JP5419570B2 - Method for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine - 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 of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine used as a raw material 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 exhibiting an excellent effect of promoting gastrointestinal motility without manifesting side effects of the central nervous system and endocrine system.

Citrate useful as such a therapeutic agent is desired to have a very high purity. Traditionally, this citrate dihydrate has been
Following formula (1)

2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine represented by the following formula (4)

It is produced via 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide represented by Naturally, in order to produce the high-purity citric acid, the raw material 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine represented by the above formula (1) is also high-purity. Is preferably used. This 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is produced by the following method.

  Specifically, it is a method in which 2-acetylaminomethylmorpholine and 4-fluorobenzyl chloride are reacted. In this method, first, a mixture containing 2-acetylaminomethylmorpholine, 4-fluorobenzyl chloride, anhydrous potassium carbonate, potassium iodide, and methyl ethyl ketone is heated to reflux for 17 hours, insoluble matter is filtered, and the obtained filtrate is filtered. Concentrate under reduced pressure. Next, chloroform and water are added to the residue and the mixture is extracted with a solvent. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is recrystallized from toluene. First manufacturing method) (see Patent Document 1).

  Further, for reasons such as cost and ease of reaction, a method of reacting 2- (4-fluorobenzylamino) ethanol with N- (2,3-epoxypropyl) phthalimide is generally employed industrially. ing. Specifically, it is a synthesis method represented by the following reaction formula.

  In this method, first, 2- (4-fluorobenzylamino) ethanol and N- (2,3-epoxypropyl) phthalimide are reacted at 80 ° C. for 3 hours without solvent. Next, after gradually adding concentrated sulfuric acid to the reaction solution, it is heated at 150 ° C. for 2 hours. The obtained solution is cooled, neutralized with an aqueous sodium hydroxide solution, extracted with chloroform, the organic layer is washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Here, 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine can be produced, but in order to obtain higher purity, an acetylation reaction is then performed. Therefore, first, acetic anhydride is added to the obtained organic layer, reacted at room temperature for 2 hours, ice water and aqueous sodium hydroxide solution are sequentially added, and the mixture is stirred at room temperature for a while. Subsequently, the organic layer is separated, washed, dried, the solvent is distilled off, and the residue is recrystallized with toluene (second production method) to give 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine Can be synthesized (see Patent Document 1 and Non-Patent Document 1).

Japanese Patent Publication No. 3-54937

Chemical Permanent Bulletin, 44 (8), 1484-1492 (1996)

  As described above, according to the methods described in Patent Document 1 and Non-Patent Document 1, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be efficiently produced and recrystallized with toluene. Therefore, a product with reasonable purity can be obtained.

  However, according to the study of the present inventor, when 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine is produced by the second production method, there may be a specific impurity (simply a specific impurity). ) Was found to be contained by about 0.1 to 1.0% according to high performance liquid chromatography (HPLC) analysis (hereinafter, in the present invention, the purity and the ratio of specific impurities (%) It is the value of area% when measured by.)

  This specific impurity is considered to be similar in structure to 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine and has a content of the above level, but 2- (aminomethyl) -4 Residue in-(4-fluorobenzyl) morpholine may cause problems in the following points. That is, using 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine containing the specific impurity as a raw material, 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine as an intermediate, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide represented by (4) and 4-amino-5- which is the drug substance When chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate is produced, these intermediates and the drug substance It was found that impurities derived from impurities remain. Therefore, in the conventional method, the impurities must be reduced from the intermediate and the drug substance, and the yield of the finally obtained citrate dihydrate may be lowered, and there is room for improvement. was there.

  Accordingly, an object of the present invention is to provide a purification method for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine. Furthermore, using highly purified 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine, highly purified 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine, 4-amino -5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide, and 4-amino-5-chloro-2-ethoxy-N-[[4- ( It is to provide a process for producing 4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate.

  In order to solve the above problems, the present inventor has conducted earnest research. In particular, a method for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine was examined. As a result, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine was recrystallized with an organic solvent containing 50% by volume or more of an ester solvent, whereby high purity 2-acetylaminomethyl-4- (4 It has been found that -fluorobenzyl) morpholine can be produced efficiently, and the present invention has been completed.

That is, the present invention
Following formula (1)

2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine represented by formula (2) is recrystallized with an organic solvent containing an ester solvent in an amount of 50% by volume or more, and 2-acetylaminomethyl-4- (4- (Fluorobenzyl) morpholine purification method.

  Furthermore, according to the present invention, highly pure 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be obtained. Therefore, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine obtained by the method of the present invention is deacetylated by a known method to obtain high-purity 2- (aminomethyl) -4- It can be (4-fluorobenzyl) morpholine.

  Moreover, since 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine obtained by the above method has high purity, the following formula (3)

Is reacted with 4-amino-5-chloro-2-ethoxybenzoic acid represented by
Following formula (4)

It can be suitably used for the production of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide represented by the formula:

Furthermore, since the obtained 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is highly pure, an aqueous citric acid solution is used. React
Following formula (5)

It is preferably used for the production of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate represented by the formula: Can do.

  According to the present invention, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be efficiently obtained in high yield and high purity. In particular, 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] Causes impurities in benzamide and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate Substances (specific impurities) can be reduced efficiently.

  Therefore, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine obtained by the present invention is 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine, 4-amino-5-chloro- 2-Ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide, and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-Morpholinyl] methyl] benzamide citrate dihydrate can be suitably used.

  In the present invention, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is recrystallized with a specific organic solvent, that is, an organic solvent containing at least 50% by volume of an ester solvent. First, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine to be recrystallized will be described.

(2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine recrystallized)
In the present invention, recrystallized 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine (hereinafter sometimes simply referred to as “crude body”) is not particularly limited, and the first production described above. It can be manufactured by the method and the second manufacturing method. Among them, according to the purification method of the present invention, the second production method, that is, the second production method in which 2- (4-fluorobenzylamino) ethanol and N- (2,3-epoxypropyl) phthalimide are reacted. The obtained 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is preferably subjected to recrystallization.

  2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine produced by this second production method is considered to be attributable to the raw material and the production method thereof, but 2-acetylaminomethyl-4- It is considered to include a compound (impurity) having a structure similar to that of (4-fluorobenzyl) morpholine. As described above, the second production method is a reaction in which morpholine ring is formed to synthesize 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine. Therefore, it is considered that specific impurities having different binding positions of the acetylaminomethyl group and the binding position of the fluoro group are generated with respect to 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine. Since various combinations of bond positions are possible, it is considered that a plurality of impurities having similar structures exist. In fact, according to the study by the present inventors, at least three specific impurities were detected according to the HPLC analysis conditions described in detail in the following examples. Specifically, according to the following HPLC analysis conditions, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine appears around 20 minutes, and before that, around 17 minutes (hereinafter, this impurity is identified as a specific impurity). (In some cases, (1)), around 22 minutes (hereinafter, this impurity may be referred to as a specific impurity (2)), around 39 minutes (hereinafter, this impurity may be referred to as a specific impurity (3)) Specific impurities can be confirmed.

  Although these specific impurities are presumed, they are considered to be compounds containing an acetylamino group, and deacetylation reaction, 4-amino-5-chloro-2-ethoxy-N-[[4- (4 -Fluorobenzyl) -2-morpholinyl] methyl] benzamide and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide quench When the acid salt dihydrate synthesis reaction was performed, impurities derived from the specific impurity were confirmed in each reaction. The present invention is particularly suitable for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine (crude) containing such specific impurities.

  The purification method of the present invention can efficiently increase the purity of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine. Therefore, as a matter of course, 2-acetylaminomethyl-4- (4-fluorobenzyl) produced by the first production method (method of reacting 2-acetylaminomethylmorpholine and 4-fluorobenzyl chloride). It can also be applied to recrystallization of morpholine.

  In the present invention, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine (crude) to be recrystallized is not particularly limited, but has a purity of 90 to 99% as measured by HPLC. It is preferable that.

  By recrystallizing a crude product having a purity in this range, highly pure 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be obtained efficiently. In particular, when a crude product is produced by the second production method, the purity of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be 93 to 99%. Further, according to the second production method, in particular, impurities (specific impurities (specific impurities (1), specific impurities (2), and specific impurities (3) total) considered to have morpholine groups and acetylamino groups. The amount)) can be in the range of 0.1 to 1%, but the present invention is particularly suitable for increasing the purity of such a crude product.

  The present invention is most characterized by recrystallizing the above crude product with an organic solvent containing 50% by volume or more of an ester solvent. Next, this organic solvent will be described.

(Organic solvent)
In the present invention, the crude product is recrystallized with an organic solvent containing 50% by volume or more of an ester solvent. First, the ester solvent will be described.

(Ester solvent)
As the ester solvent used in the present invention, a reagent or an industrial raw material can be used without any limitation. By using an organic solvent containing 50% by volume or more of an ester solvent, high-purity 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be obtained. These ester solvents are formic acid esters having 1 to 5 carbon atoms, acetic acid esters having 1 to 8 carbon atoms, propionic acid esters having 1 to 5 carbon atoms, butyric acid esters having 1 to 5 carbon atoms, and stearic acid having 1 to 5 carbon atoms. Examples thereof include esters, benzoic acid esters having 1 to 8 carbon atoms, and lactones having 5 to 6 carbon atoms. Among these, considering the ease of handling and the effect of the solvent, acetates having 1 to 8 carbon atoms are preferable. In addition, carbon number of the said ester solvent is the number except the carbon of ester group carbonyl.

  Specific examples of these ester solvents include methyl formate, ethyl formate, propyl formate, butyl formate, isobutyl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate. Pentyl acetate, isopentyl acetate, 3-methoxybutyl acetate, sec-hexyl acetate, 2-ethylbutyl acetate, 2-ethylhexyl acetate, cyclohexyl acetate, benzyl acetate, methyl propionate, ethyl propionate, butyl propionate, isopentyl propionate, Methyl butyrate, ethyl butyrate, butyl butyrate, isopentyl butyrate, methyl stearate, ethyl stearate, propyl stearate, butyl stearate, pentyl stearate, methyl benzoate, ethyl benzoate, benzoic acid Propyl, butyl benzoate, isopentyl benzoate, benzyl benzoate, .gamma.-butyrolactone, etc. ε- caprolactone. Of these, organic solvents such as formic acid ester and acetic acid ester are preferable. Furthermore, among acetic acid esters, low toxicity, relatively low boiling point, easy removal, and the resulting 2-acetylaminomethyl-4- ( 4-Fluorobenzyl) From the point of high purity of morpholine, it is preferable to use an acetic acid ester having 1 to 4 carbon atoms. Specifically, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate are used. It is preferable to do.

  In the present invention, the solvent for recrystallizing the crude product is an organic solvent containing 50% by volume or more of an ester solvent. If it contains at least 50% by volume of an ester solvent, it contains at most 50% by volume of another organic solvent, that is, an organic solvent other than the ester solvent (hereinafter sometimes referred to simply as “another organic solvent”). You can also. The other organic solvent is preferably one that can be mixed without phase separation from the ester solvent. By using such other organic solvents, the yield of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be increased. Next, other organic solvents will be described.

(Other organic solvents)
In the present invention, as the other organic solvent (organic solvent other than the ester solvent), a reagent or an industrial raw material can be used without any limitation. Specifically, at least one organic solvent selected from alcohol solvents, ketone solvents, ether solvents, hydrocarbon solvents, and halogenated hydrocarbon solvents is preferable. Especially, it is preferable that it is at least 1 type of organic solvent chosen from an alcohol solvent, an ether solvent, and an aliphatic hydrocarbon solvent from a viewpoint of high purity and high yield. In particular, at least one organic solvent selected from a chain alcohol solvent having 1 to 4 carbon atoms, a chain ether solvent having 4 to 8 carbon atoms, and an aliphatic hydrocarbon solvent having 5 to 8 carbon atoms is preferable. .

  Specific examples of the other organic solvents include alcohol solvents: methanol, ethanol, 1-propanol, 2-propanol, n-butanol, sec-butanol, tert-butanol, ether solvents; diethyl ether, dipropyl ether, Aliphatic hydrocarbons such as diisopropyl ether, dibutyl ether, tert-butyl methyl ether, and tetrahydrofuran; pentane, hexane, heptane, octane and the like. The other organic solvent may be mixed with an ester solvent when the crude product is dissolved, or may be additionally used after the crude product is once dissolved with the ester solvent.

  Next, the blending ratio of the organic solvent will be described.

(Blend ratio of organic solvent)
In the present invention, an organic solvent in which the ester solvent is 50% by volume or more is used as the crude recrystallization solvent. As long as it contains at least 50% by volume of an ester solvent, it can contain up to 50% by volume of another organic solvent, that is, an organic solvent other than the ester solvent. Therefore, the organic solvent for recrystallizing the crude product contains an ester solvent in a range of 50% by volume to 100% by volume and an organic solvent other than the ester solvent (other organic solvent) in a range of 0% by volume to 50% by volume. It is a waste.

  In the organic solvent for recrystallizing the crude product, when the proportion of the ester solvent is less than 50% by volume, 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine cannot be highly purified. In order to increase the purity of the crude product and to further reduce impurities having a morpholine residue (specific impurities (specific impurity (1), specific impurity (2), and specific impurity (3))), the ester solvent is reduced to 60%. It is preferable to use an organic solvent containing at least 70% by volume, and it is preferable to use an organic solvent containing 70% by volume or more, and the upper limit of the amount of ester solvent used in this organic solvent is 100 volumes as described above. When an organic solvent containing only the ester solvent (ester solvent 100% by volume) is used, high-purity 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be obtained and recrystallization is performed. The organic solvent used in the process can be easily recovered, and the amount of the organic solvent used can be reduced.

  In the present invention, when another organic solvent is used, the blending amount of the other organic solvent may be appropriately determined according to the type of the ester solvent. Among them, considering the purity of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine, and particularly the yield, etc., the organic solvent for recrystallizing the crude product is defined as 100% by volume, preferably an ester solvent. 50% by volume or more and 99% by volume or less, other organic solvent by 1% by volume or more and 50% by volume or less, more preferably 60% by volume or more and 95% by volume or less of the ester solvent, and other organic solvent by 5% by volume or more and 40% by volume or less. It is preferable to use a solvent containing: By setting it as this range, a yield can be improved.

  Next, a method for recrystallizing a crude product using the organic solvent will be described.

(Recrystallization method)
In the present invention, the crude product is recrystallized using the organic solvent. The method for recrystallization is not particularly limited, and a known method can be employed.

  In the present invention, the amount of organic solvent used to dissolve the crude product (the amount of ester solvent used in the case of an ester solvent alone, the amount of mixed solvent used in the case of a mixed solvent of an ester solvent and another organic solvent) is: There is no particular limitation as long as the amount for sufficiently dissolving the crude body is used. Impurities contained in the crude body, types and combinations of organic solvents to be used, mixing ratio thereof, and crystallization conditions (temperature during dissolution) ) And the like may be appropriately determined. Among them, considering the purity and yield of the obtained 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine, the amount of the organic solvent used is preferably 0.5 ml with respect to 1 g of the crude product. It is 30 ml or less, more preferably 1.0 ml or more and 25 ml or less. In particular, when only the ester solvent is used as the organic solvent, the amount used can be further reduced. In this case, the amount of the ester solvent used is preferably 0.5 ml or more and 10 ml or less, more preferably 1.0 ml or more and 7.0 ml or less, and further preferably 1.0 ml or more with respect to 1 g of the crude product. 5.0 ml or less. According to the present invention, well-purified 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be obtained even in the above range of use amount.

  In the present invention, the crude product is dissolved in the organic solvent, and 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is crystallized from the obtained solution and recrystallized. If the method of recrystallizing is concretely shown, the crude body is dissolved in the organic solvent, the organic solvent is distilled off from the resulting solution to adjust the concentration, and 2-acetylaminomethyl-4- (4- A method of crystallizing (fluorobenzyl) morpholine is mentioned (in this case, the amount of organic solvent used refers to the amount used to dissolve the crude product). Further, the crude product and the organic solvent are mixed and heated to dissolve the crude product, and then the resulting solution is cooled to 2-acetylaminomethyl-4- (4-fluorobenzyl). A method of crystallizing morpholine can also be employed. In any of the methods, when the coarse body contains various impurities and does not completely dissolve, the impurities may be filtered and recrystallized. In any method, when 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is crystallized, a seed crystal can be introduced and crystallized.

  Among the above methods, by employing the latter method, the amount of the organic solvent can be reduced, and high-purity 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is efficiently obtained in a high yield. Can be obtained. Next, a method for cooling the obtained solution after mixing the crude product and an organic solvent and dissolving the crude product by heating will be described.

  The temperature at which the crude body is dissolved in the organic solvent may be appropriately determined according to the type, amount, blending ratio, and the like of the organic solvent to be used, but is 30 ° C. or higher and the reflux temperature of the organic solvent or lower. Is preferred. Especially, in order to reduce the usage-amount of an organic solvent, it is preferable to dissolve the said rough body at the reflux temperature of an organic solvent.

  Further, the cooling rate at the time of cooling the solution obtained by dissolving the crude product tends to lower the purity if it is too fast, and is not efficient if it is too slow, so it is preferably 1 ° C./hour or more and 100 ° C. / Hour or less, more preferably 5 ° C./hour or more and 50 ° C./hour or less, particularly preferably 5 ° C./hour or more and 30 ° C./hour or less.

  Moreover, since the yield tends to decrease if the ultimate temperature at the time of cooling is too high, and the purity tends to decrease if it is too low, it is usually preferably −5 ° C. or more and 50 ° C. or less, and more preferably 0 ° C. The temperature is preferably 30 ° C. or less, and particularly preferably 0 ° C. or more and 10 ° C. or less.

  The 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine crystallized by the above method is solid-liquid separated by filtration or centrifugation, and dried by natural drying, air drying, vacuum drying, or the like. It may be isolated by

  The obtained acetylaminomethyl-4- (4-fluorobenzyl) morpholine has a very high purity, and if the conditions are optimized, the HPLC purity can be 99.5% or more. . Furthermore, in particular, the specific impurities can be reduced by recrystallizing the crude product obtained by the first production method by the above method. This specific impurity (total amount of the specific impurity (1), the specific impurity (2), and the specific impurity (3)) can be set to 0.07% or less if the conditions are optimized.

  As described above, according to the present invention, very high purity acetylaminomethyl-4- (4-fluorobenzyl) morpholine can be obtained. In particular, even with acetylaminomethyl-4- (4-fluorobenzyl) morpholine produced by the second production method, the content of the specific impurity can be further reduced. Therefore, the obtained acetylaminomethyl-4- (4-fluorobenzyl) morpholine is 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine, 4-amino-5-chloro-2-ethoxy-N -[[4- (4-Fluorobenzyl) -2-morpholinyl] methyl] benzamide and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] Methyl] benzamide citrate dihydrate can be suitably used as a raw material. Next, a method for producing 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine from 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine obtained by the recrystallization method will be described. .

(Method for producing 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine)
2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine obtained by the purification method of the present invention is deacetylated by a known method to give 2- (aminomethyl) -4- (4- Fluorobenzyl) morpholine can be prepared. Specifically, it can be produced by performing a hydrolysis reaction according to the method described in Patent Document 1. A specific method will be described. First, the obtained 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is dissolved in an acid, for example, 10% by mass hydrochloric acid, and heated to reflux to obtain an acetyl group. Deprotect. The obtained 2-aminomethyl-4- (4-fluorobenzyl) morpholine solution is neutralized with an alkaline solution, for example, an aqueous sodium hydroxide solution, and then extracted with chloroform. Thereafter, the organic layer (chloroform solution) is washed and dried to obtain a chloroform solution of 2-aminomethyl-4- (4-fluorobenzyl) morpholine. In the present invention, 2-aminomethyl-4- (4-fluorobenzyl) morpholine is taken out from the chloroform solution and purified, and can be used for the next reaction. It can also be used.

  Next, from 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine obtained by the above method, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) A method for producing -2-morpholinyl] methyl] benzamide will be described.

(Method for producing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide)
In the present invention, by reacting 2-aminomethyl-4- (4-fluorobenzyl) morpholine obtained by the above method with 4-amino-5-chloro-2-ethoxybenzoic acid, 4-amino- 5-Chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide can be prepared. For this reaction, a known method, for example, the method described in Patent Document 1 can be employed.

  A specific method will be described. First, the solution is cooled to 0 ° C. or lower in a chloroform solution of 2-aminomethyl-4- (4-fluorobenzyl) morpholine obtained by the above method. Separately, 4-amino-5-chloro-2-ethoxybenzoic acid and benzyl chlorocarbonate are mixed in chloroform at a low temperature of 0 ° C. or lower to synthesize a mixed acid anhydride. The chloroform solution of the mixed acid anhydride was added dropwise to a chloroform solution of 2-aminomethyl-4- (4-fluorobenzyl) morpholine, and 4-amino-5-chloro-2-ethoxy-N-[[4- (4 -Fluorobenzyl) -2-morpholinyl] methyl] benzamide is synthesized. The chloroform solution of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide obtained was neutralized, washed, dried, After leaving, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is produced by recrystallization from an ethanol solvent. be able to. The crude 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide after the solvent was distilled off was converted to N, N′-dimethyl. When recrystallized with a mixed solvent of formamide and water, impurities derived from the specific impurities can be further reduced at this point.

  Next, from 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide obtained by the above method, 4-amino-5-chloro- A method for producing 2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate will be described.

(Method for producing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate)
In the present invention, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide obtained by the above method is reacted with an aqueous citric acid solution. 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate can be produced. For this reaction, a known method, for example, the method described in Patent Document 1 can be employed.

  To describe a specific method, the obtained 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is mixed with methanol, ethanol, or 3-20 times citric acid hydration relative to alcohols such as isopropanol and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] by dissolving in an aqueous solution containing the product and cooling the resulting aqueous solution Benzamide citrate dihydrate can be removed as crystals.

  The crystals thus obtained can be isolated by solid-liquid separation by a known method, for example, filtration or centrifugation, followed by drying by natural drying, air drying, vacuum drying, or the like.

  The obtained 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate is obtained by using 2-acetyl as a raw material. Since aminomethyl-4- (4-fluorobenzyl) morpholine having a high purity is used, the purity is very high. In particular, since 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine having a low content of specific impurities is used as a raw material, the obtained 4-amino-5-chloro-2-ethoxy-N-[[[ 4- (4-Fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate has a small amount of impurities derived from the specific impurities and can be highly purified by a simple purification method.

  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.

  First, the measurement conditions of HLPC in each compound will be described.

(1) Analytical conditions for 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine and 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine (HPLC measurement conditions)
Apparatus: Model 2695-2489 manufactured by WATERS
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: YMC Co., Ltd. product name YMC-Pack ODS-A, inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm, pore diameter 12 nm)
Column temperature: 40 ° C. Constant temperature Sample temperature: 25 ° C. Constant temperature mobile phase A: Dissolve 5.44 g of potassium dihydrogen phosphate in 200 ml of water and add phosphoric acid to adjust to pH 4.2.
Mobile phase B: 2.72 g of potassium dihydrogen phosphate is dissolved in 1000 ml of water, 1000 ml of acetonitrile is added, and phosphoric acid is added to adjust to pH 4.2.
Transfer of mobile phase: The concentration ratio was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1, and the sample was analyzed. The total flow rate of mobile phase A and mobile phase B was 1.0 ml / min.

(Results from the above HPLC analysis)
2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine 20 minutes Specific impurity (1): 17 minutes Specific impurity (2): 22 minutes Specific impurity (3): 39 minutes was confirmed.

2- (aminomethyl) -4- (4-fluorobenzyl) morpholine 16 minutes Impurities derived from the specific impurity (1): 12 minutes Impurities derived from the specific impurity (2): 19 minutes Impurities derived from the specific impurity (3): 38 Confirmed in minutes.

(2) 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide and 4-amino-5-chloro-2-ethoxy-N -[[4- (4-Fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate analysis conditions (HPLC analysis conditions)
Apparatus: Model 2695-2489 manufactured by WATERS
Detector: UV absorptiometer (measurement wavelength: 274nm)
Column: YMC-Pack ODS-A manufactured by YMC Co., Ltd., inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm, pore diameter 12 nm)
Column temperature: 40 ° C. Constant temperature Sample temperature: 25 ° C. Constant temperature mobile phase A: Dissolve 4.9 g of potassium dihydrogen phosphate in 1800 ml of water, and adjust to pH 3.8 by adding 10 mass% phosphoric acid.
Mobile phase B: 2.2 g of potassium dihydrogen phosphate is dissolved in 800 ml of water, 1200 ml of acetonitrile is added, and 10% by mass phosphoric acid is added to adjust to pH 3.8.
Transfer of mobile phase: The concentration ratio was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 2, and the sample was analyzed. The total flow rate of mobile phase A and mobile phase B was 1.2 ml / min.

(Results from the above HPLC analysis)
4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide, and 4-amino-5-chloro-2-ethoxy-N-[[ 4- (4-Fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate: 23 minutes Impurities derived from specific impurities (1): 17 minutes Impurities derived from specific impurities (2): 30 minutes Specific impurities (3) Derived impurities: confirmed at 40 minutes.

Production Example 1
2- (4-Fluorobenzylamino) ethanol (33.8 g, 0.20 mol) and N- (2,3-epoxypropyl) phthalimide (41.4 g, 0.20 mol) were mixed and stirred at 80 ° C. for 3 hours. Thereafter, 107.8 g (1.1 mol) of concentrated sulfuric acid was added dropwise little by little, and after completion of the dropwise addition, the mixture was heated at 150 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water, neutralized with a 48 mass% aqueous sodium hydroxide solution, and extracted three times with chloroform. All chloroform used for extraction was combined, washed with water, dried, added with 20.4 g (0.20 mol) of acetic anhydride, and stirred at room temperature for 2 hours. The reaction solution was washed with water, then neutralized with a 20% by mass aqueous sodium hydroxide solution, and further washed with water. After distilling off chloroform, 44.0 g of solid 2- (acetylaminomethyl) -4- (4-fluorobenzoyl) morpholine (crude) was obtained. When purity was measured by HPLC, 2- (acetylaminomethyl) -4- (4-fluorobenzoyl) morpholine was 95.4%, specific impurity (1) was 0.180%, and specific impurity (2) was 0.173%. The specific impurity (3) was 0.183%.
Example 1
10 g of crude 2- (acetylaminomethyl) -4- (4-fluorobenzoyl) morpholine (crude) obtained in Production Example 1 was charged into a three-necked flask equipped with a Dimroth reflux tube and a thermometer, and 50 mL of ethyl acetate was added. Then, 25 ml of diisopropyl ether was added, and the crude product was dissolved at a temperature at which the organic solvent (mixed solvent of 50 ml of ethyl acetate and 25 ml of isopropyl ether) was refluxed. Crystallized. The obtained crystals were filtered and dried under vacuum for 12 hours to obtain 9.14 g (yield 91.4%) of 2- (acetylaminomethyl) -4- (4-fluorobenzoyl) morpholine white crystals. When the purity was confirmed by HPLC, the purity was 99.87%, the specific impurity (1) was 0.021%, the specific impurity (2) was 0.011%, and the specific impurity (3) was 0.014%. .

Examples 2-13
Purification was performed in the same manner as in Example 1 except that the organic solvent used in Example 1 was changed to the blending ratio, composition, and amount used shown in Table 3. The results are shown in Table 3.

Example 14
9 g (0.034 mol) of 2- (acetylaminomethyl) -4- (4-fluorobenzoyl) morpholine obtained in Example 1 was dissolved in 27 ml of chloroform, 10.6 g (0.102 mol) of concentrated hydrochloric acid was added, and the mixture was added at 100 ° C. For 6 hours. The solution after the reaction was washed with a 20% by mass aqueous sodium hydroxide solution and then with water, and dried over magnesium sulfate. Thereafter, chloroform was distilled off to obtain 7.47 g of 2-aminomethyl-4- (4-fluorobenzyl) morpholine (yield 98.0%). When the purity was confirmed by HPLC, the purity was 99.88%, the impurity derived from the specific impurity (1) was 0.022%, the impurity derived from the specific impurity (2) was 0.011%, and the impurity derived from the specific impurity (3) Impurity was 0.014%.

Example 15
7.47 g of 2-aminomethyl-4- (4-fluorobenzyl) morpholine obtained in Example 14 was dissolved in 30 ml of chloroform and cooled to −5 ° C. Separately, 7.18 g of 4-amino-5-chloro-2-ethoxybenzoic acid was dissolved in 140 ml of chloroform, cooled to −5 ° C., and benzyl chlorocarbonate was added dropwise so that the temperature did not exceed 0 ° C. After the dropwise addition, the mixture was stirred at −5 ° C. for 30 minutes, and the resulting mixed acid anhydride solution was added dropwise to a chloroform solution of 2-aminomethyl-4- (4-fluorobenzyl) morpholine so as not to exceed 0 ° C. . After dropping, the mixture was stirred at −5 ° C. for 30 minutes, then warmed to room temperature, neutralized with a 10% by mass aqueous sodium hydroxide solution, washed twice with water, and chloroform was distilled off. The obtained solid was recrystallized from ethanol to obtain 12.65 g of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide. When the purity was confirmed by HPLC, the purity was 99.90%, the impurity derived from the specific impurity (1) was 0.020%, the impurity derived from the specific impurity (2) was 0.011%, and the impurity derived from the specific impurity (3) Impurity was 0.013%.

Example 16
To 12 g of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide obtained in Example 15, ethanol 120 ml, water 120 ml, citric acid monohydrate After adding 17.9g of Japanese products and dissolving by heating, the mixture was cooled to precipitate crystals, and the crystals were filtered. The crystals were sufficiently washed with water, dried, and 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate 16 .8 g was obtained. When the purity was confirmed by HPLC, the purity was 99.90%, the impurity derived from the specific impurity (1) was 0.020%, the impurity derived from the specific impurity (2) was 0.011%, and the impurity derived from the specific impurity (3) Impurity was 0.014%.

Comparative Examples 1-4
It refine | purified by the method similar to Example 1 except having replaced the organic solvent used in Example 1 with the mixture ratio, composition, and usage-amount shown in Table 4. The results are shown in Table 4.

Comparative Example 5
2-aminomethyl-4- (4-fluorobenzyl) was prepared in the same manner as in Example 7 except that 2- (acetylaminomethyl) -4- (4-fluorobenzoyl) morpholine obtained in Comparative Example 1 was used. ) 7.40 g (97.1% yield) of morpholine was obtained. When the purity was confirmed by HPLC, the purity was 99.11%, the impurity derived from the specific impurity (1) was 0.100%, the impurity derived from the specific impurity (2) was 0.098%, and the impurity derived from the specific impurity (3) Impurity was 0.152%.

Comparative Example 6
4-amino-5-chloro-2-ethoxy-N-[[[] was obtained in the same manner as in Example 8, except that 2-aminomethyl-4- (4-fluorobenzyl) morpholine obtained in Comparative Example 5 was used. 12.8 g of 4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide was obtained. When the purity was confirmed by HPLC, the purity was 99.11%, the impurity derived from the specific impurity (1) was 0.103%, the impurity derived from the specific impurity (2) was 0.098%, and the impurity derived from the specific impurity (3) Impurity was 0.153%.

Comparative Example 7
The same as Example 9 except that 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide obtained in Comparative Example 6 was used. By the method, 16.7 g of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate was obtained. When the purity was confirmed by HPLC, the purity was 99.11%, the impurity derived from the specific impurity (1) was 0.103%, the impurity derived from the specific impurity (2) was 0.099%, and the impurity derived from the specific impurity (3) Impurity was 0.153%.

Claims (4)

Following formula (1)

2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine represented by formula (2) is recrystallized with an organic solvent containing an ester solvent in an amount of 50% by volume or more, and 2-acetylaminomethyl-4- (4- (Fluorobenzyl) morpholine purification method. After purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine by the purification method according to claim 1, the obtained 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine is deacetylated. By
Following formula (2)

A process for producing 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine represented by the formula: After producing 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine by the method according to claim 2, the obtained 2- (aminomethyl) -4- (4-fluorobenzyl) morpholine and Formula (3)

Is reacted with 4-amino-5-chloro-2-ethoxybenzoic acid represented by
Following formula (4)

4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide represented by formula (1). 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide was prepared by the method according to claim 3 and then obtained 4- Amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is reacted with an aqueous citric acid solution,
Following formula (5)

4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate dihydrate represented by the formula: