KR101485418B1 - A synthetic method of high purity mirtazapine - Google Patents

Abstract

The present invention relates to a process for preparing mirtazapine which is useful as an antidepressant and more particularly to a process for the preparation of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- The present invention relates to an improved method for synthesizing high purity mirtazapine by cyclizing a mixed acid of methanesulfonic acid and a toluene solvent. In the present invention, 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol is reacted with polyphosphoric acid and methanesulfonic acid in the presence of concentrated sulfuric acid It is possible to solve the problem of generation of heat upon addition of 10 to 30 times of division and the problem of residual starting material due to stirring of high viscosity and the use of toluene as a reaction solvent can prevent generation of tar during reaction in a high concentration of acid, In addition, ancillary solvents are not used, which is economical. In addition, by making the reaction mixture alkaline in a toluene solvent, the temperature can be easily controlled and precipitation of mirtazapine can be solved as compared with methylene chloride, and the reaction material used in the production method of the present invention can be used for commercial use Which is advantageous for mass production of mirtazapine.

Description

TECHNICAL FIELD [0001] The present invention relates to a method for producing high purity mirtazapine,

The present invention relates to a process for preparing mirtazapine which is useful as an antidepressant and more particularly to a process for the preparation of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- The present invention relates to an improved method for synthesizing high purity mirtazapine by cyclizing a mixed acid of methanesulfonic acid and a toluene solvent.

To mirtazapine (Mirtazapine) represented by formula (1) is an antidepressant drug, sold under the trade name of an antidepressant purposes ^(® Remeron) Les melons ^® received approval from the US Food and Drug Administration.

[Chemical Formula 1]

Mirtazapine can be prepared by the method described in the patent document 10-2009-0121270. The patent discloses a method for producing a mirtazapine by dropwise adding 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol represented by the formula (2) to concentrated sulfuric acid at room temperature .

(2)

However, this method using concentrated sulfuric acid has the following problems.

(1) 2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-methanol is added dropwise to concentrated sulfuric acid for a long period of time at room temperature and heat generation is severe, stirring of the mixture is insufficient, There is a problem in that it is industrially carried out because a bundle phenomenon occurs.

(2) Use of consumable organic solvent and extraction and crystallization are very complicated to use 2-propanol as an extraction solvent and concentrate to remove solvent.

③ It reacts with concentrated sulfuric acid and decolorizes and filtrates in very strong acid condition. Therefore, there is a problem in industrial production because mass production can cause corrosion of production facility.

In order to solve these problems, WO 2006008302 discloses that diluted sulfuric acid is diluted in water to proceed the cyclization reaction, and the reaction is terminated at 80 ° C. As a result of the experiment, the mixture turns dark red upon reaction at 70 ° C. or higher There is a disadvantage in that the myrtazapine is obtained as yellow crystals upon crystallization. In addition, ethyl acetate is used as a recrystallization solvent, but the yield of the ethyl acetate is remarkably low because of the good solubility of the mirtazapine.

As described above, the general method of producing mirtazapine according to the reaction with concentrated sulfuric acid and diluted sulfuric acid is difficult to control the reaction or complicate the extraction and purification process and completely prevent or reduce the problems of the color of the final product .

KR 10-2009-0121270 A WO 2006008302 A

SUMMARY OF THE INVENTION The present invention has been made in order to solve the problems of the prior art as described above, and it is an object of the present invention to provide a method for producing a high purity mirtazapine with high yield.

In order to solve the above-mentioned problems, the present invention provides a process for producing 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol from polyphosphoric acid and methanesulfonic acid And a cyclization reaction is carried out in a mixed acid. The present invention also provides a process for producing mirtazapine.

The mixed acid is prepared by using 400 to 1000 parts by weight of polyphosphoric acid and 30 to 300 parts by weight of methanesulfonic acid per 100 parts by weight of the 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- desirable.

The cyclization reaction is preferably carried out in the presence of an organic solvent.

The organic solvent is preferably at least one selected from the group consisting of toluene, xylene, benzene and chlorobenzene.

The reaction temperature of the cyclization reaction is preferably 60 to 90 < 0 > C.

The reaction time of the cyclization reaction is preferably 3 to 8 hours.

The mixed acid is preferably one or more acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid and p -toluenesulfonic acid.

In the present invention, 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol is reacted with polyphosphoric acid and methanesulfonic acid in the presence of concentrated sulfuric acid It is possible to solve the problem of generation of heat upon addition of 10 to 30 times of division and the problem of residual starting material due to stirring of high viscosity and the use of toluene as a reaction solvent can prevent generation of tar during reaction in a high concentration of acid, In addition, ancillary solvents are not used, which is economical. In addition, by forming the reaction mixture in an alkaline state in a toluene solvent, the temperature can be easily controlled and the precipitation of mirtazapine can be solved as compared with methylene chloride, and the reaction material used in the production method of the present invention can be used for commercial use And the reaction conditions are mild, which is useful for the mass production of the mirtazapine.

Figure 1 shows the reaction scheme in the synthesis of the mirtazapine of the present invention.

Hereinafter, the present invention will be described in detail.

The inventors of the present invention have found that the complexity of the mass production operation and the problems of the color of the final product, which are problematic in the general synthesis of mirtazapine, (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol as a starting material to poly It has been found that the above problems can be solved when a cyclization reaction is performed in a mixed acid of phosphoric acid and methane sulfonic acid, and the present invention has been completed.

Accordingly, the present invention relates to a process for the cyclization of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol in a mixed acid of polyphosphoric acid and methanesulfonic acid Wherein Mirtazapine is produced by a method comprising the steps of:

The mixed acid is used in an amount of 300 to 1,500 parts by weight, preferably 400 to 1,000 parts by weight, based on 100 parts by weight of the 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- 10 to 500 parts by weight, preferably 30 to 300 parts by weight, of methane sulfonic acid can be used.

The cyclization reaction may be carried out in the absence of an organic solvent or in the presence of an organic solvent. The organic solvent is preferably at least one selected from the group consisting of toluene, xylene, benzene and chlorobenzene, and most preferably toluene Do.

The reaction is preferably carried out at a reaction temperature of 35 to 120 ° C, preferably 60 to 120 ° C, more preferably 60 to 90 ° C for 3 to 8 hours in view of inhibition of tar-phase impurity formation .

The mixed acid may further include at least one acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, and p -toluenesulfonic acid.

In a preferred embodiment, the cyclization reaction is carried out by adding 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol to a mixed acid of polyphosphoric acid and methanesulfonic acid, . The reaction is preferably carried out at 60 to 90 占 폚 for 3 to 8 hours. The end of the reaction can be confirmed by TLC. After completion of the reaction, it is preferable to add 10 to 50% aqueous solution of sodium hydroxide dropwise to the reaction mixture to adjust the pH to 1 to 2, followed by decolorization in terms of color improvement and impurity removal. After decolorization and filtration, sodium hydroxide is used to adjust the pH to alkaline pH of 9-11.

Toluene is suitable as an organic solvent for adjusting the pH with an alkali. It can prevent precipitation of mirtazapine by heating at the time of extraction, and the temperature at extraction is suitably 40 to 60 ° C. The amount of toluene to be used is preferably 300 to 1500 parts by weight, more preferably 300 to 700 parts by weight, based on 100 parts by weight of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- More preferable.

The extracted organic solvent layer is concentrated under reduced pressure, and the remaining organic solvent is removed and re-concentrated with heptane to facilitate crystallization. The heptane used herein is preferably used in an amount of 100 to 300 parts by weight based on 100 parts by weight of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol.

Purification is carried out with 2-propanol and heptane in order to prepare the concentrated mirtazapine crystals with high purity. The amount of 2-propanol to be used is preferably 50 to 500 parts by weight based on 100 parts by weight of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol, 100 to 300 parts by weight. The amount of the heptane used for facilitating the crystallization is preferably 100 to 700 parts by weight based on 100 parts by weight of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol, Is used in an amount of 100 to 300 parts by weight.

The anhydrous mirtazapine crystals obtained after filtration can be dried under reduced pressure at 40 to 60 ° C.

The preparation method according to the present invention may include a method for preparing a pharmaceutically acceptable salt of the mirtazapine represented by the above formula (1). The method for preparing the pharmaceutically acceptable salt of the mirtazapine is well known in the art and is a conventional method.

The present invention will now be described in more detail with reference to the following examples, but the present invention is not limited thereto.

[ Example ]

Analysis condition

The analytical conditions used for the synthesis of the mirtazapine of Examples 1 to 4 and Comparative Examples 1 to 4 are as follows.

HPLC analysis conditions; USP Method

Analytical Instruments: Agilent 1260 System

Column: Capcell Pak C ₁₈ (5, 250 mm X 4.6 mm)

Mobile phase: acetonitrile, methanol, tetrahydrofuran, buffer (15: 12.5: 7.5: 65)

Buffer: 18 g of tetramethylammonium hydroxide pentahydrate was dissolved in 950 ml of distilled water, adjusted to pH 7.4 with phosphoric acid, and distilled water was added thereto to prepare 1 liter

Flow rate: 1.5 mL / min

Detector: UV 290 nm

Column temperature: 40 ° C

Example  One

500 g of polyphosphoric acid and 100 g of methanesulfonic acid are charged into the reactor and heated to 50 占 폚. 100 g of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol are put into the reactor and stirred for 5 hours while maintaining the temperature at 75 占 폚. After completion of the reaction is confirmed by TLC, the reaction mixture is cooled to 35 DEG C, 300 g of distilled water is added, and then a 25% aqueous sodium hydroxide solution is added dropwise to adjust the pH to 1-2. Layer separation is carried out, and 10 g of activated carbon is added to the aqueous layer, followed by stirring for 30 minutes. Decolorant is filtered and washed with 10 g of water. 500 g of toluene was added to the aqueous layer and the pH was adjusted to 10.5 to 11 with 25% aqueous sodium hydroxide solution while maintaining the temperature at less than 60 ° C, followed by layer separation. 20 g of anhydrous sodium sulfate is added to the organic layer, which is stirred for 30 minutes and then filtered. The organic layer was concentrated under reduced pressure, 100 g of 2-propanol and 150 g of heptane were added, refluxed, and stirred for 30 minutes. The temperature is gradually lowered to 25 캜, stirred for 30 minutes, and then filtered. Washing was carried out with 100 g of heptane and drying at 60 DEG C for 10 hours to obtain 69.8 g of mirtazapine. The yield was 74.5% and the HPLC purity was 99.84%.

Example  2

Except that 500 g of polyphosphoric acid and 100 g of methanesulfonic acid were used instead of 1 kg of polyphosphoric acid and 50 g of methanesulfonic acid, 73.2 g of mirtazapine was obtained. The yield was 78.2% and the HPLC purity was 99.86%.

Example  3

500 g of polyphosphoric acid, 100 g of methanesulfonic acid, and 300 g of toluene were charged into the reactor and heated to 50 캜. 100 g of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol was charged into the reactor and stirred for 5 hours while maintaining the temperature at 65 占 폚. The completion of the reaction is confirmed by TLC, the reaction mixture is cooled to 35 DEG C, 300 g of distilled water is added, and the pH is adjusted to 1 to 2 by adding dropwise a 25% aqueous solution of sodium hydroxide. Layer separation is carried out, and 10 g of activated carbon is added to the aqueous layer, followed by stirring for 30 minutes. Decolorant is filtered and washed with 10 g of water. 500 g of toluene was added to the aqueous layer and the pH was adjusted to 10.5 to 11 with 25% aqueous sodium hydroxide solution while maintaining the temperature at less than 60 ° C, followed by layer separation. 20 g of anhydrous sodium sulfate is added to the organic layer, which is stirred for 30 minutes and then filtered. The organic layer was concentrated under reduced pressure, 100 g of 2-propanol and 150 g of heptane were added, refluxed, and stirred for 30 minutes. The temperature is gradually lowered to 25 캜, stirred for 30 minutes, and then filtered. Washing was carried out with 100 g of heptane and drying at 60 DEG C for 10 hours to obtain 75.1 g of mirtazapine. The yield was 80.2% and the HPLC purity was 99.98%.

Example  4

Except that 500 g of polyphosphoric acid, 100 g of methanesulfonic acid and 300 g of toluene were used instead of 1 kg of polyphosphoric acid, 50 g of methane sulfonic acid and 500 g of toluene, to obtain 77.2 g of mirtazapine. The yield was 82.4% and the HPLC purity was 99.98%.

Comparative Example  One

Mirtazapine was prepared by the method in Example 3 of Patent Document 10-2009-0121270. Specifically, 28.3 g of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridin-3-methanol was added portionwise over about 4 hours to 102 g of 98% sulfuric acid at about 40 ° C, And the mixture was stirred at the temperature for 12 hours. 204 g of water was added dropwise to the reaction solution, and a pH of 1 to 2 was adjusted by adding dropwise a 25% aqueous solution of sodium hydroxide. 10 g of activated carbon was added, stirred at 30 ° C for 40 minutes, filtered, and washed with 54 g of water. To the filtrate, 37 g of 2-propanol was added, and a 25% aqueous sodium hydroxide solution was added dropwise at 30 ° C to adjust the pH to 11. Then, 57 g of heptane was added and the mixture was heated to 70 ° C to separate the layers. To the organic layer were added 100 g of 2-propanol and 15 g of heptane, 2 g of activated carbon was added, and the mixture was stirred at 30 캜 for 30 minutes. The decolorant was filtered and washed with 14 g of 2-propanol. The filtrate was concentrated under atmospheric pressure to a concentration of 40 g. A small amount of seed crystals of mirtazapine was added at about 53 캜, aged for 2 hours and cooled to 1 캜. The crystals were filtered and the crystals were washed with 14 g of heptane. And dried under reduced pressure at about 60 캜 to obtain 18.0 g of a myrtazapine of pale yellow crystal. The yield was 68.0% and the HPLC purity was 99.72%.

Comparative Example  2

Mirtazapine was prepared by the method described in Example 1 of WO 2006008302. Specifically, the reactor was cooled to about 10 ° C., and 35 g of demineralized water and 70 g of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- 322 g of sulfuric acid is added. After addition, the reaction mixture is maintained at 75-80 < 0 > C for 5 hours. The contents of the reactor are then cooled to room temperature and 40 g of demineralized water is added while maintaining the temperature below 25 < 0 > C. Thereafter, 57 g of toluene and 54 g of 26% aqueous ammonium hydroxide solution were added to adjust the pH to 8.9 to 9.3, followed by extraction of the mirtazapine and re-extraction of the aqueous layer with 13 g of toluene. The layered aqueous layer is re-extracted with 10 g of toluene. The organic layers were collected, treated with anhydrous sodium sulfate, and filtered. The filtrate is decolorized twice with activated carbon and filtered. The toluene was concentrated, crystallized with 140 g of ethyl acetate, and filtered to obtain 45.4 g of mirtazapine as a pale yellow crystal. The yield was 69.3% and the HPLC purity was 99.73%.

Comparative Example  3

500 g of polyphosphoric acid is added to the reactor and heated to 60 占 폚. 100 g of 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol are put into the reactor and stirred for 8 hours while maintaining the temperature at 95 ° C. After completion of the reaction is confirmed by TLC, the reaction mixture is cooled to 35 DEG C, 300 g of distilled water is added, and then a 25% aqueous sodium hydroxide solution is added dropwise to adjust the pH to 1-2. Layer separation is carried out, and 10 g of activated carbon is added to the aqueous layer, followed by stirring for 30 minutes. Decolorant is filtered and washed with 10 g of water. 500 g of toluene was added to the aqueous layer and the pH was adjusted to 10.5 to 11 with 25% aqueous sodium hydroxide solution while maintaining the temperature at less than 60 ° C, followed by layer separation. 20 g of anhydrous sodium sulfate is added to the organic layer, which is stirred for 30 minutes and then filtered. The organic layer was concentrated under reduced pressure, 100 g of 2-propanol and 150 g of heptane were added, refluxed, and stirred for 30 minutes. The temperature is gradually lowered to 25 캜, stirred for 30 minutes, and then filtered. Washing was carried out with 100 g of heptane and drying at 60 DEG C for 10 hours to obtain 64.3 g of mirtazapine. The yield was 68.7% and the HPLC purity was 99.79%.

Comparative Example  4

Synthesis was carried out in the same manner as in Comparative Example 3 except that 1 kg of polyphosphoric acid was used instead of 500 g of polyphosphoric acid to obtain 69.1 g of mirtazapine. The yield was 78.3% and the HPLC purity was 99.81%.

result

The yield, purity and color of the mirtazapine synthesized from Examples 1 to 4 and Comparative Examples 1 to 4 are summarized in Table 1 below.

Example Reaction conditions (based on 100 g starting material) yield water color Example 1 500 g of polyphosphoric acid + 100 g of methanesulfonic acid 74.5% 99.84% White Example 2 Polyphosphoric acid 1000g + methane sulfonic acid 50g 78.2% 99.86% White Example 3 Polyphosphoric acid 500 g + methane sulfonic acid 100 g + toluene 300 g 80.2% 99.98% White Example 4 Polyphosphoric acid 1000 g + methane sulfonic acid 50 g + toluene 500 g 82.4% 99.98% White Comparative Example 1 98% sulfuric acid 360 g 68.0% 99.72% Pale yellow Comparative Example 2 98% sulfuric acid 460 g + desalted water 50 g 69.3% 99.73% Pale yellow Comparative Example 3 Polyphosphoric acid 500 g 68.7% 99.79% Whitish Comparative Example 4 Polyphosphoric acid 1000 g 73.8% 99.81% Whitish

As can be seen from the above Table 1, according to the production method of the present invention, the yield, purity and color of polyphosphoric acid and methanesulfonic acid were the best when using as a mixed acid or in a toluene solvent.

As described above, the manufacturing method according to the present invention uses a high concentration of acid in the conventional production method by using polyphosphoric acid and methanesulfonic acid as a mixed acid and using a reaction solvent as toluene, The problem of agglomeration of the starting material due to agitation of the agglomerates or residues of the agglomerates and generation of tar byproducts occurring at a temperature higher than 60 deg. Further, the production method of the present invention is not only convenient in reaction conditions, but also can be carried out continuously without further purification. Therefore, the production method of the present invention is useful for mass production of high-purity mirtazapine.

Claims (7)

The process according to claim 1, wherein the methyl (2-methyl-2-phenylpiperazin-1-yl) pyridine is subjected to a cyclization reaction in a mixed acid of polyphosphoric acid and methanesulfonic acid. Process for the preparation of mirtazapine.
The method according to claim 1,
The mixed acid is prepared by using 400 to 1000 parts by weight of polyphosphoric acid and 30 to 300 parts by weight of methanesulfonic acid per 100 parts by weight of the 2- (4-methyl-2-phenylpiperazin-1-yl) pyridine- Characterized in that the method comprises the steps of:
The method according to claim 1,
Wherein the cyclization reaction is carried out in the presence of an organic solvent.
The method of claim 3,
Wherein the organic solvent is at least one selected from the group consisting of toluene, xylene, benzene and chlorobenzene.
The method according to claim 1,
Wherein the cyclization reaction is carried out at a reaction temperature of 60 to 90 占 폚.
The method according to claim 1,
Wherein the reaction time of the cyclization reaction is 3 to 8 hours.
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