of crystal separation can be reduced, the amount is preferably 1 to 12 times mol, more preferably 3 to 6 times mol relative to the raw material 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.

  The reaction temperature is -20 to 30 ° C. to suppress hydrolysis reaction of 2-aminobutyramide Schiff base (3) to 2-aminobutyramide (4) and side reaction to 4-imidazolidinone form. It is preferable to set it as a temperature range, and it is more preferable to set it as the temperature range of 0-20 degreeC. 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. In addition, since the extension of the reaction time leads to by-production of an 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.

  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 mole ratio relative to 2-aminobutyronitrile (2), the production mole ratio of 2-aminobutyramide Schiff base (3) is 2-aminobutyronitrile (2). 0.85-fold mol of 2-aminobutyramide (4) is produced at 0.08-fold mol of 2-aminobutyronitrile (2). In addition, when the water content is a molar ratio of 1.10 with respect to 2-aminobutyronitrile (2), the production molar ratio of 2-aminobutyramide Schiff base (3) is 2-aminobutyronitrile (2). The amount of 2-aminobutyramide (4) is 0.18 times that of 2-aminobutyronitrile (2) (see Table 2).

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。

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 amount of loss of 2-aminobutyramide inorganic acid salt (5), which is the target product, into 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 production | generation rate of the Schiff base is with respect to 2-aminobutyronitrile (2) obtained at the process (A). It is preferable because it becomes 0.6 times mol or more.

  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% by mass diluted in advance with water 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.

  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. Although there will be no restriction | limiting in particular if it is the quantity converted into salt (5), Usually, 1.0-1.2 with respect to 2-aminobutyronitrile (2) charged as a raw material in a process (B). It is preferable to add so that the pH of the reaction mixture after contact with the inorganic acid is 1 to 6, and particularly so that the pH is 3 to 5. The pH of the reaction mixture is preferably maintained at pH 1 to 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 maintained at a pH higher than 6, a phenomenon is observed in which some inorganic acid salts do not progress and are stopped with unstable 2-aminobutyramide, and the yield of 2-aminobutyramide inorganic acid salt is reduced. Further, when the pH is maintained at a pH lower than 1, the resulting 2-aminobutyramide inorganic acid salt is colored yellow.

In the synthesis of the 2-aminobutyramide inorganic acid salt (5), after the contact between the inorganic acid and the 2-aminobutyramide Schiff base (3), minute crystals of the 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 crystal is preferably from -10 to 20 ° C., preferably 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.

  By the way, the reaction of 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 step (B) and the water accompanying the inorganic acid aqueous solution used in step (C) are converted into 2-aminobutyramide inorganic acid salt (5 ) The amount of water in the mother liquor when the crystals are separated into solid and liquid.

  That is, since the equivalent mole of water is consumed in the process in which 2-aminobutyramide Schiff base (3) is hydrolyzed to become 2-aminobutyramide inorganic acid salt (5), 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, a reaction product having a high composition ratio of 2-aminobutyramide Schiff base (3) is obtained in step (B) by removing the water produced in step (A) as much as possible. 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.

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 ammonia content, moisture, 2-aminobutyramide The Schiff base and 2-aminobutyramide were measured by gas chromatography under the following GC analysis conditions. Moreover, nuclear magnetic resonance spectrum using etc. Identification ^{(1 H-NMR, 13 C} -NMR) 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

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 put, and ammonia was maintained while maintaining the liquid temperature at 8 ± 2 ° C. with stirring. 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, and 25.8 g of 2-aminobutyramide Schiff base (0.18 mol [0.76 times mol / 2-aminobutyronitrile]) and 2-aminobutyramide 3 95.4 g of a reaction solution containing .9 g (0.04 mol [0.16 mol / 2-aminobutyronitrile]) was obtained. The 2-aminobutyramide 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, this reaction solution and 30.7 g (0.30 mol) of a 36% aqueous hydrochloric acid solution were brought into contact with each other while maintaining a liquid temperature of 40 ° C. and a pH of 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 acquisition yield based on 2-hydroxybutyronitrile as a starting material was 69.9%, and the mother liquor loss was 10.2%. The impurity imidazolidinone was not detected. The water content of the mother liquor was 15.0%.

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 maintained while maintaining the liquid temperature at 8 ± 2 ° C. with stirring. 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. As a result, an aqueous 2-aminobutyronitrile solution was obtained. 103.8 g (0.84 mol [2-aminobutyronitrile purity 68.0%, moisture 17.0%, ammonia content 5.0%]) was obtained.
The 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 of a 2-aminobutyronitrile aqueous solution (0.84 mol, [2-aminobutyronitrile purity 70.0 %, 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]), 100.2 g (0.84 mol) of the obtained 2-aminobutyronitrile was added dropwise with stirring, sodium hydroxide 0.2%, 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, this reaction solution and 91.2 g (0.90 mol) of 36% hydrochloric acid aqueous solution were brought into contact little by little while maintaining the solution temperature at 40 ° C. to a pH of 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 acquisition yield based on 2-hydroxybutyronitrile as a starting material was 71.7% and the mother liquor loss was 9.0%, and no impurity imidazolidinone was detected. The water content of the mother liquor was 14.6%.

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 maintained while maintaining the liquid temperature at 8 ± 2 ° C. with stirring. 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. As a result, an aqueous 2-aminobutyronitrile solution was obtained. 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) / 2-aminobutyronitrile]), and 84.4 g (0.83 mol) of the upper layer solution containing 2-aminobutyronitrile was added dropwise with stirring, and sodium hydroxide 0.2% A reaction substrate solution 314.0 g consisting of a feed 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 of 2-aminobutyramide Schiff base (0.71 mol [0.84 times mol / 2-aminobutyronitrile]) and 2-aminobutyramide 7 314.0 g of a reaction solution containing 0.7 g (0.08 mol [0.09-fold 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, and 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. and further crystallized, and then filtered to obtain 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%. Impurity imidazolidinone was not detected. The water content of the mother liquor was 13.2%.

Example 4
Into a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, 15.9 g (0.18 mol) of 2-hydroxybutyronitrile was put, 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]) and reacting it at a reaction temperature of 20 ° C. for 8 hours, 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 solution 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]), 16.7 g (0.16 mol) of an upper layer solution containing 2-aminobutyronitrile subjected to reduced pressure treatment was added dropwise with stirring, and 0. 60.4 g of a reaction substrate solution comprising 2%, water 1.3% [0.24 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 21.6% and acetone 72.3% are charged. Prepared. This was reacted at a reaction temperature of 20 ° C. for 7 hours, and 19.3 g of 2-aminobutyramide 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 times 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. and further crystallized, and then filtered to give 18.4 g of white crystals of 2-aminobutyramide hydrochloride (0.13 mol, purity 99.2%, ammonium chloride 0.8%). , 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%, and no impurity imidazolidinone was detected. The water content of the mother liquor was 12.8%.

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. 1.35 mol [2.0 eq / 2-hydroxybutyronitrile]) was blown in, and then 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, the upper layer liquid 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 solution 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 which had been subjected to reduced pressure treatment was added dropwise with stirring, and sodium hydroxide was added in an amount of 0. 227.6 g of a reaction substrate solution comprising 2%, water 4.0% [0.83 equivalent / 2-aminobutyronitrile], 2-aminobutyronitrile 22.0%, acetone 71.0% charge ratio. 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, the 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 (0.48 mol, purity 99.0%, ammonium chloride 1.0%) of 2-aminobutyramide hydrochloride was obtained by filtration. , Sodium chloride 0.00%). The acquisition yield based on 2-hydroxybutyronitrile as a starting material 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%.

Comparative Example 1
2-hydroxybutyronitrile (117.4 g, 1.30 mol) was placed in a 200 mL four-necked flask equipped with a stirrer, a thermometer and a condenser, and ammonia was maintained with stirring while maintaining the liquid temperature at 8 ± 2 ° C. 27.4 g of gas (1.61 mol [1.2 eq / 2-hydroxybutyronitrile]) was added and this was reacted at a reaction temperature of 20 ° C. for 8 hours, resulting in 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.
Then, 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 an aqueous 2-aminobutyronitrile 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-aminobutylamide Schiff base (0.10 mol [0.08 times 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%.

Claims (17)

In the method for producing a 2-aminobutyramide inorganic acid salt (5) from 2-hydroxybutyronitrile (1), the production method shown in the following steps (A), (B) and (C) The manufacturing method of 2-aminobutyramide inorganic acid salt (5) characterized by including this.
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 the condition that 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 times 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).

(However, R is a methyl group or an ethyl group.)

(However, X is an inorganic acid anion.)   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).   In the step (A), ammonia is used in an amount of 1.0 to 1.5 times mol of 2-hydroxybutyronitrile (1), and the 2-aminobutyramide inorganic acid salt (5) according to claim 2 is used. Production method.   The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein ammonia water is used as ammonia in the step (A).   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 of 2-hydroxybutyronitrile (1). The manufacturing method of 2-aminobutyramide inorganic acid salt (5).   In step (B), the reaction solution containing 2-aminobutyronitrile (2) is separated into two layers by adding an inorganic strong base or an inorganic strong base aqueous solution, and water contained in the upper organic phase is removed. The reaction solution containing 2-aminobutyronitrile (2) in the upper layer is separated from the lower aqueous inorganic strong base solution after the transition to the lower aqueous phase, and the separated reaction solution is used for the reaction. 2. The method for producing 2-aminobutyramide inorganic acid salt (5) according to 1.   An inorganic strong base or an inorganic strong base aqueous solution is added to the reaction solution containing 2-aminobutyronitrile (2) so that the inorganic strong base concentration 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.   2. The process according to claim 1, wherein in 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. -Manufacturing method of aminobutyramide inorganic acid salt (5).   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-fold mol with respect to 2-aminobutyronitrile (2). ) Manufacturing method.   In the step (B), one or more inorganic strong bases selected from sodium hydroxide, potassium hydroxide and calcium hydroxide are used as the inorganic strong base. 5) Production method.   The 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein in the step (B), the ketone solvent is used in an amount of 1.0 to 12.0 times mol with respect to 2-aminobutyronitrile (2). ) Manufacturing method.   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.   In the step (C), the reaction liquid obtained in the step (B) is brought into contact with an inorganic acid or an aqueous inorganic acid solution at an acid-excess ratio such that the liquid pH after contact mixing is 1 to 6. The production method of 2-aminobutyramide inorganic acid salt (5) described in 1.   The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 1, wherein, in the 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.   Further, the step of crystallizing the liquid containing the 2-aminobutyramide inorganic acid salt (5) obtained in the step (C) directly or after pouring it into a ketone solvent, and separating the precipitated crystals into solid and liquid The manufacturing method of 2-aminobutyramide inorganic acid salt (5) of Claim 1 containing this.   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).   The method for producing a 2-aminobutyramide inorganic acid salt (5) according to claim 15, wherein the ketone solvent is acetone.