JPWO2011093439A1 - Process for producing N, N'-diallyl-1,3-diaminopropane - Google Patents

Abstract

An object of the present invention is to provide a method for producing high-purity N, N′-diallyl-1,3-diaminopropane that is high in yield and safety and can be applied to industrial production. In the present invention, the first step of reacting 1,3-diaminopropane and formaldehyde to obtain hexahydropyrimidine, the reaction of hexahydropyrimidine and allyl halide in the presence of a base, and N, N′-dialkyl A second step of obtaining 1,3-diallylhexahydropyrimidine by azolation reaction, decomposing N, N′-aminal site of 1,3-diallylhexahydropyrimidine, and N, N′-diallyl-1,3-diamino And a third step of obtaining propane. A method for producing N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof is provided. [Selection figure] None

Description

  The present invention relates to a method for producing N, N′-diallyl-1,3-diaminopropane.

  N, N'-diallyl-1,3-diaminopropane is useful as a crosslinking agent for crosslinked polyallylamine, which is useful as a therapeutic or preventive for hyperphosphatemia (Patent Document 1).

  As a method for producing N, N′-diallyl-1,3-diaminopropane, an amine is used as a starting material and 1,3-dichloropropane is reacted (Patent Document 1) and allyl chloride is used as an alkylating agent. A reaction method (Patent Document 2) is well known.

  Specifically, in the method of Patent Document 1, allylamine and 1,3-dichloropropane are reacted under heating conditions, and N, N′-diallyl-1,3-diaminopropane is synthesized by N-alkylation reaction. The obtained N, N′-diallyl-1,3-diaminopropane was isolated and purified and then subjected to a phosphating reaction using an aqueous phosphoric acid solution to effect N, N′-diallyl-1,3-diaminopropane.・ To obtain diphosphate.

  In the method of Patent Document 2, 1,3-diaminopropane and allyl chloride are reacted under heating conditions in the presence of a base, and N, N′-diallyl-1, After synthesizing 3-diaminopropane and isolating and purifying the obtained N, N′-diallyl-1,3-diaminopropane, N, N′-diallyl-1 was obtained by a chlorination reaction using a hydrogen chloride ether solution. , 3-Diaminopropane dihydrochloride is obtained.

  On the other hand, it is known that hexahydropyrimidine has unstable physical properties and is difficult to perform efficient chemical synthesis (Non-patent Documents 1 and 2). As a method for producing 1,3-diallylhexahydropyrimidine, there is a method utilizing a nucleophilic substitution reaction between an intermediate obtained by reacting 1,3-diaminopropane, excess amount of formaldehyde and benzotriazole with a metal reagent. It has been reported (Non-Patent Document 3).

  Specifically, the method of Non-Patent Document 1 is a method in which 1,3-diaminopropane and formaldehyde are reacted to synthesize hexahydropyrimidine by N, N′-amine formation reaction. Method 2 is a method in which 2-hydroxybenzaldehyde is added to the method of Non-Patent Document 1 to improve the removal of reaction by-products.

  In the method described in Non-Patent Document 3, 1,3-bis (1H-benzo [d] [1,2,3] is prepared by reacting 1,3-diaminopropane with excess amounts of formaldehyde and benzotriazole. Triazol-1-yl) methylhexahydropyrimidine is synthesized, and after isolation and purification, a metal reagent is added to perform a nucleophilic substitution reaction to obtain 1,3-diallylhexahydropyrimidine.

  In addition, although the method of introduce | transducing a sulfonyl group or a carbonyl group into a nitrogen atom of hexahydropyrimidine using an electrophilic reagent is known (nonpatent literature 1 and 4), the alkylating agent with lower electrophilicity is known. There are no reports on the N, N′-dialkylation reaction using.

International Publication No. 2009/008480 Japanese Patent No. 3952223

Evans et al., Aust. J. et al. Chem. 1967, Volume 20, p. 1643-1661 Locke et al. Org. Chem. 2007, Vol. 72, p. 4156-4162 Katritzky et al., J. MoI. Chem. Soc. Perkin Trans. 1, 1990, p. 541-547 Katritzky et al., J. MoI. Chem. Soc. Perkin Trans. 2, 1987, p. 1695-1700

  However, since the method disclosed in Patent Document 1 requires the use of a large amount of harmful allylamine (allylamine is used at a ratio of 10 mol per 1 mol of 1,3-dichloropropane), it is for the human body. It is necessary to pay attention to safety, and the production efficiency is insufficient for application to industrial production. In addition, the method disclosed in Patent Document 2 has a very low yield of N, N′-diallyl-1,3-diaminopropane dihydrochloride (11.3%), and N, N′-dialkylation. In carrying out the reaction, complicated operations such as simultaneous addition of a reaction reagent and a base, temperature control for stepwise temperature increase of the reaction, and filtration of reaction by-products are required.

  Further, the methods disclosed in Non-Patent Documents 1 and 2 have a low yield of hexahydropyrimidine, and it is necessary to perform complicated distillation purification operations for separation and purification of the mixture. In order to apply to industrial production, further improvement was necessary. In addition, the method disclosed in Non-Patent Document 3 requires the use of expensive benzotriazole in order to obtain 1,3-diallylhexahydropyrimidine (benzotriazole contains 1 mol of 1,3-diaminopropane). Before use with Grignard reagent, 1,3-bis (1H-benzo [d] [1,2,3] triazol-1-yl) methylhexahydropyrimidine Since isolation from water and subsequent high drying operations are required, the production cost and production efficiency are insufficient for industrial production.

  Furthermore, in order to use N, N′-diallyl-1,3-diaminopropane and its acid addition salt as a raw material for the synthesis of pharmaceuticals, Patent Documents 1 and 2 disclose N, N There is no disclosure or suggestion about the purity of '-diallyl-1,3-diaminopropane.

  Therefore, an object of the present invention is to provide a method for producing high-purity N, N′-diallyl-1,3-diaminopropane that has high yield and safety and can be applied to industrial production.

  As a result of intensive studies to solve the above problems, the inventors of the present invention have succeeded in continuously purifying allyl halide and base without purifying hexahydropyrimidine obtained by reaction of 1,3-diaminopropane and formaldehyde. It has been found that the N, N′-dialkylation reaction proceeds by reacting in the presence, and 1,3-diallylhexahydropyrimidine, which is a stable intermediate, can be synthesized in one pot. Furthermore, it has been found that N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof can be obtained by decomposing the N, N′-aminal site of 1,3-diallylhexahydropyrimidine with an acid, The present invention has been completed.

  In addition, the present inventors distilled and purified crude 1,3-diallylhexahydropyrimidine, and then decomposed the N, N′-aminal site to obtain extremely high purity N, N′-diallyl-1,3- It has also been found that diaminopropane or an acid addition salt thereof can be obtained.

  That is, the present invention reacts 1,3-diaminopropane and formaldehyde to obtain hexahydropyrimidine, and reacts hexahydropyrimidine and allyl halide in the presence of a base, and N, N ′ A second step of obtaining 1,3-diallylhexahydropyrimidine by a dialkylation reaction, decomposing the N, N′-aminal site of 1,3-diallylhexahydropyrimidine, and N, N′-diallyl-1,3 A third step of obtaining diaminopropane; and a method for producing N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof.

  The base is preferably sodium hydroxide.

  The allyl halide is preferably allyl chloride.

  The reaction of hexahydropyrimidine and allyl halide in the second step is preferably performed in a two-phase mixed solvent.

  The third step is preferably a step of obtaining N, N′-diallyl-1,3-diaminopropane by reacting 1,3-diallylhexahydropyrimidine and an acid.

  The acid is preferably hydrochloric acid or phosphoric acid.

  The second step is preferably a step of obtaining 1,3-diallylhexahydropyrimidine by reacting with the allyl halide without purifying the hexahydropyrimidine obtained in the first step.

  The second step preferably includes a purification step of purifying the obtained 1,3-diallylhexahydropyrimidine by distillation.

  According to the production method of the present invention, high-purity N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof as a crosslinking agent for crosslinked polyallylamine has a significantly higher yield than that of the conventional method. Can be produced at a rate. In addition, according to the present invention, there is provided a method for producing N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof applicable to industrial production, which is highly safe and eliminates complicated production steps. Can be provided.

  As used herein, the term “halogen” means a fluorine group, a chlorine group, a bromine group, or an iodine group unless otherwise specified.

The first and second steps of the present invention, that is, the step of reacting 1,3-diaminopropane and formaldehyde to obtain hexahydropyrimidine and the reaction of hexahydropyrimidine with allyl halide in the presence of a base, N, A process for obtaining 1,3-diallylhexahydropyrimidine by N′-dialkyl reaction is shown in Scheme A. Examples of the first step include a first step (A) that requires a post-treatment operation where hexahydropyrimidine is obtained, and a first step (B) that does not require a post-treatment operation. As the second step (A) in which the N, N′-dialkyl reaction is carried out using the crude hexahydropyrimidine obtained in the first step (A) as a starting material, the continuous from the first step (B). And the second step (B) in which the one-pot N, N′-dialkyl reaction is performed can be exemplified.

  The first step (A) in Scheme A consists only of the synthesis reaction of hexahydropyrimidine represented by formula (I) and the post-treatment operation of the reaction solution, and the resulting hexahydropyrimidine is isolated and purified. This is a process without operation.

  As the reaction conditions for the synthesis of hexahydropyrimidine in the first step (A), known reaction conditions (Non-patent Document 2) can be applied. The end point of the reaction can be determined, for example, by confirming the disappearance of the starting material 1,3-diaminopropane or the formation of hexahydropyrimidine by gas chromatography (hereinafter “GC”).

  The post-treatment operation for obtaining the crude hexahydropyrimidine in the first step (A) is as follows. First, after cooling the reaction solution with ice water, solid sodium hydroxide (0.50 to 2.50 mol is preferable with respect to 1 mol of 1,3-diaminopropane) is added and dissolved. The solution separates into upper and lower layers. The upper layer obtained by discarding this lower layer is crude hexahydropyrimidine.

  In the second step (A) in Scheme A, the crude hexahydropyrimidine obtained in the first step (A) and an allyl halide are reacted in the presence of a base with an N, N′-dialkylation reaction. This is a step of synthesizing 1,3-diallylhexahydropyrimidine represented by II).

  Examples of the base used in the second step (A) include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, or alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide. However, sodium hydroxide or potassium hydroxide is preferable, and sodium hydroxide is more preferable. The base is usually used as a solid or an aqueous solution.

  The amount of the base used in the second step (A) is preferably 1 to 10 mol and more preferably 1 to 6 mol with respect to 1 mol of 1,3-diaminopropane which is the starting material of the first step (A). preferable. If a large excess of base is added to the reaction solution, inorganic salts may precipitate due to saturation of the reaction solution, which may make stirring difficult. Therefore, the amount of the base is 1 mol of 1,3-diaminopropane. More preferably, it is suppressed to 1 to 5 mol.

  Examples of the allyl halide used in the second step (A) include allyl chloride and allyl bromide, and allyl chloride is preferred. As the allyl halide, a commercially available product may be used as it is.

  The amount of allyl halide used in the second step (A) is preferably 2 to 10 mol, preferably 2 to 5 mol, relative to 1 mol of 1,3-diaminopropane which is the starting material of the first step (A). Is more preferable. In addition, since the decomposition product of unreacted allyl halide remains as a by-product, the amount of allyl halide is reduced to 1,3-diaminopropane 1 in consideration of economy and suppression of the remaining by-product. More preferably, it is suppressed to 2 to 4 moles relative to moles.

  The amount of the base used in the second step (A) is preferably more than the amount of allyl halide used in the second step (A).

  The solvent used in the second step (A) is not particularly limited as long as it does not inhibit the reaction. For example, an aromatic hydrocarbon organic solvent (toluene, xylene, etc.), an amide polar organic solvent (N , N-dimethylformamide, N, N-dimethylacetamide, etc.), aliphatic ether organic solvents (tetrahydrofuran, dioxane, cyclopentyl methyl ether, tert-butyl methyl ether, etc.), aliphatic alcohol organic solvents (methanol, ethanol, 1 -Propanol, 2-propanol, etc.), sulfoxide hydrocarbon organic solvents (dimethyl sulfoxide, etc.), water solvents or mixed solvents thereof, but the solubility of 1,3-diallylhexahydropyrimidine and hexahydropyrimidine Considering tert-butylmethyl Preferably ether or water, in consideration of the production inhibition of by-products, biphasic mixed solvent of water and tert- butyl methyl ether is more preferable.

  The amount of the solvent used in the second step (A) is preferably 1 to 25 times by weight with respect to 1 weight of 1,3-diaminopropane which is the starting material of the first step (A). In consideration of suppression of product formation, 1 to 5 times by weight is more preferable.

  A phase transfer catalyst may be used for the N, N′-dialkylation reaction in the second step (A).

  Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium sulfate, quaternary phosphonium salts such as tetrabutylphosphonium chloride, and pyridinium compounds such as dodecylpyridinium chloride. Alternatively, crown ether is exemplified, but tetrabutylammonium bromide or tetrabutylammonium iodide is preferable, and tetrabutylammonium bromide is more preferable.

  The amount of the phase transfer catalyst used is preferably 0.01 to 0.10 mol, preferably 0.01 to 0.02 with respect to 1 mol of 1,3-diaminopropane which is the starting material in the first step (A). Mole is more preferred.

  The temperature of the N, N′-dialkylation reaction in the second step (A) is preferably −10 to 100 ° C., and more preferably 10 to 80 ° C. in consideration of the tendency of the reaction to accelerate at 10 ° C. or higher. Considering that the reaction is completed within 24 hours while suppressing the formation of by-products, 20 to 60 ° C. is more preferable.

  The reaction time of the N, N′-dialkylation reaction in the second step (A) is, for example, confirming the disappearance of the starting material hexahydropyrimidine or the formation of 1,3-diallylhexahydropyrimidine by GC. I can decide. Usually, the reaction is completed within 24 hours.

  In the N, N′-dialkylation reaction method of the second step (A), there is no restriction on the order of mixing the raw materials and each reagent, and the base and allyl halide are mixed and reacted in the crude hexahydropyrimidine solution. Alternatively, after mixing crude hexahydropyrimidine and allyl halide in advance, a solvent and a base may be added.

  The post-treatment operation of the reaction solution obtained in the second step (A) may be performed by combining a general washing operation and a liquid separation operation when a monophasic mixed solvent is used for the reaction. More specifically, after adding a hydrophobic organic solvent to the reaction solution, water is further added to perform a washing operation, and after removing the base and the water solvent, the organic solvent is distilled off by concentration under reduced pressure. 1,3-diallylhexahydropyrimidine can be obtained.

  About said washing | cleaning operation, it replaces with water and it is preferable to use the aqueous solution of alkali metal chlorides, such as sodium chloride, and it is more preferable that the density | concentration is 1 weight%-saturated concentration.

  Examples of the hydrophobic organic solvent include hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as diethyl ether, cyclopentyl methyl ether and tert-butyl methyl ether, dichloromethane, chloroform, and 1,2-dichloroethane. And halogenated hydrocarbon solvents such as ester solvents such as methyl acetate, ethyl acetate, and propyl acetate. Ether solvents, halogenated hydrocarbon solvents, and ester solvents are preferred, and tert-butyl methyl ether is preferred. More preferred.

  When a biphasic mixed solvent is used for the reaction, a general liquid separation operation may be performed. More specifically, crude 1,3-diallylhexahydropyrimidine can be obtained by removing the aqueous solvent by a liquid separation operation and then distilling off the organic solvent by vacuum concentration.

  A washing operation may be performed after the above liquid separation operation. Specifically, an aqueous acid solution is added to the organic layer after the liquid separation operation to perform washing, and after removing the aqueous layer and distilling off the organic solvent by concentration under reduced pressure, crude 1,3-diallylhexa Hydropyrimidine can be obtained. As the acid aqueous solution, for example, a phosphoric acid aqueous solution or a hydrochloric acid aqueous solution is preferable, and a phosphoric acid aqueous solution is more preferable.

  Examples of the method for purifying the crude 1,3-diallylhexahydropyrimidine obtained by the post-treatment operation include distillation or column chromatography.

  The first step (B) and the second step (B) in Scheme A are continuously performed from 1,3-diaminopropane as a starting material without performing the post-treatment operation in the first step (A). This is a route for advancing the reaction and synthesizing 1,3-diallylhexahydropyrimidine at once.

  As the 1,3-diaminopropane used in the first step (B), a commercially available product may be used as it is, but a product having sufficient reaction activity that is stored while avoiding contact with air is preferable.

  As the formaldehyde used in the first step (B), a commercially available formaldehyde aqueous solution (30 to 40% by weight aqueous solution) may be used as it is.

  The amount of formaldehyde used in the first step (B) is preferably 0.50 to 1.50 mol, and preferably 0.75 to 1.25 mol with respect to 1 mol of 1,3-diaminopropane as a starting material. More preferred. In addition, when an excess of formaldehyde is used, a formaldehyde cross-linked by-product is generated (Non-Patent Document 1), and therefore the amount of formaldehyde is suppressed to 0.95 to 1.15 mol per 1 mol of 1,3-diaminopropane. More preferably.

  The solvent used in the first step (B) is not particularly limited as long as it does not inhibit the reaction, but water is preferable in consideration of the solubility of 1,3-diaminopropane and formaldehyde.

  The amount of the solvent used in the first step (B) is preferably 1 to 25 times by weight with respect to 1 weight of 1,3-diaminopropane as a starting material, and considering the reaction efficiency and the suppression of the formation of by-products. 1 to 5 times by weight is more preferable.

  The reaction temperature in the first step (B) is preferably −10 to 100 ° C., more preferably 0 to 80 ° C., and further preferably 10 to 40 ° C. in consideration of reaction efficiency and suppression of byproduct formation.

  The end point of the reaction in the first step (B) can be determined, for example, by confirming the disappearance of the starting material 1,3-diaminopropane or the formation of hexahydropyrimidine by GC. In general, the reaction is completed within 5 hours.

  In the first step (B), the procedure of adding formaldehyde to the 1,3-diaminopropane solution is preferable.

  Examples of the base used in the second step (B) performed immediately after the completion of the first step (B) include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, and water. Although alkali metal hydroxides, such as sodium oxide and potassium hydroxide, are mentioned, sodium hydroxide or potassium hydroxide is preferable, and sodium hydroxide is more preferable. In addition, although a base is normally used as aqueous solution, you may use commercially available base aqueous solution (10-50 weight% aqueous solution) as it is.

  The allyl halide, solvent, phase transfer catalyst and amount thereof, reaction temperature and reaction time used in the second step (B) are the same as those in the second step (A) in Scheme A.

  There is no restriction | limiting in the order which mixes each reagent in said 2nd process (B), After adding a solvent to the reaction solution obtained by 1st process (B), it further mixes and reacts a base and an allyl halide. Alternatively, after mixing the reaction solution obtained in the first step (B) and the allyl halide, a solvent and a base may be added.

  The post-treatment operation of the reaction solution obtained in the first step (B) and the second step (B) is the same as the second step (A) in Scheme A.

Third step of the present invention, that is, a step of decomposing the N, N′-aminal site of 1,3-diallylhexahydropyrimidine to obtain N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof. And the chlorination step of N, N′-diallyl-1,3-diaminopropane is shown in Scheme B.

  Examples of the method for decomposing the N, N′-aminal moiety include hydrolysis using an inorganic acid such as hydrochloric acid, a substituted carboxylic acid such as trifluoroacetic acid, or a substituted sulfonic acid compound such as trifluoromethanesulfonic acid.

  The third step (A) in Scheme B includes the acid decomposition reaction of the N, N′-aminal site of 1,3-diallylhexahydropyrimidine represented by formula (II) and the produced N, N′-diallyl- This is a step of obtaining an acid addition salt of N, N′-diallyl-1,3-diaminopropane represented by the formula (IV) by chlorination of 1,3-diaminopropane.

  Examples of the acid used in the third step (A) include inorganic acids or organic acids such as hydrochloric acid and phosphoric acid, and phosphoric acid is preferable. In addition, as phosphoric acid, you may use commercially available phosphoric acid aqueous solution (80-90 weight% aqueous solution) as it is.

  1-10 mol is preferable with respect to 1 mol of 1, 3- diallyl hexahydropyrimidine which is a starting material, and, as for the quantity of the acid used at said 3rd process (A), 1-6 mol is more preferable. In view of economic efficiency and suppression of by-product formation, it is more preferable to suppress the amount of acid to 2 to 5 mol with respect to 1 mol of 1,3-diallylhexahydropyrimidine.

  The solvent used in the third step (A) is not particularly limited as long as it does not inhibit the reaction. For example, an aliphatic alcohol organic solvent (such as methanol, ethanol, 1-propanol, 2-propanol), An aqueous solvent or a mixed solvent thereof may be mentioned, but considering the solubility of N, N′-diallyl-1,3-diaminopropane, its acid addition salt and 1,3-diallylhexahydropyrimidine, methanol or water In consideration of the suppression of the formation of by-products, a monophasic mixed solvent of methanol and water is more preferable.

  The amount of the solvent used in the third step (A) is preferably 1 to 25 times by weight based on 1 weight of 1,3-diallylhexahydropyrimidine, and considering that the reaction is completed within 3 days, 1 10 to 10 times by weight is more preferable.

  The reaction temperature for acid decomposition of the N, N′-aminal site in the third step (A) is preferably 10 to 100 ° C., and considering the tendency of the reaction to accelerate at 40 ° C. or higher, 40 to 100 ° C. is more preferable. Preferably, considering that the reaction is completed within 3 days while suppressing the formation of by-products, 50 to 100 ° C. is more preferable.

  The reaction time for acid decomposition of the N, N′-aminal site in the third step (A) is, for example, disappearance of the starting material 1,3-diallylhexahydropyrimidine or N, N′-diallyl-1, The production of 3-diaminopropane can be determined by confirming with GC. Usually, the reaction is completed in 3 days.

  In the acid decomposition of the N, N′-aminal site in the third step (A), a procedure of adding an acid dropwise to the 1,3-diallylhexahydropyrimidine solution is preferable.

  As a post-treatment operation of the reaction solution obtained in the third step (A), the target salt may be crystallized or recrystallized by cooling the reaction solution.

  The third step (B) in Scheme B is represented by Formula (III) by an acid decomposition reaction of the N, N′-aminal site of 1,3-diallylhexahydropyrimidine represented by Formula (II). This is a step of obtaining N, N′-diallyl-1,3-diaminopropane.

  Examples of the acid used in the third step (B) include inorganic acids or organic acids such as hydrochloric acid and phosphoric acid, with hydrochloric acid being preferred. As hydrochloric acid, a commercially available aqueous hydrochloric acid solution (30 to 40% by weight in water) may be used as it is.

  The acid amount, the solvent and the amount thereof, the reaction temperature, and the reagent mixing procedure used in the third step (B) are the same as those in the third step (A) in Scheme B.

  When hydrochloric acid is used for acid decomposition of the N, N′-aminal site in the third step (B), the reaction is usually completed in 12 hours.

  The reaction temperature for acid decomposition of the N, N′-aminal site in the third step (B) is 50 to 100 ° C. in consideration of completing the reaction within 12 hours while suppressing the formation of by-products. Is preferred.

  The post-treatment operation of the reaction solution obtained in the third step (B) may be performed by combining a general washing operation and a liquid separation operation after adjusting the pH of the reaction solution with a base. More specifically, after adding a hydrophobic organic solvent to the reaction solution made basic by the addition of a base, water is further added to perform a washing operation, and after removing the base and the aqueous solvent, the organic solvent is removed by concentration under reduced pressure. To obtain crude N, N′-diallyl-1,3-diaminopropane.

  About said washing | cleaning operation, it replaces with water and it is preferable to use the aqueous solution of alkali metal chlorides, such as sodium chloride, and it is more preferable that the density | concentration is 1 weight%-saturated concentration.

  Examples of the base used for adjusting the pH include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, and more preferably sodium hydroxide. preferable. The base is usually used as an aqueous solution.

  Examples of the hydrophobic organic solvent include hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as diethyl ether, cyclopentyl methyl ether and tert-butyl methyl ether, dichloromethane, chloroform, and 1,2-dichloroethane. And halogenated hydrocarbon solvents such as ester solvents such as methyl acetate, ethyl acetate, and propyl acetate. Ether solvents, halogenated hydrocarbon solvents, and ester solvents are preferred, and tert-butyl methyl ether is preferred. Is more preferable.

  Examples of the method for purifying crude N, N′-diallyl-1,3-diaminopropane obtained by the above-described post-treatment operation include distillation or column chromatography.

  In the chlorination step in Scheme B, N, N′-diallyl-1,3-diaminopropane represented by the formula (III) is salified to give N, N′-diallyl-1 represented by the formula (IV). , 3-Diaminopropane acid addition salt.

  Examples of the acid used in the chlorination step include inorganic acids or organic acids such as hydrochloric acid and phosphoric acid, and hydrochloric acid or phosphoric acid is preferable. As hydrochloric acid and phosphoric acid, a commercially available hydrochloric acid aqueous solution (30 to 40% by weight aqueous solution) or phosphoric acid aqueous solution (80 to 90% by weight aqueous solution) may be used as they are.

  The amount of the acid used in the chlorination step is preferably 2 to 5 mol, more preferably 2 to 4 mol, relative to 1 mol of N, N'-diallyl-1,3-diaminopropane as a starting material. In view of economy and suppression of by-product formation, it is more preferable to suppress the amount of acid to 2 to 3 moles with respect to 1 mole of N, N'-diallyl-1,3-diaminopropane.

  The solvent used in the above chlorination step is not particularly limited as long as it does not inhibit chlorination. For example, aromatic hydrocarbon organic solvents (toluene, xylene, etc.), aliphatic ether organic solvents (tetrahydrofuran, dioxane, Cyclopentyl methyl ether, tert-butyl methyl ether, etc.), aliphatic alcohol-based organic solvents (methanol, ethanol, 1-propanol, 2-propanol, etc.), water solvents or mixed solvents thereof. Considering the solubility of diallyl-1,3-diaminopropane and its acid addition salt, methanol or water is preferable, and a monophasic mixed solvent of methanol and water is more preferable.

  The amount of the solvent used in the chlorination step is preferably 1 to 25 times by weight with respect to 1 weight of N, N'-diallyl-1,3-diaminopropane as a starting material.

  10-100 degreeC is preferable and the reaction temperature of said chlorination process has more preferable 40-100 degreeC when the tendency for reaction to accelerate above 40 degreeC is considered.

  In the above chlorination step, a procedure of adding an acid dropwise to the N, N′-diallyl-1,3-diaminopropane solution is preferable.

  As a post-treatment operation of the reaction solution obtained in the above chlorination step, the target salt may be crystallized or recrystallized by cooling the reaction solution.

  In order to obtain N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof with higher purity, the distillation purification of 1,3-diallylhexahydropyrimidine obtained in the second step, Recrystallization of N, N′-diallyl-1,3-diaminopropane acid addition salt obtained by distillation purification of N, N′-diallyl-1,3-diaminopropane obtained in 3 steps (B) and chlorination step The purification may be performed singly or in combination, and in particular, the above-mentioned second step preferably includes a purification step of purifying the obtained 1,3-diallylhexahydropyrimidine by distillation.

  Specifically, the distillation purification of 1,3-diallylhexahydropyrimidine obtained in the second step is performed under reduced pressure and heating conditions, and on a scale using 10 g of 1,3-diaminopropane as a starting material, If the degree of vacuum is 4.9 to 6.0 mmHg and the heating temperature in the oil bath is 78 to 85 ° C., 1,3-diallylhexahydropyrimidine (vapor temperature: 49 to 52 ° C.) can be obtained. On the scale using 444.4 g of 1,3-diaminopropane as a starting material, 1,3-diallylhexahydro can be obtained by distillation under reduced pressure with a degree of vacuum of 3 to 4 mmHg and a heating temperature in an oil bath of 100 to 125 ° C. Pyrimidine (vapor temperature: 69-75 ° C.) can be obtained.

  However, the method of combining the above purification step and other purification methods is not particularly limited, and may be appropriately determined depending on the purity before purification or the target purity after purification and the recovery rate.

  Hereinafter, the method for producing N, N′-diallyl-1,3-diaminopropane of the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

¹ H nuclear magnetic resonance spectrum (400 MHz ¹ H-NMR) was measured using a JNM-AL410 type nuclear magnetic resonance apparatus manufactured by JEOL Ltd. The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line) t (triple line), q (quadruple line), m (respectively). Multiple lines), br. (Wide). The IR spectrum was measured using an FT / IR-410 type Fourier transform infrared spectrophotometer manufactured by JEOL Ltd., and the MS spectrum was measured using a Micro Mass ZQ manufactured by Waters. In addition, elemental analysis was performed by using Vario EL III (Elemental Analysis System GmbH) manufactured by Elementar.

The process analysis in each process was performed under the following GC measurement conditions (hereinafter, “Condition A”) as necessary.
Equipment used: Shimadzu Gas Chromatograph (Shimadzu Corporation; GC-17A)
CHROMAPAC C-R7Aplus (Shimadzu Corporation)
Column used: Capillary Column (GL Sciences Inc.)
Inert Cap (registered trademark) (For Amines)
Measurement condition:
Carrier Gass: He
Column Temp. : 50 ° C
Injection Temp. : 250 ° C
Detector Temp. : 260 ° C
Temp. program:
50 ° C (5 min) -10 ° C / min-220 ° C (22 min)
Pressure: 75KPa
Flow: 39 mL / min Split 1:10

(First step (A))
An aqueous formaldehyde solution (35 wt% aqueous solution, 11.7 mL, 148 mmol) was added at 0 ° C. to a reaction solution in which 1,3-diaminopropane (10.0 g, 135 mmol) was added dropwise to distilled water (10.0 mL) at 0 ° C. The solution was added dropwise and stirred at room temperature for 2 hours. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C., sodium hydroxide (solid, 2.70 g, 67 mmol) was added to the reaction solution, and the organic layer was stirred. And the aqueous layer was separated. The obtained organic layer (crude hexahydropyrimidine) was directly used for the next reaction without purification. The GC retention time in the above condition A was 13.332 minutes for 1,3-diaminopropane and 15.599 minutes for hexahydropyrimidine.

(Second step (A))
To the organic layer (crude hexahydropyrimidine) obtained in the first step (A), tert-butyl methyl ether (18.8 mL) and an aqueous sodium hydroxide solution (48 wt% aqueous solution, 30.4 mL, 553 mmol) were brought to 0 ° C. After dropping, stirring was performed. Allyl chloride (22.5 mL, 277 mmol) and tetrabutylammonium bromide (435 mg, 1.35 mmol) were sequentially added to the biphasic reaction solution at 0 ° C., followed by stirring at room temperature for 15 hours. Water (18.8 mL) was added to the biphasic reaction solution and stirred, and then the organic layer and the aqueous layer were separated. The obtained organic layer was washed once with an aqueous sodium chloride solution (10 wt% aqueous solution, 18.8 mL), and the solvent was distilled off. The residue was purified by distillation under reduced pressure (degree of vacuum: 5.3 to 6.0 mmHg, vapor temperature: 50 to 52 ° C.) to obtain the desired 1,3-diallylhexahydropyrimidine (yield 10.98 g, yield). 49.0%) was obtained as a colorless oil. The GC retention time of the 1,3-diallylhexahydropyrimidine in the above condition A was 23.480 minutes, and the IR spectrum, ¹ H nuclear magnetic resonance spectrum, MS spectrum, and elemental analysis results were as follows.

IR (film, cm ⁻¹ ): 2940.9, 2789.5, 1644.0, 1447.3, 1338.4, 1194.7, 1104.0, 994.1, 918.0.
¹ H-NMR (CDCl ₃ ): δ 1.66-1.71 ppm (2H, m), 2.46 (4H, m), 2.99-3.02 (4H, m), 3.11 (2H, m), 5.09-5.19 (4H, m), 5.81-5.92 (2H, m).
ESI-MS: m / z = 167 (M + H) ⁺ .
Elem. Anal. : Cal. C, 72.24; H, 10.91; N, 16.85; obs. C, 71.20; H, 11.03; N, 16.90.

(First step (B) and second step (B))
To a reaction solution in which 1,3-diaminopropane (1.0 equivalent) was added dropwise to distilled water at 0 ° C., an aqueous formaldehyde solution (35 wt% aqueous solution, 1.1 equivalents) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Stirring was performed. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C. To the reaction solution, tert-butyl methyl ether and a base (equivalent) were added dropwise at 0 ° C., followed by stirring. Allyl halide (2.05 equivalent) and phase transfer catalyst (0.01 equivalent) were sequentially added to the biphasic reaction solution at 0 ° C., followed by stirring at room temperature. Process analysis was performed using GC (condition A). The GC ratio (%) after 16 hours during the reaction was determined from Formula 1.
GC ratio (1) (%) = {P / (QRS)} × 100 Equation 1
P: GC peak area value of 1,3-diallylhexahydropyrimidine Q: GC total peak area value (excluding the peak area value of the measurement sample preparation solvent)
R: GC peak area value of allyl halide S: GC peak area value of solvent used in reaction

  Table 1 shows the results of examining the GC ratio (%) in the first step (B) and the second step (B) by changing the phase transfer catalyst, the base or the amount thereof, or the allyl halide.

  From the results shown in Table 1, it is clear that the N, N′-dialkylation reaction in the second step (B) proceeds regardless of the presence or absence of a phase transfer catalyst. It has also become clear that alkali metal hydroxide or allyl chloride may be used to improve the reaction rate, and allyl chloride may be used to suppress the formation of by-products.

  Table 2 shows the results of examining the GC ratio (1) (%) in the first step (B) and the second step (B) by changing the solvent used in the reaction.

  From the results shown in Table 2, it is clear that the N, N′-dialkylation reaction in the second step (B) proceeds without any particular limitation on the type of solvent used.

  In Table 1, a more specific procedure for examining entry4 is shown below. An aqueous formaldehyde solution (35 wt% aqueous solution, 11.7 mL, 148 mmol) was added at 0 ° C. to a reaction solution in which 1,3-diaminopropane (10.0 g, 135 mmol) was added dropwise to distilled water (10.0 mL) at 0 ° C. The solution was added dropwise and stirred at room temperature for 2 hours. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C. To the reaction solution, tert-butyl methyl ether (22.5 mL) and an aqueous sodium hydroxide solution (48 wt% aqueous solution, 23.0 mL, 418 mmol) were added dropwise at 0 ° C., followed by stirring. Allyl chloride (22.5 mL, 277 mmol) and tetrabutylammonium bromide (435 mg, 1.35 mmol) were sequentially added to the biphasic reaction solution at 0 ° C., followed by stirring at room temperature for 15 hours. Water (22.5 mL) was added to the biphasic reaction solution and stirred, and then the organic layer and the aqueous layer were separated. The obtained organic layer was washed once with an aqueous sodium chloride solution (10% by weight aqueous solution, 22.5 mL), and the solvent was distilled off. The residue was purified by distillation under reduced pressure (degree of vacuum: 4.9 to 5.6 mmHg, vapor temperature: 49 to 52 ° C.) to obtain the desired 1,3-diallylhexahydropyrimidine (yield 12.90 g, yield). 57.5%) was obtained as a colorless oil.

(Third step (A))
An acid was added to the solvent at 0 ° C. and the mixture was stirred. 1,3-diallylhexahydropyrimidine (5.00 g, 30.01 mmol) was added dropwise, and the mixture was stirred under heating conditions. Process analysis was performed using GC (condition A). The GC ratio (%) after 24 hours during the reaction was determined from the formula 2.
GC ratio (2) (%) = {T / (T + U)} × 100 Equation 2
T: GC peak area value of N, N′-diallyl-1,3-diaminopropane U: GC peak area value of 1,3-diallylhexahydropyrimidine

  The above GC ratio (2) (%) in the third step (A) was examined by changing the acid or its amount, the reaction temperature, the solvent used in the reaction or the weight ratio of 1,3-diallylhexahydropyrimidine and the solvent. The results are shown in Table 3.

  From the results shown in Table 3, it is clear that the acid decomposition of the N, N′-aminal site of 1,3-diallylhexahydropyrimidine in the third step (A) proceeds under various conditions.

A specific procedure for an example of the reaction in the third step (A) in Scheme B is shown below. To a methanol solution (8.00 mL) of 1,3-diallylhexahydropyrimidine (1.00 g, 6.03 mmol), an aqueous phosphoric acid solution (85 wt% aqueous solution, 1.65 mL, 24.1 mmol) was added dropwise at 0 ° C. The mixture was stirred at 60 ° C. for 3 days. After cooling to 0 ° C., a seed crystal of N, N′-diallyl-1,3-diaminopropane · diphosphate was added to the reaction solution, followed by stirring and crystallization at 0 ° C. The produced white solid was collected by filtration and then dried under reduced pressure until a constant weight was obtained, whereby the target N, N′-diallyl-1,3-diaminopropane · 2 phosphate (yield 1.69 g, yield) 80.0%) was obtained. The GC retention time of N, N′-diallyl-1,3-diaminopropane (free form) in the above condition A was 23.081 minutes, and the ¹ H nuclear magnetic resonance spectrum and MS spectrum were as follows. .

¹ H-NMR (CDCl ₃ ); N, N′-diallyl-1,3-diaminopropane (as a free form): δ 1.45 ppm (2H, br.), 1.71 (2H, q, J = 7. 0 Hz), 2.68 (4H, t, J = 7.0 Hz), 3.25 (4H, dt, J = 1.6, 6.0 Hz), 5.08 (2H, ddd, J = 1.6) , 3.2, 10.4 Hz), 5.17 (2H, ddd, J = 1.6, 3.2, 17.2 Hz), 5.90 (2H, ddt, J = 6.0, 10.4). , 17.2 Hz).
ESI-MS; N, N′-diallyl-1,3-diaminopropane (as free form): m / z = 155 (M + H) ⁺ .

  A specific procedure for an example of the reaction in the third step (B) in Scheme B is shown below. A hydrochloric acid aqueous solution (35 to 37 wt% aqueous solution, 40.0 mL, 481 mmol) was added dropwise to a monophasic mixed solvent of distilled water (32.0 mL) and methanol (32.0 mL) at 0 ° C, followed by stirring. 1,3-diallylhexahydropyrimidine (20.0 g, 120 mmol) was added dropwise to the reaction solution at 0 ° C., followed by stirring at 90 to 98 ° C. for 3 hours and 30 minutes. After cooling to 0 ° C., an aqueous sodium hydroxide solution (48 wt% aqueous solution, 40.1 g, 481 mmol) and tert-butyl methyl ether (40.0 g) were added dropwise to the reaction solution at 0 ° C., followed by stirring. The organic layer and aqueous layer of the compatible reaction solution were separated. The solvent of the obtained organic layer was distilled off, and the residue was purified by distillation under reduced pressure (degree of vacuum: 3.0 mmHg, vapor temperature: 60-64 ° C.) to obtain the desired N, N′-diallyl- 1,3-diaminopropane (yield 16.39 g, yield 88.3%) was obtained as a colorless oil.

  Specific examples of the reaction of the chlorination step in Scheme B are shown below. A solution of N, N′-diallyl-1,3-diaminopropane (14.02 g, 90.9 mmol) in methanol (140.2 mL) and phosphoric acid aqueous solution (85 wt% aqueous solution, 12.40 mL, 182 mmol) at 0 ° C. The mixture was added dropwise and stirred at 0 ° C. for 1 hour. After heating the suspension reaction solution at 70 ° C., distilled water (10 mL) was added dropwise to the suspension reaction solution, followed by stirring and crystallization at 0 ° C. The produced white solid was collected by filtration and then dried under reduced pressure until a constant weight was obtained, whereby the desired N, N′-diallyl-1,3-diaminopropane · 2 phosphate (yield 30.48 g, yield). 95.8%).

  Without isolating and purifying the 1,3-diallylhexahydropyrimidine represented by the formula (II) obtained in the first step (B) and the second step (B) in scheme A, the third step Specific procedures for an example of a series of reactions provided for (B) are shown below. An aqueous formaldehyde solution (35 wt% aqueous solution, 23.4 mL, 297 mmol) was added at 0 ° C. to a reaction solution in which 1,3-diaminopropane (20.0 g, 270 mmol) was added dropwise to distilled water (49.0 mL) at 0 ° C. The solution was added dropwise and stirred at room temperature for 3 hours. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C. To the reaction solution, tert-butyl methyl ether (45.0 mL) and an aqueous sodium hydroxide solution (48 wt% aqueous solution, 46.0 mL, 837 mmol) were added dropwise at 0 ° C., followed by stirring. Allyl chloride (45.1 mL, 553 mmol) and tetrabutylammonium bromide (870 mg, 2.70 mmol) were sequentially added to the biphasic reaction solution at 0 ° C., followed by stirring at room temperature for 20 hours. The organic and aqueous layers were separated. The obtained organic layer was distilled off azeotropically with methanol (40.0 mL) twice. Hydrochloric acid aqueous solution (35-37 wt% aqueous solution, 89.9 mL, 1.08 mol) was added dropwise at 0 ° C. to a monophasic mixed solvent of residual distilled water (71.9 mL) and methanol (71.9 mL). Stir at ˜98 ° C. for 3 hours and 40 minutes. After cooling to 0 ° C., a sodium hydroxide aqueous solution (48 wt% aqueous solution, 89.9 g, 1.08 mol) and tert-butyl methyl ether (40.0 g) were added dropwise to the reaction solution at 0 ° C., followed by stirring. From the organic layer and aqueous layer of the biphasic reaction solution. The solvent of the obtained organic layer was distilled off, and the residue was purified by heating under reduced pressure (degree of vacuum: 3.0 mmHg, vapor temperature: 42-58 ° C.) to obtain the desired N, N′-diallyl-1. , 3-diaminopropane (yield 19.09 g, yield 45.9%) was obtained as a colorless oil.

(Reduction of N-allyl-1,3-diaminopropane or its acid addition salt)
Scheme C is contained in the obtained N, N′-diallyl-1,3-diaminopropane and its acid addition salt in a high concentration, and N, N′-diallyl-1,3-diaminopropane and its acid addition salt By-products derived from 1-allylhexahydropyrimidine (formula (V)), i.e., N-allyl-1,3-diaminopropane (formula (VI)) or acid addition salts thereof, which are difficult to separate from The byproduct pathway of Formula (VII) is shown.

  An example of distillation purification of crude 1,3-diallylhexahydropyrimidine aimed at effectively reducing N-allyl-1,3-diaminopropane or its acid addition salt in Scheme C The procedure is shown below. Formaldehyde aqueous solution (35 wt% aqueous solution, 566.0 g, 6.60 mol) was added to the reaction solution in which 1,3-diaminopropane (444.4 g, 6.00 mol) was added dropwise to distilled water (1087.9 g) at 0 ° C. The solution was added dropwise at 0 ° C. and stirred at room temperature for 3 hours. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C. To the reaction solution, tert-butyl methyl ether (731.7 g) and an aqueous sodium hydroxide solution (48 wt% aqueous solution, 1548.5 g, 18.58 mol) were added dropwise at 0 ° C., followed by stirring. After adding allyl chloride (937.4 g, 12.25 mol) and tetrabutylammonium bromide (19.0 g, 0.060 mol) to the biphasic reaction solution at 0 ° C., the mixture was stirred at room temperature for 16 hours, and then biphasic. The organic layer and aqueous layer of the reaction solution were separated, and the solvent of the obtained organic layer was distilled off. The residue was purified by distillation under reduced pressure (degree of vacuum: 3-4 mmHg, steam temperature: 69-75 ° C., oil bath temperature: 100-125 ° C.) to obtain the desired 1,3-diallylhexahydropyrimidine (yield 452). 0.0 g, yield 45.3%) was obtained as a colorless oil. On the other hand, a viscous distillation residue, which is presumed that 1-allylhexahydropyrimidine was decomposed and increased in quantity, was observed.

  Specific procedure for an example of distillation purification of crude 1,3-diallylhexahydropyrimidine aimed at effectively reducing N-allyl-1,3-diaminopropane or acid addition salt thereof in Scheme C Is shown below. To a reaction solution in which 1,3-diaminopropane (49.9 g, 0.67 mol) was added dropwise to distilled water (122.6 g) at 0 ° C., an aqueous formaldehyde solution (35 wt% aqueous solution, 61.9 g, 0.72 mol) was added. Was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C. Thereafter, tert-butyl methyl ether (84.0 g) and an aqueous sodium hydroxide solution (48 wt% aqueous solution, 176.1 g, 2.11 mol) were added dropwise to the reaction solution at 0 ° C. and stirred. After adding allyl chloride (105.1 g, 1.37 mol) and tetrabutylammonium bromide (2.3 g, 0.007 mol) to the biphasic reaction solution at 0 ° C., the mixture is stirred at room temperature for 22 hours to give a biphasic reaction solution. The organic and aqueous layers were separated. The obtained organic layer was washed once with an aqueous phosphoric acid solution (8 wt% aqueous solution, 86.5 g), and the organic layer and the aqueous layer were separated. The obtained aqueous layer was extracted with tert-butyl methyl ether (71.7 g), and all the organic layers were combined, and then the solvent was distilled off. The residue was purified by distillation under reduced pressure to obtain the desired 1,3-diallylhexahydropyrimidine (yield 51.6 g, yield 46.3%) as a colorless oil.

  In the following, the presence or absence of purification in the second step (B), third step (A), third step (B) and chlorination step in the method for producing N, N′-diallyl-1,3-diaminopropane, and purification method 1,3-diallylhexahydropyrimidine, N, N'-diallyl-1,3-diaminopropane, N, N'-diallyl-1,3-diaminopropane diphosphate and N , N'-diallyl-1,3-diaminopropane dihydrochloride, and 1-allylhexahydropyrimidine or N-allyl-1,3-diaminopropane or acid addition salt thereof contained in each step purified product The content ratio of was examined.

The purity analysis and the content ratio of the product in each step in this production method were performed under the following GC measurement conditions (hereinafter, “Condition B”) as necessary.
Equipment used: Shimadzu Gas Chromatograph (Shimadzu Corporation; GC-17A)
CHROMAPAC C-R7Aplus (Shimadzu Corporation)
Column used: Capillary Column (GL Sciences Inc.)
Inert Cap (registered trademark) (For Amines)
Measurement condition:
Carrier Gass: He
Column Temp. : 50 ° C
Injection Temp. : 250 ° C
Detector Temp. : 260 ° C
Temp. program:
50 ° C (5 min) -10 ° C / min-240 ° C (11 min)
Pressure: 75KPa
Flow: 39 mL / min Split 1:10

The GC purity of 1,3-diallylhexahydropyrimidine was calculated from Equation 3 by GC measurement under the above-mentioned condition B by weighing about 50 mg of a sample into a 50 mL volumetric flask and measuring with methanol in a constant volume.
GC purity (3) (%) = (A / B) × 100... Formula 3
A: GC peak area value of 1,3-diallylhexahydropyrimidine B: GC total peak area value (excluding the peak area value of the measurement sample preparation solvent)

In addition, the content GC ratio (%) of 1-allylhexahydropyrimidine contained in 1,3-diallylhexahydropyrimidine was obtained from Formula 3a. The GC retention time of 1-allylhexahydropyrimidine in Condition B was 20.482 minutes.
Containing GC ratio (3a) (%) = (a / b) × 100 Equation 3a
a: GC peak area value of 1-allylhexahydropyrimidine b: GC peak area value of 1,3-diallylhexahydropyrimidine

  Table 4 shows the results of examining the effects on the GC purity (3) (%) and the content GC ratio (3a) (%) with and without distillation purification for the second step (B) of several scales.

  From the results shown in Table 4, it is clear that the content of 1-allylhexahydropyrimidine is reduced by carrying out distillation purification in the second step (B), and high-purity 1,3-diallylhexahydropyrimidine is obtained. It is.

  Specific example of distillation purification of N, N′-diallyl-1,3-diaminopropane obtained from the reaction in the third step (B) using 1,3-diallylhexahydropyrimidine subjected to distillation purification as a raw material A typical procedure is shown below. Distilled water (398.5 g) was added to a methanol solution (315.5 g) of 1,3-diallylhexahydropyrimidine (246.5 g, 1.48 mol), and then an aqueous hydrochloric acid solution (35-37 wt% aqueous solution, 587.8 g). , 5.63 mol) was added dropwise at 0 ° C., and the mixture was stirred at 86 to 102 ° C. for 3 hours. After cooling to 0 ° C., an aqueous sodium hydroxide solution (48 wt% aqueous solution, 490.3 g, 5.88 mol) and tert-butyl methyl ether (298.8 g) were added dropwise to the reaction solution at 0 ° C. and stirred. From the organic layer and aqueous layer of the biphasic reaction solution. The obtained aqueous layer was extracted with tert-butyl methyl ether (150.4 g), and after combining all the organic layers, the solvent was distilled off to obtain crude N, N′-diallyl-1,3-diaminopropane. (236.6 g).

The GC purity of N, N′-diallyl-1,3-diaminopropane was calculated from Equation 4 by measuring approximately 20 mg of a sample in a 10 mL volumetric flask and measuring the volume with distilled water under the above-mentioned Condition B. did. The GC purity (4) (%) of the above-mentioned yield 236.6 g of crude N, N′-diallyl-1,3-diaminopropane was 89.00.
GC purity (4) (%) = (C / D) × 100 Equation 4
C: GC peak area value of N, N′-diallyl-1,3-diaminopropane D: GC total peak area value (excluding the peak area value of the measurement sample preparation solvent)
In addition, the content GC ratio (%) of N-allyl-1,3-diaminopropane contained in N, N′-diallyl-1,3-diaminopropane was obtained from Formula 4a. The GC retention time of N-allyl-1,3-diaminopropane in Condition B was 19.356 minutes.

Containing GC ratio (4a) (%) = (c / d) × 100 Equation 4a
c: GC peak area value of N-allyl-1,3-diaminopropane d: GC peak area value of N, N′-diallyl-1,3-diaminopropane

  A part of the obtained crude N, N′-diallyl-1,3-diaminopropane (127.7 g) was purified by simple distillation under reduced pressure to obtain the desired N, N′-diallyl-1,3-diamino. Propane (yield 98.7 g, GC purity (4) (%): 92.44) was obtained as a colorless oil.

  Furthermore, a glass tube having a length of 38 cm and an inner diameter of about 2 cm, in which a part (127.9 g) of the obtained crude N, N′-diallyl-1,3-diaminopropane was filled with 3 mm Dickson packing and SUS304 was used. And purified by precision distillation under reduced pressure to obtain the desired N, N′-diallyl-1,3-diaminopropane (yield 53.3 g, GC purity (4) (%): 99.52) as a colorless oil. Obtained.

  Table 5 shows the results of examining the effects on the GC purity (4) (%) and the content GC ratio (4a) (%) due to differences in the purity of raw materials or purification methods for the third step (B) of the two scales. Show.

  From the results shown in Table 5, high-purity N, N can be obtained by using the high-purity 1,3-diallylhexahydropyrimidine purified by distillation in the second step (B) as a starting material in the third step (B). It is clear that '-diallyl-1,3-diaminopropane can be obtained and the purity can be further increased by further distillation purification.

  A chlorination step of N, N′-diallyl-1,3-diaminopropane obtained from the reaction in the third step (B) using 1,3-diallylhexahydropyrimidine purified by distillation as a raw material, and further purified by distillation A specific procedure for an example is shown below. To a monophasic mixed solvent of distilled water (32.0 mL) and methanol (32.0 mL), an aqueous hydrochloric acid solution (35 to 37 wt% aqueous solution, 37.8 g, 362.8 mmol) was added dropwise at 0 ° C. and stirred. 1,3-diallylhexahydropyrimidine (20.0 g, 120 mmol) purified by distillation was added dropwise to the reaction solution at 0 ° C., followed by stirring at 90 to 99 ° C. for 3 hours. After cooling to 0 ° C., an aqueous sodium hydroxide solution (48 wt% aqueous solution, 39.1 g, 469 mmol) and tert-butyl methyl ether were added dropwise to the reaction solution at 0 ° C. The layer and the aqueous layer were separated. The obtained aqueous layer was extracted with tert-butyl methyl ether, all the organic layers were combined, the solvent was distilled off, and the resulting residue was heated under reduced pressure (degree of vacuum: 3.5 mmHg, vapor temperature: 49 To 58 ° C.) and N, N′-diallyl-1,3-diaminopropane (yield 16.6 g, yield 89.2%, GC purity (4) (%): 95.50) was colorless. Obtained as an oil.

  To a methanol solution (9.85 g) of the obtained N, N′-diallyl-1,3-diaminopropane (16.6 g, 107.4 mmol), a hydrochloric acid methanol solution (6.65 wt% methanol solution, 117.6 g, 214.5 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. The suspension reaction solution was heated in an oil bath at 69 ° C., and stirred and crystallized at 0 ° C. The produced white solid was collected by filtration and then dried under reduced pressure until a constant weight was obtained, whereby the desired N, N′-diallyl-1,3-diaminopropane dihydrochloride (yield 13.86 g, yield 56). 8%).

  On the other hand, an aqueous solution of phosphoric acid (an 85 wt% aqueous solution, an aqueous solution of N, N′-diallyl-1,3-diaminopropane (53.0 g, 0.344 mol) shown in entry 5 of Table 6 in 418.2 g). 79.5 g, 0.690 mol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Distilled water (40.9 g) was added dropwise to the suspension reaction solution, and then heated in an oil bath at 70 ° C., and then the suspension reaction solution was stirred and crystallized at 0 ° C. The produced white solid was collected by filtration and then dried under reduced pressure until a constant weight was obtained, whereby the desired N, N′-diallyl-1,3-diaminopropane · 2 phosphate (yield 115.7 g, yield). 95.9%).

  About the phosphate and hydrochloride of N, N'-diallyl-1,3-diaminopropane, GC measurement can be performed by pretreatment with an anion exchange resin. A specific procedure for an example of pretreatment using a strongly basic anion exchange resin (quaternary ammonium salt) as an anion exchange resin is shown below. A 90 mg sample was weighed into a 10 mL volumetric flask and made up to volume with distilled water. About 900 mg of pre-treated anion exchange resin (Diaion SANUPB) is weighed into a 10 mL test tube, and 5 mL of the sample aqueous solution is added thereto using a whole pipette, and then shaken at room temperature for 60 minutes using a shaker and then centrifuged. The supernatant was used as a measurement sample.

  As a pretreatment of the anion exchange resin, 3 g of the anion exchange resin is placed on the filter paper set in the Kiriyama funnel, and 30 mL of distilled water is dropped onto the anion exchange resin with a Komagome pipette, and it is naturally dried and then sucked. A bottle and a diaphragm pump were connected to perform further suction drying.

  The measurement sample was subjected to GC measurement under the above condition B, and the GC purity was calculated from Equation 4.

  Table 6 shows the results of examining the effects on the GC purity (4) (%) and the content GC ratio (4a) (%) due to the difference in the purity of the raw materials for several scale chlorination steps.

  From the results shown in Table 6, N, N′-diallyl-1,3-diaminopropane, which was purified by distillation in the second step (B) and further purified by distillation in the third step (B), was used as a starting material. Thus, it is clear that high purity N, N′-diallyl-1,3-diaminopropane hydrochloride and phosphate can be obtained.

  A specific procedure for an example of the reaction in the third step (A) in Scheme B using 1,3-diallylhexahydropyrimidine obtained by distillation purification as a raw material is shown below. A hydrochloric acid aqueous solution (35 to 37 wt% aqueous solution, 37.5 g, 359.8 mmol) was added dropwise to a monophasic mixed solvent of distilled water (32.0 mL) and methanol (32.0 mL) at 0 ° C, followed by stirring. 1,3-diallylhexahydropyrimidine (19.9 g, 119.9 mmol) was added dropwise to the reaction solution at 0 ° C., followed by stirring at 90 to 99 ° C. for 3 hours. After air cooling to room temperature, the mixture was concentrated and dried under reduced pressure to obtain crude crystals (27.19 g). Ethanol (152.6 g) was added, the suspension reaction solution was heated in an oil bath (bath temperature: 90 ° C.), distilled water (13 g) was added dropwise to the suspension reaction solution, and stirred crystals at 0 ° C. Analysis was performed. The produced white solid was collected by filtration and then dried under reduced pressure until a constant weight was obtained, whereby the desired N, N′-diallyl-1,3-diaminopropane dihydrochloride (yield 21.8 g, yield 80). 1%, GC purity (4) (%): 99.98).

  In Scheme A, hexahydropyrimidine represented by the formula (I) was synthesized by a known production method (Non-patent Document 1), and distillation purification (Non-Patent Document 1) was attempted. Distillation residue, which was thought to be decomposed and multimerized, was produced, and hexahydropyrimidine was only obtained in low yield as a mixture with 1,3-diaminopropane. The specific procedure is shown in the following (Reference Example).

(Reference example)
An aqueous formaldehyde solution (35 wt% aqueous solution, 46.7 mL, 593 mmol) was added at 0 ° C. to a reaction solution in which 1,3-diaminopropane (40.0 g, 540 mmol) was added dropwise to distilled water (40.0 mL) at 0 ° C. The solution was added dropwise and stirred at room temperature for 2 hours. After confirming the disappearance of 1,3-diaminopropane and the formation of hexahydropyrimidine, the reaction solution was cooled to 0 ° C. Sodium hydroxide (solid, 16.19 g, 405 mmol) was added to the reaction solution at 0 ° C., followed by stirring. The organic layer of the biphasic reaction solution separated into the organic layer and the aqueous layer was dried over sodium hydroxide (8.89 g), and the solid was separated by filtration. The filtrate was purified by distillation under reduced pressure (degree of vacuum: 2.5 kPa, steam temperature: 28 to 48 ° C.) to obtain a colorless oily mixture (yield 11.14 g) containing the desired hexahydropyrimidine. The weight of the distillation residue after distillation under reduced pressure was 31.57 g, which was a highly viscous substance.

  The production method of the present invention can be used for the production of N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof useful as a crosslinking agent for crosslinked polyallylamine or an acid addition salt thereof.

Claims (8)

A first step of reacting 1,3-diaminopropane and formaldehyde to obtain hexahydropyrimidine;
A second step of reacting hexahydropyrimidine with allyl halide in the presence of a base to obtain 1,3-diallylhexahydropyrimidine by N, N′-dialkylation reaction;
A third step of decomposing the N, N′-aminal site of 1,3-diallylhexahydropyrimidine to obtain N, N′-diallyl-1,3-diaminopropane;
A process for producing N, N′-diallyl-1,3-diaminopropane or an acid addition salt thereof.   The manufacturing method according to claim 1, wherein the base is sodium hydroxide.   The method according to claim 1 or 2, wherein the allyl halide is allyl chloride.   The method according to any one of claims 1 to 3, wherein the reaction between hexahydropyrimidine and allyl halide in the second step is performed in a two-phase mixed solvent.   5. The third step is a step according to claim 1, wherein 1,3-diallylhexahydropyrimidine is reacted with an acid to obtain N, N′-diallyl-1,3-diaminopropane. The manufacturing method as described.   The manufacturing method according to claim 5, wherein the acid is hydrochloric acid or phosphoric acid.   The second step is a step of obtaining 1,3-diallylhexahydropyrimidine by reacting with the allyl halide without purifying the hexahydropyrimidine obtained in the first step. A manufacturing method according to claim 1.   The said 2nd process is a manufacturing method as described in any one of Claims 1-7 including the refinement | purification process of distilling and purifying the obtained 1, 3- diallyl hexahydro pyrimidine.