JP2005126332A - Method for producing formamidine acetate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a means for producing high-purity formamidine acetate in high yield by an economical and simple method. <P>SOLUTION: A method for production is carried out as follows. A reaction is made to proceed under refluxing conditions when the formamidine acetate is produced by the reaction of a trialkyl orthoformate with acetic acid and ammonia. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing formamidine acetate.

  Formamidine acetate is widely used in industry as an intermediate in the production process of imidazole, pyrimidine, triazine and the like, which are main components of pharmaceuticals, agricultural chemicals, and dyes.

  Various studies have been made on the method for producing this formamidine acetate. Among them, a method of reacting orthoformate trialkyl ester, acetic acid and ammonia is useful, and several reports have been made about this.

  For example, a formamidine acetate salt is produced at a yield of 84% by heating a mixed solution of triethyl orthoformate and acetic acid to 130 to 135 ° C. and reacting by introducing ammonia gas into the mixed solution. A method is known (see Non-Patent Document 1).

  Non-Patent Document 1 also describes a method of producing formamidine acetate in a yield of 73% by reacting a mixture of orthoformate triethyl ester and ammonium acetate by heating to 130-135 ° C. Has been.

  However, the method described in Non-Patent Document 1 has a problem that the yield is not sufficient and the energy efficiency is poor because the reaction temperature is high.

  Also, a mixed solution of ortho formic acid triethyl ester and acetic acid was heated to 115 ° C. at the beginning of the reaction and reacted by introducing ammonia gas into the mixed solution, thereby yielding formamidine acetate in a yield of 84 to 88%. (See Non-Patent Document 2).

  However, the method of Non-Patent Document 2 also has a problem that the yield is not sufficient and the reaction temperature is high.

  Further, a mixed solution of trimethyl orthoformate, acetic acid and 1-propanol is heated to 90 ° C. and reacted by introducing ammonia gas into the mixed solution to produce formamidine acetate in a yield of 90%. Is disclosed (see Patent Document 1).

  However, in the method of Patent Document 1, methanol is by-produced, and formamidine acetate is very easily dissolved in this methanol. For this reason, when formamidine acetate is finally obtained, the remaining methanol must be distilled off, and since the solvent (1-propanol) is used, the operation is complicated. . Further, as described above, there is a problem that the yield is not sufficient.

  Further, amides such as formamide and acetamide are added as a catalyst to a mixed solution of orthoformate triethyl ester and acetic acid, and the mixed solution is heated to 110 ° C. at the beginning of the reaction and reacted by introducing ammonia gas, A method for producing formamidine acetate in a yield of 80 to 83% is disclosed (see Patent Document 2).

In the method described in Patent Document 2, a catalyst is used. However, the yield is insufficient, and it is difficult to recognize the advantage of using the catalyst. Further, the final yield is increased to 95% by reusing the crystallization mother liquor in the final crystallization stage, but this method has a problem that the operation becomes complicated.
German Patent Application No. 4001160 German Patent Application Publication No. 4422273 Journal of American Chemical Society, 82, 3138-3141 (1960) Organic Synthesis Collection Volume 5, 582-584 (1973)

  An object of the present invention is to provide a means for producing a high purity formamidine acetate in a high yield by an economical and simple method.

  In the present invention, when producing formamidine acetate by the reaction of orthoalkyl trialkyl ester, acetic acid and ammonia, the by-produced alcohol is left in the reaction system without distilling off. The invention has been completed by finding that the purity and yield of the formamidine acetate obtained are unexpectedly improved by recovering the product formamidine acetate by a crystallization process using it as a solvent. The present invention achieves an improvement in the purity and yield of the formamidine acetate obtained by allowing the reaction to proceed under reflux conditions.

  According to the present invention, highly pure formamidine acetate can be produced. For this reason, the present invention is useful when it is used as an intermediate in a production process of a pharmaceutical or the like that requires a high-purity raw material. Moreover, according to this invention, the yield at the time of manufacturing formamidine acetate can be improved greatly by a simple and economical method. Therefore, the present invention is very useful when applied to industrial mass production.

  The present invention is represented by chemical formula (1):

In the method for producing formamidine acetate by reacting an orthoformate trialkyl ester, acetic acid and ammonia represented by the formula, a step of reacting orthoformate trialkyl ester, acetic acid and ammonia under reflux conditions (in the present specification) And a step of crystallizing formamidine acetate using the alcohol produced by the reaction (also referred to herein as a “crystallization step”). A method for producing formamidine acetate.

  Formamidine acetate is produced from orthoformate trialkyl ester, acetic acid and ammonia by the reaction shown in the following chemical reaction formula (2).

  The present invention is characterized in that the formamidine acetate is recovered by a crystallization process using the alcohol as a solvent by allowing the above reaction to proceed under reflux conditions and leaving the by-produced alcohol in the reaction system. Have

  Conventionally, when formamidine acetate is produced from orthoformic acid triethyl ester, acetic acid and ammonia, ethanol produced as a by-product must be distilled out of the reaction system in order to further proceed the reaction based on the principle of equilibrium. It was common and it was considered that it was not preferable to leave it in the reaction system by refluxing or the like.

  In contrast, in the present invention, since the reaction proceeds under reflux conditions, ethanol produced as a by-product remains in the reaction system, contrary to the conventional case. Nevertheless, according to the present invention, the crystallization process can be applied because formamidine acetate is precipitated in ethanol after completion of the reaction. Thereby, it was possible to recover formamidine acetate with high purity and high yield.

  Hereinafter, although one preferable embodiment is described for each step of the production method of the present invention, the technical scope of the present invention is not limited to the following embodiment.

  First, a preferred embodiment of the reaction stage will be described. In addition, the reaction stage in this invention should just produce | generate formamidine acetate by reaction of the said raw material, and is not necessarily restrict | limited to the following aspects.

  First, orthoformate trialkyl ester, acetic acid and ammonia used as raw materials are prepared.

  The orthoalkyl trialkyl ester is not particularly limited with respect to its purity and availability. A commercially available product may be used, or in some cases, it may be synthesized by itself.

  In the present invention, “orthoformate trialkyl ester” means a compound represented by the following chemical formula (1), unless otherwise specified.

  Conventionally, a method in which a methyl ester is used as the alkyl ester when a formamidine acetate is produced from a trialkyl orthoformate is also known. However, when formamidine acetate is produced using methyl ester, methanol is by-produced. Since the solubility of formamidine acetate in methanol is extremely high, in this case, the formamidine acetate cannot be crystallized after the reaction, and the application of the present invention is difficult.

  On the other hand, the solubility of formamidine acetate in alcohols having 2 or more carbon atoms is lower than the solubility in methanol. The present invention has been made paying attention to this point, and when producing formamidine acetate using a trialkyl orthoformate having 2 or more carbon atoms, by-product alcohol remains in the reaction system. By making it possible, application of the crystallization process after completion | finish of reaction was enabled. Thereby, this invention can improve the purity and yield of the formamidine acetate obtained by very simple operation.

Therefore, in the orthoformate trialkyl ester represented by the chemical formula (1), R ¹ is an alkyl group having 2 or more carbon atoms. The alkyl group may be linear, branched or cyclic. The number of carbon atoms of the alkyl group is not particularly limited, but is preferably 2 to 12, more preferably 2 to 6, and further preferably 2 to 4. Specific examples of the alkyl group include an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and the like. Alkyl groups other than these may be used.

  The alkyl group is particularly preferably an ethyl group. That is, in the present invention, it is particularly preferable to produce formamidine acetate by reacting orthoformate triethyl ester, acetic acid and ammonia. In this case, ethanol is produced as a by-product, and the reaction solution after the completion of the reaction uses ethanol as a main solvent. However, when formamidine acetate is crystallized from such a reaction solution, the formamidine acetate is obtained with higher purity and higher This is because it is obtained in a yield. In addition, ortho-formate triethyl ester is preferably used because it is inexpensive and can be applied to various uses after ethanol produced as a by-product is separated from formamidine acetate. Therefore, the case where the orthoalkyl trialkyl ester is ortho formic acid triethyl ester will be described below, but the technical scope of the present invention is not limited to the following embodiments.

  Acetic acid and ammonia are not particularly limited with respect to their purity and availability. A commercially available product may be used, or in some cases, it may be synthesized by itself. In addition, it is preferable that water does not exist in a reaction liquid, since ortho formic acid triethyl ester will decompose | disassemble by reacting with water. Therefore, in order to improve the yield, it is preferable to use glacial acetic acid as acetic acid and anhydrous ammonia as ammonia.

  In the present invention, the reaction solution contains orthoformic acid triethyl ester, acetic acid and ammonia, and formamidine acetate and ethanol produced as the reaction proceeds. In some cases, by-products from reactions other than the above reactions may be contained.

  In the present invention, the formamidine acetate is recovered by crystallizing formamidine acetate from a reaction solution containing ethanol as a by-product by the reaction as a main solvent in the crystallization stage described later. As long as salt recovery is not hindered, other substances such as a solvent may be further added to the reaction solution before or during the reaction, and there is no particular problem. In such a case, a preferable embodiment is an embodiment in which a substance other than ethanol is not further added. Ethanol is a by-product of the reaction, and is a substance used as a solvent in the crystallization stage in the present invention. Therefore, the spirit of the present invention is not impaired by adding ethanol. A more preferred embodiment is an embodiment in which no substances other than orthoformic acid triethyl ester, acetic acid and ammonia which are raw materials for the reaction are further added. According to such an embodiment, it is preferable because no ethanol other than the raw material is used and ethanol produced as a by-product by the reaction can be effectively used as a solvent in the subsequent crystallization stage.

  In the reaction stage, the aspect of reacting orthoformate triethyl ester, acetic acid and ammonia is not particularly limited, but for example, the aspect of introducing ammonia gas into a mixture of orthoformate triethyl ester and acetic acid is simple and preferable. Therefore, in the following description, a method for producing formamidine acetate using such an embodiment will be described. However, if formamidine acetate is produced by the reaction of orthoformic acid triethyl ester, acetic acid and ammonia. Other embodiments may be adopted.

  First, ortho formic acid triethyl ester and acetic acid are mixed. Here, preferably, the mixture of the ortho formic acid triethyl ester and acetic acid is stirred. At this time, the atmosphere around the reaction solution is not particularly limited, but preferably the atmosphere around the reaction solution is replaced with an inert gas such as nitrogen or argon in order to prevent decomposition of triethyl orthoformate by water vapor in the air. Is done.

  When the orthoethyl triethyl ester and acetic acid are sufficiently mixed, ammonia gas is introduced to start the reaction. Here, it is preferable that the reaction solution is constantly stirred during the reaction.

  In the present invention, when the reaction is allowed to proceed, it is sufficient that the reaction is performed under reflux conditions, and other specific embodiments are not particularly limited.

  In the present invention, the “reflux condition” refers to a condition in which ethanol produced as a by-product is refluxed into the reaction system when the reaction proceeds and remains in the system even when the reaction is completed. In the present invention, the mode for setting the reflux condition is not particularly limited as long as it is a mode capable of refluxing by-produced ethanol into the reaction system.

  For example, an embodiment for connecting the reflux condenser to the reaction vessel to cause the reaction to proceed under a temperature condition equal to or higher than the temperature at which ethanol evaporates and to actually reflux ethanol is included. In the case where the reaction is allowed to proceed under a temperature condition equal to or lower than the temperature at which ethanol evaporates without using a reflux condenser and ethanol produced as a by-product can remain in the reaction system, “ Included in “reflux conditions”.

  In the present invention, the boiling point of the reaction solution varies as the reaction proceeds. Therefore, it is difficult to clearly define the reaction temperature for the reflux condition, and there is no particular limitation. Here, in the present invention, when the formamidine acetate is produced under reflux conditions, the mode for adjusting the reaction temperature is not particularly limited, but preferred modes include the following modes.

  Since the reaction shown in the chemical reaction formula (2) is an exothermic reaction, the temperature of the reaction liquid rises at the initial stage of the reaction due to the heat of reaction generated during the reaction. Here, in order to prevent side reactions accompanying the rapid progress of the reaction and ammonia diffusion, it is preferable to adjust the reaction temperature below the boiling point of ethanol by adjusting the amount of ammonia gas introduced in the initial stage of the reaction. . As the reaction proceeds, the temperature of the reaction solution rises gradually due to the heat of reaction. Therefore, the reaction solution is heated by a well-known method to further advance the reaction. At this time, when the heating is started, the boiling point is approximately 90 ° C., and ethanol is by-produced as the reaction further proceeds. Therefore, the boiling point approaches the boiling point of ethanol. Therefore, according to this, the reaction temperature may be adjusted to a temperature not higher than the boiling point of the reaction solution. Note that the boiling point of ethanol at normal pressure (1 atm) is 78.3 ° C. For example, when the reaction is performed under normal pressure, the temperature condition can be adjusted using this temperature as a guide.

  The present invention is characterized in that the reaction temperature is adjusted, and other reaction conditions and aspects of the apparatus used for the reaction are not particularly limited, and conventionally known aspects can be appropriately used.

  For example, the pressure conditions of the reaction system are not particularly limited, but normal pressure conditions are preferably used in that the reaction can proceed with a simple apparatus. In the present invention, it should be noted that the boiling point of the reaction solution also varies as the pressure condition of the reaction system varies.

  In the present invention, if the disappearance of orthoalkyl trialkyl ester due to side reactions such as hydrolysis and thermal decomposition and the emission of introduced ammonia gas are not taken into account, the trialkyl ester of orthoformate, acetic acid and ammonia are stoichiometric. By using the amount, the reaction is completed, and formamidine acetate is obtained according to the stoichiometry. However, in order to increase the reaction rate and to ensure completion of the reaction, an excessive amount of trialkyl orthoformate and / or ammonia may be added to the reaction system. Here, according to the stoichiometry, from the above chemical reaction formula (2), the reaction is carried out at a molar ratio of orthoformate trialkyl ester: acetic acid: ammonia = 1: 1: 2 to form 1 mol of formamidine acetate. However, the trialkyl ester of orthoformate is preferably 1.0 to 2.0 mol, more preferably 1.0 to 1.2 mol with respect to 1 mol of acetic acid, and ammonia is preferably with respect to 1 mol of acetic acid. Is 2.0 to 4.0 mol, more preferably 2.0 to 2.4 mol. If the amount of trialkyl orthoformate or ammonia added to acetic acid is too small, the reaction will not proceed sufficiently, and conversely, if it is too much, the effect will not be obtained, and the process of recovering the raw materials may be complicated. is there. In addition, it is preferable not to employ | adopt the conditions which acetic acid exists excessively with respect to orthoformate trialkylester or ammonia since a post-processing process may become complicated.

  In the present invention, since the reaction proceeds under reflux conditions, ethanol by-produced by the reaction remains in the reaction solution without being distilled off. Therefore, the formamidine acetate produced by the reaction is partially dissolved in the by-produced alcohol, and the amount exceeding the solubility is precipitated as the reaction proceeds, and the reaction solution is in a slurry state when the reaction is completed. Become.

  Next, a preferred embodiment of the crystallization stage will be described. The crystallization step in the present invention is not necessarily limited to the following modes as long as formamidine acetate can be recovered from the reaction solution by a crystallization method using an alcohol by-produced by the reaction as a solvent.

  “Crystallization” refers to an operation of precipitating crystals from a liquid phase, thereby separating or concentrating specific components as crystals from the liquid phase. In general, since the heat of crystallization is much smaller than the heat of evaporation, the crystallization method is widely used as an energy saving separation method for the separation of various compounds.

  In the present invention, when the reaction solution obtained upon completion of the reaction is cooled, the solubility of formamidine acetate in the reaction solution containing alcohol as the main solvent decreases, so that formamidine acetate can be almost precipitated. Thereby, it becomes possible to obtain a highly pure formamidine acetate by a simple operation. Although the cooling temperature in the crystallization stage is not particularly limited, it is preferably cooled to a temperature at which by-produced alcohol does not evaporate under normal pressure, more preferably -10 to 10 ° C. In the crystallization stage, the alcohol in the reaction solution may be distilled off before cooling to such an extent that the ease of operation is not impaired.

  It is preferable that the formamidine acetate precipitated in the crystallization step is further solid-liquid separated by a conventional method. The solid-liquid separation method is not particularly limited, and for example, a filtration method, a centrifugal separation method, or the like can be used.

  When the reaction solution is purified by a filtration method, general knowledge about filtration can be used. For example, suction filtration or pressure filtration can be applied to shorten the filtration time. Thereafter, the obtained formamidine acetate wet body can be dried by a conventional method to finally obtain formamidine acetate.

  The formamidine acetate produced according to the present invention is used as an intermediate in the production process of imidazole, pyrimidine, triazine and the like, which are main components such as pharmaceuticals, agricultural chemicals and dyes. Here, according to the present invention, a formamidine acetate having a higher purity than that of the prior art can be obtained. Therefore, the formamidine acetate produced according to the present invention is extremely useful as a raw material in the production process in which a high-purity raw material is required. In addition, according to the present invention, the yield when producing formamidine acetate can be improved by a simple and economical method. Therefore, the present invention is extremely useful as a production method for mass production industrially. It is.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example, a following example is only an example for demonstrating this invention in detail, and, thereby, the technical scope of this invention is not limited at all.

Example 1
To a 1000 mL four-necked round bottom flask (reaction vessel) connected with a stirrer, a reflux condenser, a gas introduction tube and a thermometer, 540 g (3.64 mol) of orthoformate triethyl ester and 200 g (3.33 mol) of glacial acetic acid were added. And an average of 10 g of anhydrous ammonia gas was started per hour while stirring under a nitrogen stream. At the start of introduction, the reaction vessel was immersed in a room temperature water bath. The introduction of anhydrous ammonia gas started when the reaction solution temperature was normal, and the reaction solution temperature was allowed to rise naturally. When 50 g of anhydrous ammonia gas was introduced, the reaction solution was heated by heating the water bath, and then the introduction of anhydrous ammonia gas was continued while maintaining the reflux state. A total of 118 g (6.93 mol) of anhydrous ammonia gas was introduced until the introduction was completed. At this time, the reaction solution was in a reflux state at about the reflux temperature of ethanol, and the reaction was completed. Next, the reaction solution was cooled to 0 ° C. to sufficiently precipitate formamidine acetate, and solid-liquid separation was performed by a conventional method to obtain a formamidine acetate wet crystal. The obtained formamidine acetate wet crystals were dried under reduced pressure by a conventional method to obtain 332 g (3.19 mol) of formamidine acetate. The yield based on acetic acid was 96%, and the purity of the formamidine acetate obtained was 99.7% according to the purity analysis by the internal standard method using a high performance liquid chromatograph. Further, when the filtrate was evaporated to dryness, 3% of formamidine acetate was confirmed as a yield based on acetic acid. Therefore, the total yield (reaction yield) of formamidine acetate was 99% with respect to acetic acid.

Example 2
To a 1000 mL four-necked round bottom flask (reaction vessel) connected with a stirrer, a reflux condenser, a gas inlet tube and a thermometer, 494 g (3.33 mol) of orthoethyl triformate and 200 g (3.33 mol) of glacial acetic acid were added. And an average of 10 g of anhydrous ammonia gas was started per hour while stirring under a nitrogen stream. At the start of introduction, the reaction vessel was immersed in a room temperature water bath. The introduction of anhydrous ammonia gas started when the reaction solution temperature was normal, and the reaction solution temperature was allowed to rise naturally. When 50 g of anhydrous ammonia gas was introduced, the reaction solution was heated by heating the water bath, and then the introduction of anhydrous ammonia gas was continued while maintaining the reflux state. Anhydrous ammonia gas was introduced in a total of 113.5 g (6.66 mol) until the introduction was completed. At this time, the reaction solution was in a reflux state at about the reflux temperature of ethanol, and the reaction was completed. Next, the reaction solution was cooled to 0 ° C. to sufficiently precipitate formamidine acetate, and solid-liquid separation was performed by a conventional method to obtain a formamidine acetate wet crystal. The obtained formamidine acetate wet crystals were dried under reduced pressure by a conventional method to obtain 326 g (3.13 mol) of formamidine acetate. The yield based on acetic acid was 94%, and the purity of the formamidine acetate obtained was 99.6% according to the purity analysis by the internal standard method using a high performance liquid chromatograph. Further, when the filtrate was evaporated to dryness, 3% of formamidine acetate was confirmed as a yield based on acetic acid. Therefore, the total yield (reaction yield) of formamidine acetate was 97% with respect to acetic acid.

Claims (3)

Chemical formula (1):

In the process for producing formamidine acetate by reacting trialkyl orthoformate represented by the formula: acetic acid and ammonia,
Reacting orthoalkyl trialkyl ester, acetic acid and ammonia under reflux conditions;
Crystallizing formamidine acetate using the alcohol produced by the reaction;
A process for producing formamidine acetate, comprising:   The production method according to claim 1, wherein the orthoformate trialkyl ester is orthoformate triethyl ester.   The molar ratio of orthoformate trialkyl ester used in the reaction to acetic acid is 1.0 to 2.0, and the molar ratio of ammonia used in the reaction to acetic acid is 2.0 to 4.0. The manufacturing method according to claim 1, wherein: