WO2016093193A1 - Method for manufacturing trimethyl adamantyl ammonium hydroxide - Google Patents

Abstract

This method for manufacturing an N,N,N-trimethyl adamantyl ammonium hydroxide has, in sequence, (A) a step for obtaining an N,N-dimethyl adamantyl amine by dimethylating 1-aminoadamantane, (B) a step for reacting the N,N-dimethyl adamantyl amine and a quaternising agent and obtaining an N,N,N-trimethyl adamantyl ammonium salt, and (C) a step for obtaining an N,N,N-trimethyl adamantyl ammonium hydroxide from the N,N,N-trimethyl adamantyl ammonium salt. Steps (A) and (B) are performed using a protic polar solvent and a non-polar solvent that has a solubility parameter of 10 or less.

Description

Method for producing trimethyladamantyl ammonium hydroxide

The present invention relates to a method for producing trimethyladamantyl ammonium hydroxide.

Since adamantane derivatives have various properties depending on their structures, they are widely used in various industries as pharmaceutical raw materials, optical disk substrates, optical fibers, resin materials for photoresists, and the like.

Among them, trimethyladamantyl ammonium hydroxide is an industrially important compound that is used as a template agent (structure-directing agent) for zeolite.

Patent Document 1 below discloses a method for synthesizing trimethyladamantyl ammonium hydroxide.
First, amantadine hydrochloride (1-aminoadamantane hydrochloride) is prepared as a starting material, and dehydrochlorination is performed by reacting with a base such as an alkali metal hydroxide to obtain 1-aminoadamantane (dehydrochlorination). Next, 1-aminoadamantane, formic acid, and formaldehyde or paraformaldehyde are reacted in an alcohol solvent to obtain N, N-dimethyladamantylamine (dimethylation). Subsequently, N, N-dimethyladamantylamine is reacted with methyl halide to give 1-adamantanetrimethylammonium halogen salt (quaternization). Finally, anion exchange is performed on 1-adamantane trimethylammonium halogen salt using an OH type ion exchanger to obtain trimethyladamantyl ammonium hydroxide (ion exchange).

Patent Document 2 below discloses a method of synthesizing trimethyladamantyl ammonium hydroxide by a quaternization method different from the above.
First, similarly to the method described in Patent Document 1, amantadine hydrochloride is prepared as a starting material, and the steps of dehydrochlorination and dimethylation are sequentially performed. Subsequently, dimethyl sulfate and N, N-dimethyladamantylamine are reacted using water or an alcohol miscible with water as a reaction solvent to obtain 1-adamantyltrimethylammonium sulfate (quaternization). Finally, anion exchange is performed using an OH type ion exchanger to obtain trimethyladamantyl ammonium hydroxide (ion exchange).
A conventional synthesis method represented by Patent Document 1 can be represented by, for example, the scheme shown in FIG.

Japanese Unexamined Patent Publication No. 2011-246429 Japanese Unexamined Patent Publication No. 2012-520263

However, in the method for synthesizing trimethyladamantyl ammonium hydroxide described in Patent Document 1, it is necessary to use expensive methyl halide for quaternization, and there is a problem that the production cost is increased.

In addition, in the method for synthesizing trimethyladamantyl ammonium hydroxide described in Patent Document 2, quaternization is performed because a protic polar solvent such as water or water-miscible lower alcohol is used as a quaternization reaction solvent. In order to proceed efficiently, it was necessary to carry out under a high temperature of 120 to 200 ° C. and under a pressure of 5 to 300 bar, and there was a problem that the equipment cost and the manufacturing cost were increased.

Therefore, an object of the present invention is to provide a method capable of producing trimethyladamantyl ammonium hydroxide at low cost and high yield.

As a result of intensive investigations, the present inventors have determined that the step of dimethylating 1-aminoadamantane and the step of quaternizing the obtained N, N-dimethyladamantylamine are carried out by using a protic polar solvent and a solubility parameter. The present inventors have found that the conventional problems as described above can be solved by using a nonpolar solvent of 10 or less, and have completed the present invention.
That is, the present invention is as follows.

The method for producing N, N, N-trimethyladamantylammonium hydroxide of the present invention has the following steps (A) to (C) in order, and the following steps (A) and (B) include a protic polar solvent and a solubility. This is a production method using a nonpolar solvent having a parameter of 10 or less.
(A) a step of obtaining N, N-dimethyladamantylamine by dimethylating 1-aminoadamantane;
(B) reacting the N, N-dimethyladamantylamine with a quaternizing agent to obtain an N, N, N-trimethyladamantyl ammonium salt; and (C) the N, N, N-trimethyladamantyl ammonium salt. Obtaining N, N, N-trimethyladamantyl ammonium hydroxide from

In the present invention, the dimethylation and quaternization reactions are carried out using a protic polar solvent and a nonpolar solvent having a solubility parameter of 10 or less (hereinafter also referred to as a nonpolar solvent). In dimethylation, a protic polar solvent contains a dimethylation reagent, a nonpolar solvent contains 1-aminoadamantane, and the interface of each solvent becomes a reaction field. As an extraction phase of the product N, N-dimethyladamantylamine (hereinafter also referred to as DMAA), the protic polar solvent acts as a phase to which reaction by-products are transferred. The protic polar solvent and nonpolar solvent containing DMAA after dimethylation can be used as they are in the subsequent quaternization step, and the simplification of the step is achieved.
In quaternization, the nonpolar solvent serves as a reaction phase between DMAA and a quaternizing agent, and the protic polar solvent serves as an extraction phase for the quaternized product N, N, N-trimethyladamantyl ammonium salt. For example, when dimethyl sulfate is used as the quaternizing agent, the quaternized product is N, N, N-trimethyladamantyl ammonium methyl sulfate (hereinafter also referred to as TMAA-MeSO ₄ ). Since the produced N, N, N-trimethyladamantyl ammonium salt is hydrophilic, it moves to a protic polar solvent, and the quaternization equilibrium reaction is greatly biased toward the reaction product. As a result, at normal pressure In addition, a quantitative quaternization reaction is possible.

The solubility parameter (SP value) is a value defined by the regular solution theory introduced by Hildebrand, and is a measure of the solubility of the binary solution.

Further, only N, N-dimethyladamantylamine obtained in step (A) is in a nonpolar solvent, and only N, N, N-trimethyladamantylammonium salt obtained in step (B) is in a protic polar solvent. Therefore, these intermediates can be transferred to a continuous process without isolation. Therefore, processes can be reduced and manufacturing costs can be suppressed. The N, N, N-trimethyladamantyl ammonium salt also contains N, N, N-trimethyladamantyl ammonium hydroxide, but in this case, step (C) is unnecessary.

In the production method of the present invention, steps (A) to (C) can be performed under normal pressure. Thereby, since the reaction conditions under the high temperature and the high pressure in the technique described in Patent Document 2 are not required, it is possible to significantly suppress the equipment cost and the manufacturing cost.

In the production method of the present invention, the nonpolar solvent is preferably at least one of toluene and xylene.
Since toluene and xylene are relatively inexpensive and have a boiling point of 100 ° C. or higher, the amount of evaporation when heated can be suppressed. Therefore, N, N, N-trimethyladamantyl ammonium salt can be obtained with high yield by heating so that the reaction can proceed easily.

In the production method of the present invention, the protic polar solvent is preferably at least one of water and methanol.
Since water and methanol are relatively inexpensive and the solubility of N, N, N-trimethyladamantyl ammonium salt is high, almost the entire amount of N, N, N-trimethyladamantyl ammonium salt can be dissolved in a protic polar solvent. it can. In particular, in the case of water, N, N, N-trimethyladamantyl ammonium hydroxide is preferred because it does not require solvent substitution when used as a zeolitic template agent (structure-directing agent).

In the production method of the present invention, it is desirable to react 1-aminoadamantane, formic acid and formaldehyde or paraformaldehyde in step (A) to obtain N, N-dimethyladamantylamine. This is because N, N-dimethyladamantylamine can be obtained quantitatively.

In the production method of the present invention, in step (B), after reacting N, N-dimethyladamantylamine with a quaternizing agent in a nonpolar solvent, a protic polar solvent is added, and the product N, N, It is desirable to perform an operation of extracting N, N-trimethyladamantyl ammonium salt to the protic polar solvent side.
Thereby, a side reaction between the protic polar solvent and the quaternizing agent can be avoided.

In the production method of the present invention, it is desirable that the quaternizing agent is at least one of dimethyl sulfate and dimethyl carbonate.
It is not necessary to use an expensive quaternization reagent such as methyl halide in the technique described in Patent Document 1, and it does not require reaction conditions under high temperature and high pressure in the technique described in Patent Document 2. It becomes possible to remarkably suppress the facility cost and the manufacturing cost.

In the production method of the present invention, it is desirable that the N, N, N-trimethyladamantyl ammonium salt obtained in step (B) is contained at least 95% with respect to the total mass of the product.
By increasing the yield of N, N, N-trimethyladamantyl ammonium salt in the step (B), N, N, N-trimethyladamantyl ammonium hydroxide can be obtained with good yield.

In the production method of the present invention, it is desirable to use a strongly basic anion exchanger in the step (C). By using a strongly basic anion exchanger, ion exchange can be easily performed.

In the production method of the present invention, the amount of N, N, N-trimethyladamantyl ammonium methyl sulfate contained in the N, N, N-trimethyladamantyl ammonium hydroxide solution obtained in step (C) is 0.5. It is desirable that the content is not more than mass% and the amount of alkali metal is not more than 1000 ppm.
This indicates that the reaction and production are progressing as intended.

In the production method of the present invention, it is preferable that the step (C) further includes a step of removing the solvent from the obtained N, N, N-trimethyladamantyl ammonium hydroxide solution and concentrating to 15% by mass or more. Concentration makes it easy to use as a zeolitic template agent (structure-directing agent).

In the production method of the present invention, it is desirable to obtain 1-aminoadamantane by reacting 1-aminoadamantane hydrochloride with a base.
Since 1-aminoadamantane hydrochloride is structurally stable and has high storage stability, it is easier to obtain than N, N-dimethyladamantylamine, making it easier to use N, N, N-trimethyladamantylammonium hydroxide. Can be manufactured.

In the production method of the present invention, before the step (A), the 1-aminoadamantane hydrochloride was dehydrochlorinated using a two-phase solvent containing a protic polar solvent and a nonpolar solvent to obtain 1-aminoadamantane. Thereafter, the subsequent step (A) can be carried out without isolating the 1-aminoadamantane.
With this process, structurally stable 1-aminoadamantane hydrochloride can be used as a starting material and the process can be shifted to the subsequent process (A) without isolating the intermediate, enabling a continuous process and reducing production costs. can do.

DMAA, which is an intermediate in the production process of N, N, N-trimethyladamantyl ammonium hydroxide, is lipophilic, and N, N, N-trimethyladamantyl ammonium salt is hydrophilic. The production method of the present invention makes use of the lipophilic / hydrophilic properties of these intermediates, and by using a protic polar solvent and a nonpolar solvent in combination, the product can be obtained based on the partition coefficient of each intermediate. It moves selectively to the solvent side with high affinity. Therefore, the equilibrium is biased toward the product side, and a high-yield reaction is possible by atmospheric pressure synthesis. In addition, by using such a two-phase solvent, the necessary purification operation can be performed together with the reaction, so that it is possible to proceed to the next reaction continuously. Therefore, according to the present invention, trimethyladamantyl ammonium hydroxide can be produced at low cost and high yield.
Furthermore, it can be said that the quaternization step purifies the nonpolar solvent, and the nonpolar solvent can be reused, which further reduces the cost.

FIG. 1 is a diagram for explaining a method for synthesizing trimethyladamantyl ammonium hydroxide of the present invention. FIG. 2 is a diagram for explaining a conventional method for synthesizing trimethyladamantyl ammonium hydroxide.

Hereinafter, the present invention will be described in more detail.
The production method of the present invention includes (A) a step of obtaining N, N-dimethyladamantylamine by dimethylating 1-aminoadamantane (amantadine) in the method for synthesizing trimethyladamantylammonium hydroxide; The step of reacting N, N-dimethyladamantylamine with a quaternizing agent to obtain N, N, N-trimethyladamantyl ammonium salt uses a protic polar solvent and a nonpolar solvent having a solubility parameter of 10 or less. It is characterized by being performed.

Hereinafter, each process suitable for implementing the production method of the present invention will be described.
It is preferable to use amantadine hydrochloride which is easily available as a starting material in the production method of the present invention. In this case, as shown in FIG. 1, the production method of the present invention can be carried out through the steps of dehydrochlorination, dimethylation, quaternization and ion exchange of amantadine hydrochloride. FIG. 1 shows an example in which the protic polar solvent is water and the nonpolar solvent is toluene.

(Dehydrochlorination process)
In the dehydrochlorination step, a protic polar solvent and a two-phase solvent containing a nonpolar solvent having a solubility parameter of 10 or less are used, and 1-aminoadamantane hydrochloride as a starting material is dissolved in the protic polar solvent and reacted with a base. The step of obtaining 1-aminoadamantane is preferred. The types of protic polar solvent and nonpolar solvent will be described in detail below.
Moreover, as this base, an alkali metal hydroxide etc. are preferable, for example, sodium hydroxide is preferable. Sodium hydroxide is usually added to the reaction system as an aqueous solution, and the concentration of the aqueous sodium hydroxide solution is usually about 25 to 50% by mass. The reaction is performed for several hours, for example, at a temperature of about 50 ° C. In the dehydrochlorination step, the proportion of the protic polar solvent used is, for example, 1.0 to 1.5 times, preferably 1.0 to 1.1 times the volume of 1-aminoadamantane hydrochloride. For example, water, which is a solvent for sodium hydroxide, is included in the protic polar solvent. The ratio of the protic polar solvent to the nonpolar solvent used is the former: the latter (volume ratio), for example, 5 to 9: 5 to 1, and preferably 6 to 8: 4 to 2.

The reaction between 1-aminoadamantane hydrochloride and a base is carried out in a protic polar solvent, and dehydrochlorinated 1-aminoadamantane is transferred into a nonpolar solvent. This two-phase solvent can be used in the subsequent dimethylation step.
If 1-aminoadamantane is directly available, it is not necessary to perform the dehydrochlorination step, and 1-aminoadamantane can be dissolved in the nonpolar solvent and the subsequent dimethylation step can be performed.

(Dimethylation process)
Next, 1-aminoadamantane obtained in the dehydrochlorination step, formic acid, and formaldehyde or paraformaldehyde are reacted using a two-phase solvent including a protic polar solvent and a nonpolar solvent, and N, N-dimethyl is reacted. Adamantylamine (DMAA) is obtained. This dimethylation step corresponds to step (A) in the present invention.
The dimethylation step is an Eschweiler-Clark methylation reaction, which is a reductive amination reaction that introduces a methyl group into a primary amine. The Eschweiler-Clark reaction is an excess of formic acid in the primary amine. , And excess formaldehyde or paraformaldehyde is added and heated to reduce to a secondary amine. Thereby, a methyl group is introduced into the primary amine, and a methyl group is introduced into the secondary amine by the same reaction mechanism, so that the tertiary amine can be obtained efficiently and with high purity and high yield. Can do. The formic acid to be used is preferably added to the reaction system as a formic acid aqueous solution of about 75 to 97% by mass. The amount of formic acid used is usually preferably 0.3 to 0.7 molar times, more preferably 0.4 to 0.5 molar times with respect to formaldehyde or paraformaldehyde. Formaldehyde or paraformaldehyde is preferably added to the reaction system as an aqueous solution of about 30 to 50% by mass. The amount of formaldehyde or paraformaldehyde used is usually preferably 2 to 20 mol times and more preferably 3 to 8 mol times relative to 1-aminoadamantane. The temperature in the reaction system after addition of formic acid and formaldehyde or paraformaldehyde is preferably about 50 to 90 ° C.
The kind of nonpolar solvent will be described in detail below.

In dimethylation, formaldehyde or paraformaldehyde is contained in the protic polar solvent, 1-aminoadamantane is contained in the nonpolar solvent, and the interface of each solvent becomes a reaction field, and the nonpolar solvent generates dimethylation. As an extraction phase of the product DMAA, the protic polar solvent acts as a phase to which reaction by-products are transferred. Since the two-phase solvent can serve as a solvent for the subsequent quaternization step, the DMAA isolation operation can be omitted. That is, since it is possible to move to the step (B) without isolating the DMAA obtained in the step (A), the number of steps can be reduced and the manufacturing cost can be suppressed. In addition, since the protic polar solvent after a dimethylation process contains the reaction by-product, you may discard it as needed.

(Quaternization process)
In the quaternization step in the present invention, the DMAA obtained in the above dimethylation step and the quaternizing agent are reacted with each other using a protic polar solvent and a nonpolar solvent, and N, N, N-trimethyladamantyl ammonium salt is reacted. Get. This quaternization step corresponds to step (B) in the present invention.
Hereinafter, the case where dimethyl sulfate is used as the quaternizing agent will be described as an example. In this case, the quaternized product is N, N, N-trimethyladamantyl ammonium methyl sulfate (hereinafter also referred to as TMAA-MeSO ₄ ).

DMAA and quaternizing agent (dimethyl sulfate) are lipophilic substances and are miscible with nonpolar solvents, but hardly dissolve in protic polar solvents. On the other hand, TMAA-MeSO _4, which is a quaternization reaction product, is an organic salt and is therefore a hydrophilic substance and exhibits high solubility in a protic polar solvent, but hardly dissolves in a nonpolar solvent. For this reason, the raw material (DMAA) exists in a nonpolar solvent, and the quaternization reaction itself proceeds in the nonpolar solvent. Thereafter, the produced TMAA-MeSO ₄ moves to the protic polar solvent side. Therefore, the reaction product TMAA-MeSO ₄ is hardly present in the nonpolar solvent in which the reaction is carried out, and the quaternization equilibrium reaction can be greatly biased toward the reaction product. . As a result, quantitative quaternization reaction is possible even at normal pressure. Therefore, the production cost of trimethyladamantyl ammonium hydroxide can be greatly reduced.

In the quaternization step, the ratio of the nonpolar solvent used is, for example, 1.0 to 12.0 times, preferably 2.0 to 8.0 times the total capacity of DMAA and the quaternizing agent. is there.
The proportion of the protic polar solvent used is, for example, 1.0 to 12.0 times, preferably 2.0 to 8.0 times the total capacity of DMAA and the quaternizing agent.
Preferably, after reacting in a nonpolar solvent, a protic polar solvent is added.
In addition, when the two-phase solvent after the said dimethylation process is in the said range, it is not necessary to adjust the usage-amount of a protic polar solvent and a nonpolar solvent.

Examples of the quaternizing agent include at least one selected from dimethyl sulfate, dimethyl carbonate, and the like. Among them, dimethyl sulfate is preferable from the viewpoint of reactivity.

The reaction between N, N-dimethyladamantylamine and the quaternizing agent can be performed under normal pressure. In addition, the quaternization process can also be performed under pressure in a range that does not adversely affect the effects of the present invention as necessary. The reaction temperature in the quaternization reaction is, for example, 20 ° C. to 120 ° C., preferably 50 ° C. to 80 ° C.

In the quaternization step, the protic polar solvent may be added at any time before the start of the reaction of the quaternization step, during the reaction, or after the end of the reaction (95 mol% or more, the reaction has progressed). Among these, addition after completion of the reaction is preferable. Thereby, when using water as a protic polar solvent and using dimethyl sulfate as a quaternizing agent, a side reaction between water and dimethyl sulfate can be avoided.

Also, the ratio of dimethyl sulfate to DMAA is, for example, 0.90 to 1.30, preferably 0.90 to 1.10.

The product TMAA-MeSO ₄ is obtained by the quaternization step as described above. After completion of the quaternization step, it is selectively transferred to the TMAA-MeSO ₄ side by a protic polar solvent, so that it can be purified.

According to the quaternization step as described above, TMAA-MeSO ₄ is contained, for example, at least 95%, preferably at least 99.5%, based on the total mass of the product (the total mass of the quaternary ammonium salts). %included. By increasing the yield of TMAA-MeSO ₄ in the step (B), N, N, N-trimethyladamantyl ammonium hydroxide can be obtained with good yield.

The nonpolar solvent used in the present invention will be described.
The solubility parameter (SP value) of the nonpolar solvent needs to be 10 or less (nonpolar solvent) as described above. It is particularly preferable that the SP value is 9 or less.

Examples of the nonpolar solvents that can be used in the present invention include aromatic hydrocarbon solvents such as toluene, xylene, mesitylene, naphthalene, ethylbenzene, methylbenzene, methylethylbenzene, diethylbenzene, triethylbenzene, dimethylethylbenzene, methyldiethylbenzene, and tetralin. Examples include hydrocarbon solvents such as decalin, ethers such as diethyl ether, and nonpolar solvents such as ethyl acetate, and one or more of these can be used in combination.
Among these, at least one selected from toluene and xylene is particularly preferable because it can be suitably used as a DMAA extraction solvent and a quaternization reaction solvent after the dimethylation reaction.

Next, the protic polar solvent used in the present invention will be described.
Examples of the protic polar solvent include protic polar solvents having a solubility at 5 ° C. of TMAA-MeSO ₄ of 5 g / dL or more, such as alcohols such as water, methanol, ethanol, propanol, butanol, benzyl alcohol, diethylene glycol monomethyl ether, Examples include alcohol solvents such as polyhydric alcohols such as ethylene glycol and glycerin, and one or more of these can be used in combination. By using these protic polar solvents, it is possible to continuously carry out the quaternization step and the ion exchange step while omitting the isolation and purification operations of TMAA-MeSO ₄ . Therefore, the production cost of trimethyladamantyl ammonium hydroxide can be greatly reduced.
Especially, the ion exchange process which is a post process can be advanced efficiently by using at least 1 sort (s) chosen from water and methanol.

(Ion exchange process)
The ion exchange step is a step of obtaining trimethyladamantyl ammonium hydroxide (TMAA-OH) from TMAA-MeSO ₄ obtained in the quaternization step, and corresponds to step (C) of the present invention.
Specifically, in the ion exchange step, an anion exchange is performed on the TMAA-MeSO ₄ obtained in the quaternization step using a strongly basic anion exchanger, for example, an OH type ion exchanger. To obtain TMAA-OH. That is, after adding an OH type ion exchanger, for example, an OH type ion exchange resin, to the solution containing TMAA-MeSO ₄ obtained in the quaternization step, the resin is removed by filtration or the like. A method of charging a solution containing TMAA-MeSO ₄ obtained in the quaternization step into a column packed with a type of ion exchange resin and using water or alcohol as a developing solvent and allowing it to flow out from the column outlet, etc. . By using a strongly basic anion exchanger, ion exchange can be easily performed.
As the OH type ion exchange resin, any strongly basic one can be used. For example, Amberlite IRA400J (organo), Diaion SA10A (Mitsubishi Chemical), SANUPB (Mitsubishi Resin), DOWEX MONOSSPHERE 550A (manufactured by DOW Chemical), Muromac A2004 (manufactured by Muromachi Technos), and the like are typical examples.

The amount of TMAA-MeSO ₄ contained in the N, N, N-trimethyladamantyl ammonium hydroxide solution after the ion exchange step is 0.5% by mass or less, preferably 0.1% by mass or less, alkali metal Is 1000 ppm or less, preferably 100 ppm or less.

After the ion exchange step, water as a solvent is removed from the obtained N, N, N-trimethyladamantyl ammonium hydroxide solution, and the concentration of N, N, N-trimethyladamantyl ammonium hydroxide is adjusted. A step of concentrating to 15% by mass or more can be further provided. By passing through such a concentration step, it can be used as a template agent (structure-directing agent) for zeolite. Further, it is advantageous in that the volume during transportation / storage can be reduced.
Examples of means for removing water include simple distillation, evaporator, flash distillation, and thin film evaporator.

Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited to the following examples.

<Example 1>
(Dehydrochlorination process)
To a 500 ml three-necked flask equipped with a reflux condenser, a thermometer, and a stirrer, 96.9 g of toluene and 36.7 g of ion-exchanged water were added, and then 14.0 g of a 48 mass% sodium hydroxide aqueous solution [0.17 mol] with stirring. Was slowly added dropwise and stirred for 10 minutes. Thereafter, 30.0 g of amantadine hydrochloride [FW: 187.1, 0.16 mol] was slowly added. After raising the temperature of the reaction system to 50 ° C., dehydrochlorination reaction was performed by stirring for 1 hour.

(Dimethylation process)
A two-phase solvent containing amantadine obtained in the dehydrochlorination step was placed in a 500 ml three-necked flask equipped with a reflux condenser, a thermometer, and a stirrer, and 29.1 g of 76 mass% formic acid aqueous solution [FW: 46.0] under stirring. 0.48 mol] was added over 15 minutes, and 65.1 g of 37% by weight aqueous formaldehyde solution [FW: 30.0, 0.81 mol] was added over 15 minutes. After completion of the dropwise addition, the temperature was raised to 80 ° C. and the reaction was performed for 6 hours. After the reaction solution was cooled to 50 ° C. or lower, excess formic acid and formaldehyde were deactivated using a 48 mass% aqueous sodium hydroxide solution, and the pH of the reaction solution aqueous layer was adjusted to 10 or more. 157 ml of toluene and 70 g of ion-exchanged water were added as an extraction solvent, and the organic phase was extracted, and a solution corresponding to 27.8 g of N, N-dimethyladamantylamine [FW: 179.3, yield 98.5%] (transparent liquid) Got. By gas chromatography (apparatus: GC-2010, manufactured by Shimadzu Corporation) column: DB-1 (0.25 mm × 30 m, 0.25 um), carrier gas: He, vaporization temperature: 270 ° C., detector: FID (300 ° C.)) The purity obtained from the peak area was 99.5% or more.

(Quaternization process)
In a 500 ml three-necked flask equipped with a reflux condenser, a thermometer, and a stirrer, 27.8 g [FW: 179.3, 0] of the organic phase (N, N-dimethyladamantylamine) obtained in the dimethylation step and extracted with toluene was obtained. .16 mol]), and the temperature was raised to 50 ° C. Next, 19.8 g of dimethyl sulfate [FW: 126.1, 0.16 mol] was slowly added dropwise with stirring, and then the reaction system was heated to 80 ° C. and reacted at normal pressure for 4 hours. Thereafter, 412 g of ion-exchanged water was added to the reaction system, and the produced N, N, N-trimethyladamantyl ammonium methyl sulfate was isolated by extraction into an ion-exchanged water phase. The amount of N, N, N-trimethyladamantyl ammonium methyl sulfate contained in the ion-exchanged water phase was 45.8 g [FW: 305.4, yield 96.7%]. Liquid chromatography (Apparatus: Waters Alliance 2795 Column: Xbridge C18 Film thickness: 3.5 μm Size: 4.6 × 150 mm Temperature: 40 ° C. Eluent: 0.1% formic acid / CH ₃ CN = 9/1 detector : Purity was determined from the peak area by MS), and the purity was 99.5% or more.

(Ion exchange process)
The column was filled with 400 ml of strongly basic ion exchange resin (SANUPB (manufactured by Mitsubishi Chemical)), and ion-exchanged water was passed at a water flow rate of SV4 and washed sufficiently. Next, an aqueous solution corresponding to 45.0 g [FW: 305.4, 0.15 mol] of N, N, N-trimethyladamantyl ammonium methyl sulfate obtained in the quaternization step was poured into the column. Then, ion exchange water as a developing solvent was added at SV4, and an effluent of 6 volumes of ion exchange resin was recovered, and N, N, N-trimethyladamantyl ammonium hydroxide [FW: 211.4, yield 98% An aqueous solution was obtained. The recovered aqueous solution was concentrated by heating at 40 ° C. so that the concentration of N, N, N-trimethyladamantyl ammonium hydroxide was 25% by mass. Liquid chromatography (Apparatus: Waters Alliance 2795 Column: Xbridge C18 Film thickness: 3.5 μm Size: 4.6 × 150 mm Temperature: 40 ° C. Eluent: 0.1% formic acid / CH ₃ CN = 9/1 detector : Purity was determined from the peak area by MS) and found to be 99.5% or more.
Containing alkali metal by ICP (appliance: 2.7 ICL of H ₂ O and 30.3 mL of 69% HNO are added to 3.0 mL of 710 ICP-OES sample (TMAA-OH) manufactured by Agilent Technologies, Inc.) When the amount was measured, it was less than 500 ppm.
When spectrum data was measured by nuclear magnetic resonance spectrum (apparatus: JOEL 300 MHz solvent: d6-DMSO integration frequency: 16 times), ¹ H-NMR (300 MHz): 1.6 ppm (b ′, 6H), 2.0 ppm ( d ′, 6H), 2.2 ppm (c ′, 3H), and 2.9 ppm (a ′, 9H), and it was confirmed that the structure was represented by the following formula (1). By titration using a 0.1N aqueous HCl solution as the neutralizing agent and a phenolphthalein solution as the indicator, it was confirmed that the methyl sulfate ion was ion-exchanged 99.5% or more to the hydroxy ion.

<Example 2>
Through the same dehydrochlorination step as in Example 1, and further through the dimethylation step as in Example 1 except that xylene was used in place of toluene as the extraction solvent, a solution of N, N-dimethyladamantylamine (2) (Corresponding to 27.8 g (0.16 mol) of N, N-dimethyladamantylamine) was obtained.

(Quaternization process)
Solution (2) and 150 g of ion-exchanged water were added to a 500 ml three-necked flask equipped with a reflux condenser, a thermometer, and a stirrer, and the temperature was raised to 50 ° C. Next, 21.7 g (0.17 mol) of dimethyl sulfate was slowly added dropwise with stirring, and then the reaction system was heated to 80 ° C. and reacted at normal pressure for 4 hours. Thereafter, the aqueous phase was isolated to obtain an aqueous solution corresponding to 45.0 g of N, N, N-trimethyladamantyl ammonium methyl sulfate (yield 95%). When the purity was measured by liquid chromatography in the same manner as in Example 1, it was 99.5% or more.

(Ion exchange process)
An aqueous solution of N, N, N-trimethyladamantyl ammonium hydroxide was obtained through an ion exchange step in the same manner as in Example 1 (yield 98%). The recovered aqueous solution was concentrated by heating at 40 ° C. so that the concentration of N, N, N-trimethyladamantyl ammonium hydroxide was 25% by mass.
As in Example 1, when the purity was measured by liquid chromatography, it was 99.5% or more. When the alkali metal content was measured by ICP, it was less than 500 ppm, and the spectrum data was measured by nuclear magnetic resonance spectrum. ¹ H-NMR (300 MHz): 1.6 ppm (b ′, 6H), 2.0 ppm (d ′, 6H), 2.2 ppm (c ′, 3H), 2.9 ppm (a ′, 9H) It was confirmed that the structure was shown by the above formula (1). By titration using a 0.1N aqueous HCl solution as the neutralizing agent and a phenolphthalein solution as the indicator, it was confirmed that the methyl sulfate ion was ion-exchanged 99.5% or more to the hydroxy ion.

Although the invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. This application is based on a Japanese patent application filed on December 9, 2014 (Japanese Patent Application No. 2014-249023), the contents of which are incorporated herein by reference.

Claims (14)

1. A method for producing N, N, N-trimethyladamantylammonium hydroxide having the following steps (A) to (C) in order, wherein the following steps (A) and (B) include a protic polar solvent and a solubility parameter: A method for producing N, N, N-trimethyladamantyl ammonium hydroxide, which is carried out using 10 or less nonpolar solvent.
   (A) a step of obtaining N, N-dimethyladamantylamine by dimethylating 1-aminoadamantane;
   (B) reacting the N, N-dimethyladamantylamine with a quaternizing agent to obtain an N, N, N-trimethyladamantyl ammonium salt; and (C) the N, N, N-trimethyladamantyl ammonium salt. Obtaining N, N, N-trimethyladamantyl ammonium hydroxide from
2. The process proceeds to the subsequent step (B) without isolating the N, N-dimethyladamantylamine obtained in the step (A), and the N, N, N-trimethyladamantyl obtained in the step (B) The manufacturing method of Claim 1 which transfers to the following process (C), without isolating ammonium salt.
3. The production method according to claim 1 or 2, wherein the steps (A) to (C) are carried out under normal pressure.
4. The production method according to any one of claims 1 to 3, wherein the nonpolar solvent is at least one of toluene and xylene.
5. The production method according to any one of claims 1 to 4, wherein the protic polar solvent is at least one of water and methanol.
6. The production method according to any one of claims 1 to 5, wherein in the step (A), 1-aminoadamantane, formic acid, and formaldehyde or paraformaldehyde are reacted to obtain N, N-dimethyladamantylamine. .
7. In the step (B), after reacting the N, N-dimethyladamantylamine and the quaternizing agent in the nonpolar solvent, the protic polar solvent is added, and the product N, N, The production method according to any one of claims 1 to 6, wherein an operation of extracting N-trimethyladamantyl ammonium salt to the protic polar solvent side is performed.
8. The production method according to any one of claims 1 to 7, wherein the quaternizing agent is at least one of dimethyl sulfate and dimethyl carbonate.
9. The production method according to any one of claims 1 to 8, wherein the N, N, N-trimethyladamantyl ammonium salt obtained in the step (B) is contained at least 95% with respect to the total mass of the product.
10. The production method according to any one of claims 1 to 9, wherein a strong basic anion exchanger is used in the step (C).
11. The amount of N, N, N-trimethyladamantyl ammonium methyl sulfate contained in the N, N, N-trimethyladamantyl ammonium hydroxide solution obtained by the step (C) is 0.5% by mass or less; The production method according to any one of claims 1 to 10, wherein the amount of alkali metal is 1000 ppm or less.
12. The step (C) further comprises a step of removing the solvent from the obtained N, N, N-trimethyladamantyl ammonium hydroxide solution and concentrating to 15% by mass or more. The manufacturing method as described in.
13. The production method according to any one of claims 1 to 12, wherein the 1-aminoadamantane is obtained by a reaction of 1-aminoadamantane hydrochloride and a base.
14. Prior to the step (A), the 1-aminoadamantane hydrochloride was dehydrochlorinated using a two-phase solvent containing a protic polar solvent and a nonpolar solvent having a solubility parameter of 10 or less to obtain 1-aminoadamantane. The production method according to claim 13, wherein the process proceeds to the subsequent step (A) without isolating the 1-aminoadamantane.

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