KR20150075187A - A Novel Method for Preparing of Telmisartan - Google Patents

Abstract

The present invention relates to a manufacturing method of telmisartan used as an angiotensin II receptor blocker (ARB)-based hypertension medicine and telmisartan manufactured by the method wherein a condensation reaction for obtaining an intermediate during a telmisartan manufacturing procedure is conducted in a solvent with an ionic liquid, thereby significantly shortening the reaction time by one to two hours compared with the conventional method; and a hydrolysis reaction of the intermediate for manufacturing telmisartan is conducted by controlling the ratio of water with a hydroxyl group, thereby significantly improving filtering efficiency, the process rate, and process convenience and obtaining high-purity and high-yield telmisartan without further purification.

Description

A Novel Method for Preparation of Telmisartan < RTI ID = 0.0 >

The present invention relates to a method for producing telmisartan, which is used as an ARB (angiotensin II receptor blocker) type hypertensive agent, and telmisartan prepared by the above method.

ARB (angiotensin II receptor blocker) type hypertension is the most recently developed hypertension treatment. Representative products include valsartan (diovan), losartan (cozza), irbesartan (aprovel), candesartan cilexetil (atakan) or olmesartan medoxomil olmesartan medoxomil (Olmetec). They are known to have a long-term protective effect as well as a hypotensive effect. ARB hypertension is closely related to various diseases such as angiotensin (Angiontenis Ⅱ) in our body (mainly in the heart, kidney or blood vessels).

The resulting angiotensin shrinks the blood vessels upon exposure to the AT1 (Angiontensin Ⅰ) receptor, causing hypertension, and causing oxidative stress or inflammation, leading to various cardiovascular diseases. On the other hand, when angiotensin attaches to the AT2 receptor, it works on our body such as expanding blood vessels, reducing inflammation, or regenerating tissues.

ARB agents selectively act on these to block the AT1 receptor and not the AT2 receptor. This means that the side effects are less than the CCB blockers and ACE inhibitors, which are high blood pressure drugs. The present invention relates to a method for rapidly producing telmisartan represented by the following formula (4), which is one of ARB series therapeutic agents, in high purity.

Conventionally, in the synthesis of telmisartan represented by the following general formula (4), compounds represented by the following general formulas (1) and (2) are stirred at room temperature for 12 hours or more in the presence of a base to obtain a compound represented by the following general formula But also a method of separating a compound represented by the following formula (1) has also been disadvantageous in that it takes a lot of time and labor industrially using extraction.

Further, the reaction conditions for obtaining a compound (telmisartan) represented by the following general formula (4) as a hydrolysis condition from a compound represented by the following general formula (3) take a long reaction time and the filtration after the completion of the reaction is poor, And there is a disadvantage in that a considerable time is required for the operation.

In the meantime, the method of preparing telmisartan by the above reaction process is disclosed in U.S. Patent No. 7,501,448, European Patent Publication No. 1,748,990, European Patent Publication No. 1,805,146, and International Patent Publication No. WO 2009/006860.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have sought to develop a method for greatly improving production efficiency, such as shortening of reaction time, in the production of telmisartan, which is used as an ARB (angiotensin II receptor blocker) hypertensive agent. As a result, the hydrolysis reaction was carried out by obtaining an intermediate in a solvent environment containing an ionic liquid and controlling the ratio of water containing a hydroxyl group. As a result, the reaction time was remarkably shortened as compared with the conventional method and high purity and high yield Of telmisartan can be obtained, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a method for producing telmisartan.

Another object of the present invention is to provide telmisartan prepared by the above-described method of the present invention.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a process for preparing telmisartan represented by the following formula (4), comprising the steps of: (a) reacting a compound represented by the following formula Is condensed in an organic solvent, an ionic liquid and a basic aqueous solution to obtain a compound represented by the following formula (3); (b) hydrolyzing the compound of Formula 3 in an organic solvent and a basic aqueous solution; And (c) adding an acidic aqueous solution to the result of step (b) to obtain telmisartan.

Formula 1

(2)

(3)

Formula 4

The present inventors have sought to develop a method for greatly improving production efficiency, such as shortening of reaction time, in the production of telmisartan, which is used as an ARB (angiotensin II receptor blocker) hypertensive agent. As a result, the hydrolysis reaction was carried out by obtaining an intermediate in a solvent environment containing an ionic liquid and controlling the ratio of water containing a hydroxyl group. As a result, the reaction time was remarkably shortened as compared with the conventional method and high purity and high yield Of telmisartan can be obtained.

Hereinafter, the method of the present invention for producing telmisartan will be described step by step as follows:

(a) condensation reaction and obtaining the compound represented by Formula 3

First, the process of the present invention is a step of condensing a compound represented by Formula 1 and a compound represented by Formula 2 in an organic solvent, an ionic liquid and a basic aqueous solution to obtain a compound represented by Formula 3 below.

Compound of the formula (1) used in the method of the present invention is 4-methyl-6- (1-methyl -1 H - benzimidazol-2-yl) -2-propyl -1 H - benzimidazole jolyigo, The compound represented by Formula 2 is methyl 2- [4- (bromomethyl) phenyl] benzoate.

According to one embodiment of the present invention, the compound represented by the formula (2) in the step (a) is contained in an amount of 0.9 to 1.3 equivalents relative to 1 equivalent of the compound represented by the formula (1), more preferably 1.0 to 1.2 equivalents .

According to another embodiment, in the present invention, the compound represented by the formula (1) and the compound represented by the formula (2) are used in the condensation reaction at a weight ratio of 1: 0.9-1.3, more preferably a weight ratio of 1: 1.0-1.2 .

The organic solvent used in the step (a) of the present invention may be any of various organic solvents known in the art and is preferably selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene , Acetone, methyl acetate, methylene chloride, chloroform, ether, petroleum ether, benzene, ethylene glycol, propylene glycol and butylene glycol, more preferably ethanol, cyclohexane, toluene or acetone, It is acetone.

According to another embodiment of the present invention, the ionic liquid of the step (a) is contained in an amount of 1-20% by weight, more preferably 1-15% by weight, based on the weight of the compound represented by the formula By weight, and even more preferably 2-10% by weight.

One of the greatest features of the present invention is that a condensation reaction time of 12 hours or more is conventionally required by incorporating an ionic liquid in a solvent environment causing a condensation reaction between the compound represented by Formula 1 and the compound represented by Formula 2 1-2 hours.

According to another embodiment of the present invention, the cation constituting the ionic liquid of step (a) is at least one selected from the group consisting of ammonium cations, imidazolium cations, oxazolium cations, piperidinium cations, pyrazinium cations, pyrazolium cations, A pyridinium cation, a pyridinium cation, a pyrimidinium cation, a pyrrolidinium cation, a pyrrolinium cation, a pyrrolinium cation, a sulfonium cation, and a triazolium cation, more preferably an ammonium cation, A sulfonium cation, or a triazolium cation, and even more preferably an ammonium cation or imidazolium.

According to another embodiment of the present invention, the anion constituting the ionic liquid of step (a) is selected from the group consisting of an ethylsulfate anion, a tetrafluoroborate anion, a tosylate anion, a methanesulfon anion and a methylenesulfone anion More preferably a tetrafluoroborate anion, a tosylate anion, a methanesulfonate anion or a methylenesulfone anion, and still more preferably a tetrafluoroborate anion or a methylenesulfone anion.

According to another embodiment of the present invention, the ionic liquid of step (a) is selected from the group consisting of 1-ethyl-3-methylimidazolium ethylsulfate, 1-ethyl-3-methylimidazolium tetrafluoroborate, 1- Ethyl-3-methylimidazolium tosylate, 1-ethyl-3-methylimidazolium methanesulfonate, 1-ethyl-3-methylimidazolium free plate, Butyl-3-methylimidazolium dicarboxylate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium bis (trifluormethylsulfonyl) Butyl-3-methylimidazolium triflate, 1-butyl-3-methylimidazolium methanesulfonate, 1-butyl-3-methylimidazolium trifluoromethylene sulfonate, 1,3 -Didecyl-2-methylimidazolium bis (trifluormethylsulfonyl) imide, amyltriethylammonium bis (trifluo Butyl-2,3-dimethylimidazolium triflate, 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1- (2-hydroxyethyl) -3 -Methylimidazolium tetrafluoroborate, 1-decyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylpyridinium tetrafluoroborate, 1 -butyl-4-methylpyridinium tetrafluoro (Trifluoromethylsulfonyl) imide, methyltrioctylammonium bis (trifluoromethylsulfanyl) imide, 1-methyl-3-ethylimidazolium tetrafluoroborate, (Trifluoromethylsulfonyl) imide, triethylsulfonium bis (trifluoromethylsulfonyl) imide and diethylmethylsulfonium bis (trifluoromethylsulfonyl) imide, butyltrimethylammonium bis ≪ / RTI > is selected from the group consisting of < RTI ID = 0.0 > Butyl-3-methylimidazolium methanesulfonate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium bis (triflouromethylsulfonyl) imide Butyl-3-methylimidazolium methanesulfonate, 1-butyl-3-methylimidazolium trifluoromethylene sulfonate, 1,3-didecyl-2-methylimidazolium bis Amyltrimethylammonium bis (trifluormethylenesulfonyl) imide, 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1-allyl-3-ethylimidazolium Methyltrioctylammonium bis (trifluoromethylsulfonyl) imide or butyltrimethylammonium bis (trifluoromethylsulfonyl) imide, and most preferably 1-butyl-3-methylimide 1-butyl-3-methylimidazolium triflur Amyltriethylammonium bis (trifluormethylenesulfonyl) imide, or 1-allyl-3-ethylimidazolium tetrafluoroborate.

According to another embodiment of the present invention, the basic aqueous solution of step (a) has a concentration of 30-70%, more preferably a concentration of 40-60%.

In the present invention, the base of the basic aqueous solution used for deriving the condensation reaction in step (a) is preferably at least one selected from the group consisting of NaOH, KOH, Ba (OH) 2, Ca (OH) 2, NH4OH, , More preferably NaOH or KOH, still more preferably KOH, still more preferably 1.0-1.5 equivalents of KOH with respect to one equivalent of the compound represented by the general formula (1).

The condensation reaction of the step (a), which is carried out in a solvent environment containing the ionic liquid, is conducted for 1 to 2 hours, more preferably at room temperature (23 to 25 ° C) for 1 to 2 hours.

In this way, methyl 2- (4 - {[4-methyl-6- (1-methyl-1H-benzimidazol- -Propyl-1H-benzimidazol-1-yl] methyl} phenyl) benzoate, and the compound of Formula 3 was obtained in a purity of 99.2-99.7% and a yield of 78-90%.

The method of the present invention comprises the steps of charging and stirring purified water to obtain a compound of the above formula (3) in high purity and high yield; And washing with an organic solvent (preferably, acetone) and purified water under reduced pressure filtration.

(b) hydrolysis of the compound represented by the general formula (3 )

Next, the method of the present invention includes a step of hydrolyzing the compound represented by Formula 3 in an organic solvent and a basic aqueous solution.

According to another embodiment of the present invention, the organic solvent of step (b) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, methylene chloride, chloroform, ether , Petroleum ether, benzene, ethylene glycol, propylene glycol and butylene glycol, more preferably methanol, ethanol, cyclohexane, toluene, chloroform or ether, and most preferably methanol.

According to another embodiment of the present invention, the basic aqueous solution of step (b) has a concentration of 30-70%, more preferably 40-60%.

In the present invention, the basic aqueous base solution of step (b) used for inducing the hydrolysis reaction may be prepared by adding NaOH, KOH, Ba (OH) 2, Ca (OH) 2, NH4OH, And more preferably NaOH or KOH.

According to another embodiment of the present invention, the basic aqueous solution of step (b) comprises 10-30% (v / v) based on the volume of the organic solvent of step (b).

When the content of the basic aqueous solution is less than 10% (v / v) based on the volume of the organic solvent, the reaction time becomes long. When the content of the basic aqueous solution exceeds 30% (v / v) .

According to another embodiment of the present invention, the hydrolysis reaction of step (b) is carried out at a room temperature (23-25 ° C) to a temperature of 50-60 ° C for 1-3 hours.

According to another embodiment of the present invention, after step (b), cooling to room temperature (23-25 ° C); And washing with an organic solvent (preferably methanol) under reduced pressure filtration.

(c) Addition of an acidic aqueous solution and obtaining telmisartan

Finally, the process of the present invention involves the step of adding an acidic aqueous solution (acetic acid) to the result of step (b) to obtain telmisartan.

As the acid of the acidic aqueous solution used in the present invention, various acids known in the art can be used, and preferably acetic acid, hydrochloric acid, sulfuric acid or nitric acid can be used.

According to another embodiment of the present invention, the pH is adjusted to 5-5.5 by the addition of the acidic aqueous solution of step (c).

In this way telmisartan can be produced which is used as an ARB (angiotensin II receptor blocker) hypertensive agent, and telmisartan is obtained with a purity of 99.92-99.99% and a yield of 85-95%.

The method of the present invention includes the steps of charging and stirring an organic solvent (preferably, methanol) to obtain telmisartan of high purity and high yield; Washing with an organic solvent (preferably, methanol) and purified water under reduced pressure filtration; And vacuum drying at a temperature of 50-70 < 0 > C for 12-24 hours.

According to another aspect of the present invention, the present invention provides telmisartan prepared by the above-described method of the present invention.

Since the telmisartan of the present invention is produced by the method of the present invention described above, the description common to both is omitted in order to avoid excessive complexity of the specification according to the repetitive description.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides a method for producing telmisartan used as an ARB (angiotensin II receptor blocker) system hypertensive agent and telmisartan prepared by the above method.

(b) The method of the present invention is carried out in a solvent containing an ionic liquid to obtain an intermediate during the production of telmisartan, and the reaction time is greatly shortened to 1-2 hours as compared with the conventional method.

(c) The process of the present invention provides a hydrolysis reaction of intermediates for the preparation of telmisartan by controlling the proportion of water containing hydroxyl groups, which greatly improves filtration, process speed and process convenience, High yield of telmisartan was obtained.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Methylimidazol-2-yl) -2-propyl-1H-benzimidazol-1 -yl] methyl} Phenyl) benzoate (Formula 3)

50 g of 4-methyl-6- (1-methyl- 1H -benzimidazol-2-yl) -2-propyl-1 H- benzimidazole (Formula 1), 300 ml of acetone, Butyl-3-methylimidazolium tetrafluoroborate (DPB, 5% by weight based on the ionic liquid raw material) was mixed and stirred for 10 minutes. Thereafter, a 50% aqueous solution of potassium hydroxide (13.8 g of potassium hydroxide 1.3 equivalents + 13.8 ml of purified water) was added dropwise over about 20 minutes, followed by stirring for 30 minutes. Then, 55 g of methyl 2- [4- (bromomethyl) phenyl] benzoate (Formula 2, 1.1 eq.) Was added thereto, and the reaction was terminated by stirring at 24 ° C for 1 hour. Then, 150 ml of purified water was added thereto, followed by stirring for 1 hour. Then, it was filtered with reduced pressure and washed with 25 ml of acetone and 25 ml of purified water. The filtered solid was vacuum-dried at 40 ° C for 12 hours to obtain methyl 2- (4 - {[4-methyl-6- (1-methyl-1H-benzimidazol- Yl) methyl} phenyl) benzoate (Formula 3) 77 g (yield: 89%, purity: 99.58%) of a pale yellow solid was obtained.

_{^{1 H (CDCl 3) 1.00 (}} t, 3H J = 7.4Hz), 1.839 ~ 1.913 (m, 2H), 2.79 (s, 3H), 2.93 (t, 2H, J = 8Hz), 3.58 (s, 3H) 2H, J = 7.6 Hz), 3.82 (s, 3H), 5.46 (s, 2H), 7.1 (d, 2H, J = 5.2 Hz), 7.24-7.54

Examples 2 to 4: Preparation of methyl 2- (4 - {[4-methyl-6- (1-methyl-1H-benzimidazol- 1-yl] methyl} phenyl) benzoate (Formula 3)

The reaction was carried out in the same manner as in Example 1, except that methyl 2- (4 - {[4-methyl-6- (1-methyl-1 H-benzimidazol- ) -2-propyl-1H-benzimidazol-1-yl] methyl} phenyl) benzoate (ETLS (P-1)).

Specifically, 2.5 g of 1-butyl-3-methylimidazolium trifluoromethylene sulphonate (DPB 5% as a raw material) was used as the ionic liquid, and the reaction was conducted for 1 hour and 30 minutes to obtain light yellow ETLS 70 g (yield: 80%, purity: 99.45%) was obtained and used as Example 2, and amyltriethylammonium bis (trifluoromethylenesulfonyl) imide (Yield: 78.3%, purity: 99.64%) was obtained and used as Example 3, and the reaction was carried out for 1 hour to obtain 68 g of light yellow ETLS (P-1) 2.5 g of 1-allyl-3-ethylimidazolium tetrafluoroborate (DPB 5% as a raw material) was used as the liquid and the reaction was conducted for 1 hour and 30 minutes to obtain 73 g of light yellow ETLS (P-1) 84%, purity: 99.2%) was obtained and used as Example 4.

Example 5: Preparation of telmisartan (Formula 4)

Scheme 1

Methyl-1H- benzimidazol-2-yl) -2-propyl-1H-benzimidazol-1 -yl] methyl} phenyl ) Benzoate (Formula 3) and 500 ml of methanol were mixed, followed by stirring for 10 minutes. 85 ml of a 50% sodium hydroxide aqueous solution or a 50% aqueous solution of potassium hydroxide (17% relative to the solvent: sodium hydroxide or potassium hydroxide, 42.5 g, purified water 85 ml) was added dropwise over 10 minutes and the mixture was heated to 56 ° C and stirred for 1 hour Gt; 25 C < / RTI > after termination. The reaction solution was filtered through a vacuum filter packed with 15 g of celite (15% of the raw material) and washed with 200 ml of methanol. Then, 150 ml of acetic acid was used to adjust the pH to 5-5.5 to precipitate crystals. 100 ml of methanol was then added thereto and stirred for 30 minutes. It was then washed with 100 ml of methanol while filtering under reduced pressure, and then washed with 400 ml of purified water. And dried in vacuo at 60 캜 for 16 hours to obtain 92 g of a white telmisartan (Formula 4) crystalline solid (yield: 95%, purity: 99.94%).

_{^{1 H NMR (CDCl 3) 1.00}} (t, 3H, J = 7.2Hz), 2.00 ~ 2.058 (m, 2H), 2.73 (s, 3H), 3.17 (t, 2H, J = 8Hz), 3.782 (s, 2H, J = 7.6 Hz), 7.44-7.52 (m, 7H), 8.04 (d, IH) , J = 7.2 Hz), 8.41 (d, 1H, J = 7.6 Hz)

Examples 6 to 15: Preparation of telmisartan (Formula 4) according to the use range of 50% sodium hydroxide or potassium hydroxide aqueous solution

Telmisartan (Formula 4) was prepared in the same manner as in Example 5 except that 50% sodium hydroxide aqueous solution or 50% aqueous potassium hydroxide solution was used at different contents and reaction times, and the results are summarized in Table 1 below :

- 50% sodium hydroxide
Content relative to aqueous solvent
(%) 50% potassium hydroxide
Content relative to aqueous solvent
(%) Reaction time
(hr) Telmisartan manufacture
(Formula 4) Example 6 10 - 3 Yield: 92.5%
Purity: 99.921% Example 7 - 10 3 Yield: 90.4%
Purity: 99.96% Example 8 12 - 2 Yield: 93.2%
Purity: 99.93% Example 9 - 12 2 Yield: 91.2%
Purity: 99.9% Example 10 15 - 2 Yield: 93.5%
Purity: 99.95% Example 11 - 15 2 Yield: 92%
Purity: 99.88% Example 12 20 - One Yield: 90.1%
Purity: 99.97% Example 13 - 20 One Yield: 88%
Purity: 99.96% Example 14 30 - One Yield: 88.4%,
Purity: 99.99% Example 15 - 30 One Yield: 85%
Purity: 99.99%

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

A method for producing telmisartan represented by the following formula (4), comprising the steps of:
(a) condensing a compound represented by the following formula (1) and a compound represented by the following formula (2) in an organic solvent, an ionic liquid and a basic aqueous solution to obtain a compound represented by the following formula (3);
(b) hydrolyzing the compound of Formula 3 in an organic solvent and a basic aqueous solution; And
(c) adding an acidic aqueous solution to the result of step (b) to obtain telmisartan.
Formula 1

(2)

(3)

Formula 4

The method according to claim 1, wherein the compound represented by formula (2) in step (a) is contained in an amount of 0.9 to 1.3 equivalents based on 1 equivalent of the compound represented by formula (1).
The method according to claim 1, wherein the organic solvent in steps (a) and (b) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, methylene chloride, Wherein the solvent is an organic solvent selected from the group consisting of ether, petroleum ether, benzene, ethylene glycol, propylene glycol and butylene glycol.
The method according to claim 1, wherein the ionic liquid of step (a) is contained in an amount of 1-20% by weight based on the weight of the compound represented by the formula (1).
The method of claim 1, wherein the cation constituting the ionic liquid of step (a) is selected from the group consisting of ammonium cations, imidazolium cations, oxazolium cations, piperidinium cations, pyrazinium cations, pyrazolium cations, pyridazinium A cation selected from the group consisting of a cation, a pyridinium cation, a pyrimidinium cation, a pyrrolidinium cation, a pyrrolinium cation, a pyrrolinium cation, a sulfonium cation, and a triazolium cation, Is an anion selected from the group consisting of an ethylsulfate anion, a tetrafluoroborate anion, a tosylate anion, a methanesulfon anion, and a methylenesulfone anion.
3. The method of claim 1, wherein the ionic liquid of step (a) is selected from the group consisting of 1-ethyl-3-methylimidazolium ethyl sulfate, 1-ethyl-3-methylimidazolium tetrafluoroborate, Methylimidazolium tosylate, 1-ethyl-3-methylimidazolium methanesulfonate, 1-ethyl-3-methylimidazolium free plate, 1- 1-butyl-3-methylimidazolium bis (trifluormethylsulfonyl) imide, 1-butyl-3-methylimidazolium dicyanamide, 1-butyl-3-methylimidazolium tetrafluoroborate, Butyl-3-methylimidazolium triflate, 1-butyl-3-methylimidazolium methanesulfonate, 1-butyl-3-methylimidazolium trifluoromethylene sulfonate, 2-methylimidazolium bis (trifluormethylsulfonyl) imide, amyltriethylammonium bis (trifluormethylenesulfonyl) imide Butyl-2,3-dimethylimidazolium triflate, 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1- (2-hydroxyethyl) -3-methylimidazolium tetra 3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylpyridinium tetrafluoroborate, 1-butyl-4-methylpyridinium tetrafluoroborate, 1-allyl (Trifluoromethylsulfonyl) imide, methyltrioctylammonium bis (trifluoromethylsulfonyl) imide, butyl 3-ethylimidazolium tetrafluoroborate, 1-methyl-1propylpiperidinium bis (Trimethylammonium) bis (trifluoromethylsulfonyl) imide, triethylsulfonium bis (trifluoromethylsulfonyl) imide and diethylmethylsulfonium bis (trifluoromethylsulfonyl) imide. ≪ / RTI >
The method according to claim 1, wherein the basic aqueous solution of steps (a) and (b) has a concentration of 30-70%.
The method of claim 1, wherein the base of the basic aqueous solution, wherein step (a) and (b) is composed of NaOH, KOH, Ba (OH) 2, Ca (OH) 2, NH 4 OH, amine and Al (OH) ₃ ≪ / RTI >
The method according to claim 1, wherein the condensation reaction of step (a) is carried out for 1 to 2 hours.
The method according to claim 1, wherein the basic aqueous solution of step (b) comprises 10-30% (v / v) based on the volume of the organic solvent of step (b).
2. The method according to claim 1, wherein the hydrolysis reaction of step (b) is carried out at a temperature of 50-60 DEG C for 1-3 hours.
The method of claim 1, wherein the acid of the acidic aqueous solution of step (c) is acetic acid, hydrochloric acid, sulfuric acid or nitric acid.
The method of claim 1, wherein the pH is adjusted to 5-5.5 by the addition of the acidic aqueous solution of step (c).