JP5743474B2 - Process for producing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate - Google Patents

Description

  The present invention relates to 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] useful as a therapeutic agent exhibiting an excellent gastrointestinal motility promoting effect. The present invention relates to a novel purification method for benzamide citrate dihydrate.

  4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate (hereinafter simply referred to as “citrate dihydrate”). May not have a dopamine D2 receptor blocking action like metoclopramide. Therefore, the citrate dihydrate is useful as a therapeutic agent that does not exhibit side effects of the central nervous system and endocrine system and exhibits an excellent effect of promoting gastrointestinal motility (see Patent Document 1). ).

  This citrate dihydrate is represented by the following formula: 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter, In some cases, an amide compound is used as a raw material, and the raw material is reacted with an aqueous citric acid solution.

  More specifically, as a method for producing citrate dihydrate, the amide compound is heated in a 10% by mass citric acid aqueous solution to dissolve the amide compound as a raw material, and then cooled as it is. A method for precipitating acid salt dihydrate is known (see Patent Document 1). Also known is a method for producing citrate dihydrate by reacting an amide compound and citric acid for 30 minutes at a reflux temperature in a 50% by volume isopropyl alcohol aqueous solution (see Patent Document 2). According to these methods, citrate dihydrate can be obtained efficiently.

  Since citrate dihydrate is the final product, it is desired to have a higher purity. This citrate dihydrate is not a chemical bond between an amide compound and citric acid. Therefore, it is difficult to purify by recrystallization or the like, and it is desirable not to generate by-products as much as possible at the time of the reaction between the amide compound and citric acid.

  From the viewpoint of the generation of such a by-product, the present inventors conducted a supplementary test of the prior art. As a result, it was found that by-products may be generated in the above method, and there is room for improvement.

Japanese Patent Publication No. 3-54937 JP 2008-247753 A

  Accordingly, an object of the present invention is to provide 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate with fewer by-products. The object is to produce a product (citrate dihydrate). Also, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citric acid and citric acid are equimolar salts. An object of the present invention is to provide a method for producing a citrate dihydrate, in which the salt is likely to be a dihydrate.

  In order to solve the above problems, the present inventor has conducted earnest research. Then, as a result of elucidation of the by-product generated in the reaction between the amide compound and citric acid, it was considered that a by-product in which the amino group of the amide compound reacted with the carboxyl group of citric acid was generated. Further, as a result of further investigation, in the methods described in Patent Document 1 and Patent Document 2, the reaction temperature must be 75 ° C. or higher, but the production of by-products is affected by this reaction temperature. Obtained knowledge. As a result, it has been found that carrying out the reaction in a specific temperature range is effective in suppressing the formation of by-products, and that citrate dihydrate can be efficiently produced. It came to be completed.

That is, the present invention comprises mixing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide, water, and a water-soluble organic solvent. In this way, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is dispersed in a mixed solvent of water and a water-soluble organic solvent. 4-amino-5-chloro-2-ethoxy-N-[[4- (4- (4-amino acids)] was prepared so that the temperature of the reaction liquid obtained by adding citric acid to the slurry liquid was 35 ° C. or higher and 60 ° C. or lower. 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-], characterized by reacting fluorobenzyl) -2-morpholinyl] methyl] benzamide with citric acid Morpholi [Lu] methyl] benzamide citrate dihydrate, wherein the amount of water contained in the slurry liquid is 4-amino-5-chloro-2-ethoxy-N-[[4- (4 -Fluorobenzyl) -2-morpholinyl] methyl] benzamide with respect to 100 parts by mass of 500 parts by mass or more and 1500 parts by mass or less, and the amount of the water-soluble organic solvent contained in the slurry liquid is 4-amino-5- Chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is 100 parts by mass or more and 1500 parts by mass or less, and in the reaction solution, Water is 30% by mass to 70% by mass, and the water-soluble organic solvent is 30% by mass to 70% by mass in 100% by mass of a mixed solvent of water and a water-soluble organic solvent.

  Furthermore, in the present invention, it is preferable to use ethanol or acetone as the water-soluble organic solvent. By using ethanol or acetone, production of by-products can be further suppressed.

  According to the present invention, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate (with few by-products) Citrate dihydrate) can be prepared.

  In addition, the reaction of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide compound) with citric acid is carried out by slurry of the amide compound. By carrying out by adding citric acid to the solution, precipitation of citrate during the reaction can be suppressed, and citrate dihydrate can be produced with easy process control. Specifically, by adding citric acid to the slurry liquid, a citrate salt that easily precipitates is generated little by little in the mixed solvent (reaction liquid) even in the present invention where the reaction is performed at a relatively low temperature. Therefore, the slurry liquid becomes a transparent solution, and the progress of the reaction can be confirmed visually.

  In the production of this citrate dihydrate, there is no analytical method suitable for confirming the progress of the reaction. For example, in the analysis by high performance liquid chromatography (hereinafter sometimes referred to as HPLC), since citric acid is removed from citrate dihydrate under the analysis conditions, the progress of the reaction cannot be confirmed from the area value. . In other analysis methods such as infrared absorption spectrum measurement, it is difficult to clearly distinguish the citrate of the amide compound and the mixture of the amide compound and citric acid.

  Therefore, by adding citric acid to the slurry liquid of the amide compound, it is possible to confirm the progress of the reaction not only by controlling the reaction time but also by visual observation.

  Furthermore, the amount of water in the slurry before the citric acid was added was changed to 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide 100. Citrate can be efficiently made into a dihydrate by setting it as 500 to 2000 mass parts with respect to a mass part. When water in the above range is included in the slurry liquid to which citric acid is added, sufficient water is present around the citrate dihydrate when it is formed. It is thought that things can be obtained efficiently.

  As described above, the method of the present invention can efficiently produce citrate dihydrate with less by-products, and is a method with high industrial utility value.

  The present invention relates to the reaction of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide compound) with citric acid. The reaction solvent is characterized by being carried out at a specific reaction temperature. In the following, description will be given in order. First, the amide compound will be described.

(Amide compound)
4-Amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide compound) used in the present invention should be produced by the following method. Can do. Specifically, it can be produced by the methods described in Patent Documents 1 and 2.

  Specifically, 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine and 4-amino-5-chloro-2-ethoxybenzoic acid, a halogenated hydrocarbon such as methylene chloride or chloroform, or Using a ketone solvent such as acetone or methyl ethyl ketone, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, N, N'-carbonyldisuccinate What is necessary is just to make it react with condensing agents, such as an acid imide and 1-ethoxycarbonyl-2-ethoxy-1, 2- dihydroquinone.

  4-amino-5-chloro-2-ethoxybenzoic acid as a lower alkyl ester, activated ester, acid anhydride, acid halide, etc., and 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine What is necessary is just to make it react. In the case of an acid anhydride, a symmetric acid anhydride or a mixed acid anhydride may be used. Examples of the mixed acid anhydride include 4-amino-5-chloro-2-ethoxybenzoic acid, ethyl chlorocarbonate, alkyl chlorocarbonate such as isobutyl chlorocarbonate, aralkyl chlorocarbonate such as benzyl chlorocarbonate, and phenyl chlorocarbonate. Examples include aryl chlorocarbonate.

  By carrying out the above reaction, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide compound) is synthesized. Can do. The obtained crude product may be crystallized with ethanol (Patent Document 1), or an amide compound is crystallized as it is from a reaction solvent (Patent Document 2) to obtain a highly purified amide compound. Furthermore, in order to obtain a high purity amide compound, it is preferable to recrystallize with a solvent containing amides such as N, N-dimethylformamide or nitriles.

  The amide compound used in the present invention is preferably purified by the above method, and preferably has a purity of 99.00% or more in terms of HPLC peak area%.

(citric acid)
As the citric acid used in the present invention, any reagent or industrial raw material can be used without any limitation. Moreover, it is possible to use either citric acid anhydride or citric acid hydrate with or without hydration.

  In the present invention, the amount of citric acid used is at least 1 mol of citric acid per mol of amide compound, that is, the minimum amount necessary for all amide compounds to be citrate. Among these, in consideration of reactivity, ease of post-treatment, economy, etc., citric acid is used in an amount of 1.0 mol to 20.0 mol, preferably 1.5 mol to 15.0, per mol of the amide compound. It is used in an amount of 2.0 mol or less, more preferably 2.0 mol or more and 10.0 mol or less, and particularly preferably 2.0 mol or more and 5.0 mol or less. The amount of citric acid used corresponds to the total amount of citric acid to be added when citric acid is added to the amide compound slurry. In addition, although mentioned in full detail below, the citric acid aqueous solution can also be used in this case.

  Next, the reaction between the amide compound and citric acid will be described in detail. First, the water and water-soluble organic solvent to be used will be described.

(water)
In the present invention, water is used as part of the reaction solvent (part of the mixed solvent). Examples of the water used include normal water that does not adversely influence the reaction, such as distilled water, tap water, ion exchange water, pure water, and ultrapure water.

(Water-soluble organic solvent)
In the present invention, the amide compound and citric acid are reacted in a mixed solvent of water and a water-soluble organic solvent. In the present invention, the water-soluble organic solvent is a solvent that dissolves at a rate of 50% by volume or more with water at 23 ° C.

  Examples of the water-soluble organic solvent include alcohols having 1 to 4 carbon atoms, ketones such as acetone, amides, nitriles, water-soluble ethers, sulfoxides, and heterocyclic compounds. Specifically, methanol, ethanol, 1-propanol, isopropyl alcohol, t-butanol, propargyl alcohol, allyl alcohol, acetone, tetrahydrofuran, acetamide, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, etc. Can be mentioned. These solvents may be used alone or in combination of two or more.

  Among these, alcohols having 1 to 3 carbon atoms such as methanol, ethanol, 1-propanol, isopropyl alcohol, and the like are preferable from the viewpoint of low toxicity, relatively low boiling point, and easy removal. Ketones, tetrahydrofuran, acetamide, acetonitrile. Of these, ethanol or acetone is most preferable. Ethanol or acetone is highly soluble in amide compounds and citrate dihydrate, and the amount of the mixed solvent can be reduced. Moreover, the reactivity of an amide compound and a citric acid can be improved by using ethanol or acetone.

(Reaction in a mixed solvent of water and water-soluble organic solvent)
(Reaction temperature)
In the present invention, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (in a mixed solvent of water and a water-soluble organic solvent) The greatest feature is that the amide compound) and citric acid are reacted at a temperature of 35 ° C. or higher and 60 ° C. or lower. What is necessary is just to confirm the temperature of the mixed solvent (reaction liquid) with which this temperature is making amide compound and citric acid react. Hereinafter, this temperature may be referred to as a reaction temperature.

  In the present invention, when the reaction temperature is less than 30 ° C., the solubility of the amide compound is lowered, and the reaction is not completed or the reaction time is long, which is not preferable. On the other hand, when the reaction temperature exceeds 70 ° C., a by-product presumed that the amino group of the amide compound and the carboxyl group of citric acid are reacted is not preferable. In consideration of suppressing the reaction time and the formation of by-products, the reaction temperature is preferably 30 ° C. or higher and 60 ° C. or lower, more preferably 35 ° C. or higher and 60 ° C. or lower, and most preferably 40 ° C. or higher and 60 ° C. or lower. If the reaction temperature satisfies this range, it may be controlled to a constant temperature during the reaction, or the temperature of the reaction solution can be changed.

(Mixed solvent, mixing method)
In the present invention, an amide compound and citric acid are reacted in a mixed solvent of the water and the water-soluble organic solvent. The reaction between the amide compound and citric acid may be carried out by mixing the two in a mixed solvent so that they are in contact with each other. The method of mixing both is not particularly limited, and specifically,
(I) a method of mixing a total amount of an amide compound and a total amount of citric acid in a mixed solvent;
(Ii) Amide compound slurried with water, a water-soluble organic solvent, or a mixed solvent in a mixed solvent, and citric acid diluted with water, a water-soluble organic solvent, or a mixed solvent as necessary. Adding both at the same time and mixing both,
(Iii) If necessary, add amide compound slurried with water, water-soluble organic solvent, or mixed solvent to citric acid diluted with water, water-soluble organic solvent, or mixed solvent, if necessary. How to mix,
(Iv) Prepare a slurry liquid of amide compound with water, water-soluble organic solvent, or mixed solvent, and add citric acid diluted with water, water-soluble organic solvent, or mixed solvent to the slurry liquid as necessary. To mix the two
Etc.

  In the present invention, the use ratio of water and the water-soluble organic solvent is such that the mixed solvent is 100% by mass, the water-soluble organic solvent is 30% by mass to 70% by mass, and the water is 30% by mass to 70% by mass. preferable. Furthermore, it is preferable that the water-soluble organic solvent is 40% by mass or more and 60% by mass or less and the water is 40% by mass or more and 60% by mass or less. When the use ratio of water and the water-soluble organic solvent in the mixed solvent satisfies the above range, the solubility of the amide compound and citrate can be increased. As a result, it becomes easy to produce an equimolar salt of an amide compound and citric acid and a dihydrate of the salt. In addition, this use ratio points out the ratio of water and a water-soluble organic solvent in all the mixed solvents. For example, in the mixing method (iv) above, it refers to the ratio of water and a water-soluble organic solvent in the mixed solvent when the whole amount of the amide compound and citric acid is mixed.

  In this invention, if the usage-amount of a mixed solvent is the said usage ratio, it is preferable to set it as 1000 to 4000 mass parts with respect to 100 mass parts of amide compounds. By using the mixed solvent in the above usage ratio in the above usage amount, the solubility of the amide compound and citrate can be increased. Furthermore, not only the dihydrate can be easily produced, but also the operability can be improved. In addition, this usage-amount also points out the whole quantity of a mixed solvent when the whole quantity of an amide compound and a citric acid are mixed similarly to the said usage rate.

  Moreover, it becomes easy to manufacture the citric acid dihydrate listed in the Japanese Pharmacopoeia by using the mixed solvent of the use ratio and the use amount. Specifically, it becomes easy to produce citrate dihydrate having a molar ratio of amide compound to citric acid of 1: 1. The citrate dihydrate in the present invention is listed in the Japanese Pharmacopoeia as the drug substance name “mosapride”. And as a parameter | index showing the ratio of the amide compound and citric acid in a citric acid dihydrate, the ratio is normalized by the quantitative method, The value (quantitative value) is 98.5-101.0%. (If the molar ratio is 1: 1, this value is 100%.) If it is the mixed solvent of the said usage rate and usage-amount, manufacture of the citrate dihydrate which satisfies this fixed value will become easy.

  Moreover, the citrate of an amide compound can be made into a dihydrate efficiently by using the mixed solvent of the said usage rate and usage amount. Citrate dihydrate (mosapride) is also standardized by the Japanese Pharmacopoeia with respect to the amount of water, and the amount of water is 5.0 mass% or more and 6.5 mass% or less (2 water). In the case of only a Japanese product, the water content is 5.5% by mass.) If it is the mixed solvent of the said usage rate and usage-amount, manufacture of the citrate dihydrate which satisfies this water content will become easy.

  In the present invention, in order to react the amide compound and citric acid, it is preferable to mix both with stirring. As the reaction container used for the reaction, a glass container, a stainless steel container, a Teflon (registered trademark) container, a glass lining container, or the like can be used. The reaction vessel is preferably equipped with a thermometer or a temperature sensor. It is preferable to carry out the reaction by stirring with a mechanical stirrer, magnetic stirrer or the like in such a reaction vessel, and in the case of large-scale production, a mixed solvent containing an amide compound and citric acid is mixed with a stirring blade or the like. It is preferable to stir.

  In the present invention, the reaction time between the amide compound and citric acid is not limited because it varies depending on the amount of the water-soluble organic solvent and water used, the amount of citric acid, and the reaction temperature. 0.1 to 10 hours is sufficient after the entire amount of citric acid is charged. This time is the time after the total amount of the amide compound used in the reaction and the total amount of citric acid are mixed in the mixed solvent.

(Preferred mixing method (reaction method))
The method of the present invention is characterized in that the reaction is performed at a low temperature as compared with the prior art. As a result, while by-products can be suppressed, the solubility of the amide compound and citrate in the mixed solvent tends to be lower than that of the prior art. Therefore, in order to reduce the amount of the mixed solvent used, to facilitate the control of the reaction temperature, and to easily carry out the reaction visually, it is possible to mix both by the method (iv). preferable.

  That is, (iv) A slurry liquid of an amide compound is prepared with water, a water-soluble organic solvent, or a mixed solvent, and citric acid diluted with water, a water-soluble organic solvent, or a mixed solvent as necessary in the slurry liquid This is a method of mixing both of them.

  Among these methods, by mixing an amide compound, water, and a water-soluble organic solvent, a slurry liquid in which the amide compound is dispersed in the mixed solvent is obtained, and a method of adding a citric acid aqueous solution to the slurry liquid is adopted. It is preferable to do. When preparing this slurry liquid, the addition order of the amide compound, water, and the water-soluble organic solvent into the reaction vessel may be any order. After mixing the two components in advance, the mixture is mixed with the other components. You can also.

  Moreover, when adding a citric acid aqueous solution, it is preferable to stir the slurry.

  According to such a method, the reaction between the amide compound and citric acid can be allowed to proceed gradually. Therefore, the reaction temperature can be easily controlled even in the present invention at a relatively low temperature. Also, since citrate dihydrate is gradually formed, citrate dihydrate is easily dissolved in the mixed solvent, and the progress of the reaction (completion of the reaction) can be visually confirmed. it is conceivable that.

  Also in this case, it is preferable that the use ratio of water and the water-soluble organic solvent and the use amount of the mixed solvent satisfy the above ranges when the total amount of the amide compound and the total amount of citric acid are mixed. That is, when the total amount of the amide compound and the total amount of citric acid are mixed, water is 30% by mass to 70% by mass and the water-soluble organic solvent is 30% by mass to 70% by mass in 100% by mass of the mixed solvent. It is preferable that Moreover, it is this usage rate, Comprising: It is preferable that the usage-amount of a mixed solvent becomes 1000 to 4000 mass parts with respect to 100 mass parts of amide compounds. In addition, the preferable range of a usage rate and usage-amount is the same as the said range.

  In the amide compound slurry before adding citric acid, the amount of water is preferably 500 parts by mass or more and 2000 parts by mass or less, and more preferably 500 parts by mass or more and 1500 parts by mass with respect to 100 parts by mass of the amide compound. It is preferable that it is below mass parts. When the amount of water in the slurry satisfies the above range, the reaction efficiency can be increased, and the citrate of the amide compound can be efficiently converted into a dihydrate. In addition, when the amount of water satisfies the above range, the obtained citrate hydrate has a water content (5.0% by mass to 6.5% by mass) standardized by the Japanese Pharmacopoeia. ). That is, when the amount of water is contained in the slurry before the citric acid is added, the resulting product is converted into a citrate dihydrate having a moisture content that satisfies the specification range. Can be easily. This is because when an amide compound and citric acid react with each other, a citrate is formed, and an amount of water that satisfies the above range is present in the vicinity thereof, so that the citrate is easily obtained as a dihydrate. It is estimated that

  In addition, in the slurry of the amide compound before adding citric acid, the amount of the water-soluble organic solvent is preferably 500 parts by mass or more and 2000 parts by mass or less with respect to 100 parts by mass of the amide compound, and further 500 masses. It is preferable that it is 1 part by mass or more and 1500 parts by mass or less. Water is a poor solvent for amide compounds. However, the presence of water in the above range in the slurry allows efficient dihydrate formation. Therefore, in order to enhance the solubility of the amide compound, the amount of the water-soluble organic solvent is preferably in the above range. When the amount of the water-soluble organic solvent in the slurry satisfies the above range, the amide compound is easily dissolved, and the citric acid satisfying the value (quantitative value) of 98.5 to 101.0% by the quantitative method. It becomes easy to produce a salt dihydrate.

  In this method, it is preferable to add citric acid to the slurry liquid being stirred. As the citric acid, solid citric acid can be added to the slurry liquid as it is, but it is preferable to add an aqueous solution of citric acid in consideration of operability and reaction time. When a citric acid aqueous solution is used, the concentration may be appropriately determined according to the amount of water and water-soluble organic solvent contained in the slurry liquid. That is, in the reaction solution after the addition of the citric acid aqueous solution is completed, the respective usage ratios in the mixed solvent of water and the water-soluble organic solvent are 30% by mass or more and 70% by mass or more for water, and 30% by mass or more for water-soluble organic solvent What is necessary is just to use the quantity which satisfies the mass% or more and the usage-amount of this mixed solvent will be 1000 to 4000 mass parts with respect to 100 mass parts of amide compounds. In addition, a suitable usage rate and usage amount are also the same as the said range. When this condition is satisfied and operability is taken into consideration, it is preferable to use an aqueous citric acid solution having a citric acid concentration of 30% by mass to 60% by mass.

  The time for adding citric acid to the stirring slurry is preferably 1 to 60 minutes, depending on the scale of the reaction. Also when adding the citric acid aqueous solution of the said concentration range, it is preferable that addition time is the said range. By satisfying this time, citrate dihydrate can be efficiently produced. The method of adding is not particularly limited, and can be charged into the reaction vessel using a metering pump, a dropping funnel or the like.

  In such a mixing method (reaction method), while adding citric acid (citric acid aqueous solution) to the slurry liquid and during the reaction, the reaction liquid (citric acid is added to the slurry solution). The temperature of the solution) must be controlled to 30 ° C. or higher and 70 ° C. or lower. The preferable temperature of this reaction liquid is also the same as the above range, preferably 30 ° C. or more and 60 ° C. or less, more preferably 35 ° C. or more and 60 ° C. or less, and most preferably 40 ° C. or more and 60 ° C. or less. By adding citric acid (citric acid aqueous solution) to the slurry liquid, the completion of the reaction can be confirmed when the reaction liquid becomes transparent, but after adding citric acid (citric acid aqueous solution), usually 0.1% It is preferable that the temperature of the reaction solution is within the above range for 10 hours.

(Removal of citrate dihydrate)
In the present invention, the citrate dihydrate produced according to the above method can be crystallized and taken out by cooling the reaction solution after the reaction as it is. Since the yield decreases when the temperature reached at the time of cooling is too high, it is usually preferably carried out in the range of 0 ° C. or higher and lower than 30 ° C., more preferably 5 ° C. or higher and 20 ° C. or lower. Furthermore, at the time of crystallization by cooling, after preparing a supersaturated solution, seed crystals and the like can be added at an arbitrary temperature for crystallization.

  The citrate dihydrate crystals obtained as described above are solid-liquid separated by filtration, centrifugation, etc., and excess citric acid is sufficiently removed by water, followed by natural drying, air drying, vacuum Isolated by drying, such as by drying.

  The obtained citrate dihydrate can suppress the formation of by-products that are thought to be the reaction of the amino group of the amide compound and the carboxyl group of citric acid. If the conditions are further optimized, the progress of the reaction can be confirmed visually. Furthermore, it is easy to obtain a citrate dihydrate satisfying a quantitative value listed in the Japanese Pharmacopoeia of 98.5 to 101.0% and a water content of 5.0% by mass to 6.5% by mass. Can be manufactured.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples.

(Purity measurement, production rate of by-products)
The purity was measured by high performance liquid chromatography (HPLC) using the following apparatus and conditions. In HPLC analysis under these conditions, the retention time of the amide compound and citrate dihydrate is around 7.4 minutes, and the retention time of the by-product is around 3.3 minutes. The production rate of by-products was also shown as peak area%.
Apparatus: 2695 manufactured by Waters.
Detector: Ultraviolet spectrophotometer (Waters 2489).
Detection wavelength: 220 nm.
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm filled with octadecylsilylated silica gel having an average particle size of 5 μm (YMC-Pack ODS-A manufactured by YMC).
Mobile phase: After adding 4.1 g of potassium dihydrogen phosphate to 3 L of water and adjusting the pH to 3.5 by adding phosphoric acid, 0.61 g of sodium 1-pentanesulfonate was added to 700 mL of this aqueous solution, and 300 mL of acetonitrile. A mixed solution.
Flow rate: 1.0 mL per minute.
Column temperature: constant temperature around 40 ° C.

(Measurement of water content)
The moisture content was measured with an automatic moisture measuring device (KF) using the following devices and conditions.
Apparatus: CA-100 manufactured by Mitsubishi Chemical.
Method: Karl Fischer volumetric titration method.
Titration reagent: Aquamicron titrant SS-Z 3 mg manufactured by Mitsubishi Chemical.
Solvent: anhydrous methanol.

(Measurement of quantitative value)
Measurement of the quantitative value by the automatic titration apparatus was performed by the following apparatus and conditions. In addition, when the quantitative value measured on these conditions exceeds 100%, it shows that amide | amido compound is contained more compared with a citric acid, and citrate formation has not progressed completely.
Apparatus: Hiranuma Sangyo Co., Ltd. COM-2000.
Method: Non-water titration method.
Titration reagent: 0.1 mol / L perchloric acid (for non-aqueous titration).
Solvent: acetic acid (for non-aqueous titration).

Production Example 1
(Production of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (Production of amide compound))
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 50.0 g (233.3 mmol) of 4-amino-5-chloro-2-ethoxybenzoic acid was dissolved in 1000 mL of methylene chloride under a nitrogen atmosphere, and triethylamine was dissolved. After 24.7 g (243.3 mmol) was added, 43.3 g (243.3 mol) of benzyl chloroformate was added dropwise over 40 minutes so that the reaction temperature was −5 ° C. or lower. Then, it stirred at 0 degreeC for 3 hours.

  The obtained reaction mixture was placed in a 1000 mL methylene chloride solution of 53.3 g (233.3 mmol) of 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine cooled to −5 ° C. or lower under a nitrogen atmosphere. It was dripped over 40 minutes so that reaction temperature might be -5 degrees C or less. After stirring at room temperature for 1 hour, 1000 mL of water was added, and after shaking with a separatory funnel, the organic layer was separated. Furthermore, 2000 g of 10 mass% sodium hydroxide aqueous solution was added, and the same operation was performed. The obtained organic layer was washed twice with 1500 mL of ion-exchanged water, and then the organic layer was concentrated to obtain 120.0 g of a white solid.

  After adding 1157 mL of dimethylformamide to the obtained white solid and dissolving it, 267 mL of water was added. The solution was gradually cooled to 5 ° C. and held at 5 ° C. for 2 hours, and the precipitated crystals were separated by furnace. The obtained white crystals were dried under reduced pressure, and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (amide) was obtained as high-purity white crystals. Compound) 66.0 g (156.3 mmol) was obtained. The yield was 67.0% and the HPLC purity was 99.94%.

Example 1
To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 10.0 g (23.8 mmol) of an amide compound having a HPLC purity of 99.94% produced in Production Example 1, 80 g of ethanol, and 80 g of water were added. A slurry was obtained by stirring. The obtained slurry was heated to 50 ° C. Subsequently, an aqueous citric acid solution (temperature of the aqueous solution of 50 ° C.) in which 13.6 g (71.2 mmol) of citric acid was dissolved in 20 g of water was gradually added dropwise to the slurry over 10 minutes. (The temperature of the reaction solution when the aqueous citric acid solution was dropped was adjusted to 50 ° C. (reaction temperature 50 ° C.)). After dropwise addition of the citric acid aqueous solution, the mixture was reacted at 50 ° C. for 1 hour (reaction temperature 50 ° C. During this time, it was visually confirmed that the reaction solution became transparent). Thereafter, the obtained reaction solution was gradually cooled to 10 ° C. and held for 1 hour. The precipitated solid was removed by furnace filtration under reduced pressure, and the cake was washed twice with 30 g of water. The obtained white solid was dried under reduced pressure at an external temperature of 40 ° C., and then 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide as a white solid. 14.1 g (21.8 mmol) of citrate dihydrate (citrate dihydrate) was obtained. Yield: 91.4%, HPLC purity: 99.94%, by-product: not detected (not detected), water content: 5.8%, quantitative value: 100.5%. Table 1 shows the results. The yield of citrate dihydrate is a value obtained by simply measuring the mass of the obtained solid.

Examples 4 , 5 , 7, 8, 11
In Example 1, the type and amount of the water-soluble organic solvent, the amount of water, the concentration of the aqueous citric acid solution used, the reaction temperature, and the reaction time were the same as in Example 1, except that the conditions shown in Table 1 were used. The method produced citrate dihydrate. The results are shown in Table 1. In each example, it was confirmed that the reaction solution became transparent after the addition of an aqueous citric acid solution.

Comparative Example 1
To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 1.2 g (2.8 mmol) of the amide compound having a purity of 99.94% produced in Production Example 1 was added, and a 10% by mass citric acid aqueous solution 48. 0 g was added and stirred. Subsequently, the obtained slurry was heated and heated until all of the amide compound was dissolved. After confirming that the amide compound was completely dissolved at 83 ° C., the solution was gradually cooled to 10 ° C. or lower and held for 1 hour. The precipitated solid was removed by furnace filtration under reduced pressure, and the cake was washed twice with 3.6 g of water. The obtained white solid was dried under reduced pressure at an external temperature of 40 ° C., and then 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide as a white solid. 1.7 g (2.7 mmol) of citrate dihydrate (citrate dihydrate) was obtained. Yield: 95.7%, HPLC purity: 99.78%, by-product: 0.160%, water content: 5.8%, quantitative value: 100.5%.

Comparative Example 2
To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 3.4 g (17.5 mmol) of citric acid hydrate and 37 g of water were added and stirred to dissolve the citric acid hydrate, and then isopropyl alcohol. 29 g was added. Subsequently, 3.7 g (8.8 mmol) of the amide compound having an HPLC purity of 99.94% produced in Production Example 1 was added, and the resulting slurry was heated and reacted for 30 minutes under reflux conditions (the reflux temperature was 79 ° C.). After the reaction, it was gradually cooled to 10 ° C. or lower and held for 1 hour. The precipitated solid was removed by furnace filtration under reduced pressure, and the cake was washed twice with 11 g of water. The obtained white solid was dried under reduced pressure at an external temperature of 40 ° C., and then 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide as a white solid. Citrate dihydrate (citrate dihydrate) 5.2 g (8.0 mmol) was obtained. Yield: 91.0%, HPLC purity: 99.92%, by-product: 0.014%, water content: 5.9%, quantitative value: 100.7%.

Comparative Examples 3-9
In Example 1, citrate dihydrate was produced in the same manner as in Example 1 except that the amount of water-soluble organic solvent, the amount of water, the reaction temperature, and the reaction time were changed to the conditions shown in Table 2. did. The results are shown in Table 2.

Claims (2)

By mixing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide, water, and a water-soluble organic solvent, water and water-soluble A slurry liquid in which 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is dispersed in a mixed solvent with an organic solvent is obtained. 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-] was prepared so that the temperature of the reaction solution obtained by adding citric acid to the solution was 35 ° C. or more and 60 ° C. or less. 4-Amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benza characterized by reacting morpholinyl] methyl] benzamide and citric acid A method of manufacturing a solo salt dihydrate,
The amount of water contained in the slurry liquid is 100 parts by mass of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide. 500 parts by weight or more and 1500 parts by weight or less,
The amount of the water-soluble organic solvent contained in the slurry liquid is 100 parts by mass of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide. On the other hand, it is 800 parts by weight or more and 1500 parts by weight or less,
In the reaction solution, in 100% by mass of a mixed solvent of water and a water-soluble organic solvent, water is 30% by mass to 70% by mass and the water-soluble organic solvent is 30% by mass to 70% by mass.   The 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2 according to claim 1, wherein the water-soluble organic solvent is ethanol or acetone. -Morpholinyl] methyl] benzamide citrate dihydrate.