KR101251561B1 - Novel intermediates useful for the preparation of aripiprazole, the preparation method thereof and the preparation method of aripiprazole using the same - Google Patents

Abstract

PURPOSE: A novel intermediate for preparing high purity aripiprazole and a method for preparing the same are provided to obtain a large amount of high purity aripiprazole. CONSTITUTION: A method for preparing a carbostyril derivative of chemical formula 6 comprises: a step of reacting 7-hydroxy-3,4-dihydrocarbostyril of chemical formula 2 and 4-halobutane acetate of chemical formula 3 under the presence of a base and a solvent to prepare 7-(4-acetoxybutoxy)-3,4-dihydrocarbostyril of chemical formula 4; a step of reacting 7-(4-acetoxybutoxy)-3,4-dihydrocarbostyril of chemical formula 4 with a base under the presence of a solvent to prepare 7-(4-hydroxybutoxy)-3,4-dihydrocarbostyril of chemical formula 5; and a step of preparing the carbostyril derivative from 7-(4-hydroxybutoxy)-3,4-dihydrocarbostyril of chemical formula 5.

Description

Novel intermediates useful for the preparation of aripiprazole, the preparation method approximately and the preparation method of aripiprazole using the same}

The present invention relates to novel intermediates useful for the production of Aripiprazole, a method for preparing the same, and a method for preparing Aripiprazole using the same.

[Formula 1]:

[Formula 1]

7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy} -3,4-dihydrocarbostyryl, represented by, is named aripiprazole.

Aripiprazole is a known drug known to be useful for treating schizophrenia as a therapeutic agent for atypical psychosis, and schizophrenia is a common type of psychosis characterized by delusions, hallucinations and excessive atrophy from others (J. Med. Chem). , Vol. 41, pp. 658-667 (1998)).

Aripiprazole in U.S. Patent Application Publication No. 2006 / 0,258,869 has strong affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors, dopamine D4, serotonin 5-HT2c and 5-HT7, α1-adrenergic agonists and histamine A psychotropic drug that exhibits mild affinity for the H1 receptor and mild affinity for the serotonin reuptake site, the mechanism of action of aripiprazole, like other drugs that are effective for schizophrenia, is not known, but the efficacy of aripiprazole is known to affect D2 and 5- It has been stated that it has been proposed to be mediated through a combination of partial agonist activity at the HT1A receptor and antagonist activity at the 5-HT2A receptor.

As a method for synthesizing aripiprazole, a total of five synthetic routes were proposed as shown in Scheme 1 in US Pat. No. 5,006,528.

[Reaction Scheme 1]

The above methods can synthesize aripiprazole with 7-hydroxy-2- (1H) -quinoline as the main skeleton, but the yield is low and byproducts such as dimers (US Patent Publication No. 2006 / 0,258,869) and isomers are formed. The disadvantage is that it is difficult to remove. In addition, US Patent No. 7,872,132 proposed a synthesis method using an indanone derivative, such as Scheme 2.

[Reaction Scheme 2]

The method presented above is a method proposed to minimize the isomer form generated when synthesizing 7-hydroxy-2,3-dihydrocarbostyryl. However, there is a risk of explosion in the reaction using sodium azide to produce indanone with quinoline, which is a risk in mass production.

In addition, considering that international standards such as the ICH guideline recommend the impurity content to be 0.1% or less, when the criteria are not met, the industrial value is low as a pharmaceutical manufacturing technique.

Accordingly, there is a need to overcome the above disadvantages and to provide an improved method for preparing aripiprazole having a purity of 99.9% or more.

United States Patent Application Publication No. 2006 / 0,258,869 U.S. Patent No. 5,006,528 United States Patent No. 7,872,132

It is an object of the present invention to provide novel intermediates useful for the preparation of aripiprazole and methods for their preparation.

Another object of the present invention is to provide a method for producing aripiprazole of high purity using the novel intermediate in high yield.

Another object of the present invention is to provide a method for producing aripiprazole in a high yield suitable for mass production because the reaction conditions are gentle and the reaction time is not long.

The present invention provides 7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of formula 4 and 7- (4-hydroxybutoxy)-of formula 5, which are novel intermediates useful for preparing aripiprazole. 3,4-dihydrocarbostyryl is provided.

[Formula 4]

[Chemical Formula 5]

When the aripiprazole is prepared using the new intermediate, it is possible to prepare aripiprazole having a high purity of 99.9% or more due to the low content of impurities, and the reaction conditions are gentle and the reaction time does not take long, so it is suitable for mass production.

7- (4- Acetoxybutoxy ) -3,4- Of dihydrocarbostyryl  Produce

7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of Chemical Formula 4 is represented by the following Scheme 3 with 7-hydroxy-3,4-dihydrocarbostyryl and Chemical Formula 3 4-halobutane acetate may be prepared by reaction in the presence of a base and a solvent.

Scheme 3

7-hydroxy-3,4-dihydrocarbostyryl of Chemical Formula 2 is a known compound, the synthesis method of which is described in detail in US 2006 / 0,079,690. In addition, 4-halobutane acetate of Formula 3 is also a known compound, the synthesis method of which is described in detail in US Patent No. 2,513,504.

4-halobutane acetate of Formula 3 is about 1.0 to 2.0 molar equivalents, preferably about 1.0 to 1.5 molar equivalents based on 1.0 mole equivalent of 7-hydroxy-3,4-dihydrocarbostyryl of Formula 2 Can be used.

The base used in the reaction of Scheme 3 may be selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate or triethylamine, preferably sodium hydroxide.

The solvent used in the reaction of Scheme 3 is at least one selected from the group consisting of purified water, hexane, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, dimethylformamide, or dimethyl sulfoxide. It may be chosen, it is preferable to use dimethyl sulfoxide.

In addition, the reaction of Scheme 3 may be performed for 1 to 10 hours at a temperature of 0 ℃ to 100 ℃, preferably at 5 ℃ to 15 ℃.

7- (4- Hydroxybutoxy ) -3,4- Of dihydrocarbostyryl  Produce

7- (4-hydroxybutoxy) -3,4-dihydrocarbostyryl of Chemical Formula 5 is substituted with 7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of Chemical Formula 4 It can be prepared by reaction with a base in a solvent.

[Reaction Scheme 4]

As a base usable in the reaction of Scheme 4, a general alkali base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate or potassium hydrogen carbonate may be used, and preferably potassium carbonate may be used.

The base may be used in an amount of about 1.0 to 5.0 molar equivalents, preferably about 1.0 to 1.5 molar equivalents, relative to 1.0 molar equivalent of 7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of formula (4). have.

The solvent used in the reaction of Scheme 4 may use purified water and an alcohol mixed solvent, preferably purified water and methanol.

In addition, the reaction of Scheme 4 may be performed for 1 to 10 hours at a temperature of 0 ℃ to 100 ℃, preferably may be carried out at 50 ℃ to 80 ℃.

Carbostyryl  Preparation of Derivatives

The present invention provides a method for preparing a carbostyryl derivative of formula (6) from 7- (4-hydroxybutoxy) -3,4-hydrocarbostyryl of formula (5) prepared using the above method.

Scheme 5

The carbostyryl derivative of Formula 6 converts the hydroxyl group of 7- (4-hydroxybutoxy) -3,4-hydrocarbostyryl to a good leaving group (X) by a method commonly used in the art. can do.

Aripiprazole  Produce

The present invention provides a preparation of aripiprazole by reacting a carbostyryl derivative of formula (6) prepared by the above method with 1- (2,3-dichlorophenyl) piperazine of formula (7). Provide a method.

[Reaction Scheme 6]

In the reaction of Scheme 6, the carbostyryl derivative of Formula 6 and 1- (2,3-dichlorophenyl) piperazine of Formula 7 are compounds known from US Patent No. 5,006,528, which are reacted by a known method. Aripiprazole of Formula 1 may be prepared.

Aripiprazole production method of the present invention can be produced in a high yield of aripiprazole of 99.9% or more high purity using a novel intermediate, it is a method of high industrial value because the reaction conditions are moderate and the reaction time is not suitable for mass production.

When preparing aripiprazole using the novel intermediate of the present invention, it is possible to prepare aripiprazole of high purity by avoiding the formation of impurities, and is suitable for mass production.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are only for illustrating the present invention, and the present invention is not limited thereto.

[ Used equipment  And measurement conditions]

^-1 H NMR: 400 MHz FT-NMR Spectrometer (Varian Unityinova 400)

-Melting Point: Melting Point Measuring Device (B-540, BUCHI)

MS: Varian MS System with 3800 GC

HPLC: Varian Prostar

[ Example  One] 7- (4- Acetoxybutoxy ) -3,4- Of dihydrocarbostyryl  Produce

17.7 g of caustic soda is added and 300 ml of dimethyl sulfoxide is injected. At room temperature, 60.0 g (0.36 mol) of 7-hydroxy-3,4-dihydrocarbostyryl was added thereto, and the temperature was raised to 30 ° C., followed by reaction for 3 hours. Cool the reaction solution to 10 ° C. and slowly add 86.07 g (0.44 mol) of 4-bromobutyl acetate. After stirring for 7 hours, 600 ml of purified water was injected and stirred at 10 ° C for 1 hour. Crystals precipitated in the reaction solution were filtered through a Buchner funnel (Coors) and the residue was washed with 300 ml of purified water. The crystals were dried at 70 ° C. to give 92 g of a white 7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl (yield 90.2%).

MS (m / z); Theoretical 277.32 / found 277

¹ H-NMR (δ, CDCl ₃ ): 9.4 (NH, s), 7.0 (1H, d), 6.5 (1H, d), 6.4 (1H, s), 4.1 (2H, t), 3.9 (2H , t), 2.8 (2H, t), 2.6 (2H, t), 2.0 (3H, s), 1.8 (2H, m), 1.8 (2H, m)

Purity: 98.7%

[ Example  2] 7- (4- Hydroxybutoxy ) -3,4- Of dihydrocarbostyryl  Produce

92 g (0.33 mol) of 7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl obtained in Example 1 were diluted with 460 ml of methanol and 460 ml of purified water, and 59.6 g (0.43 mol) of potassium carbonate ) Was added and the temperature was raised to 70 ° C. and refluxed for 3 hours. The temperature of the reaction solution was cooled to room temperature, 460 ml of purified water was injected, and then cooled to 10 ° C. The resulting crystals were filtered through a Buchner funnel (Coors) and the residue was washed with 300 ml of purified water. The crystals were dried at 70 ° C. to give 72 g (yield 92%) of white 7- (4-hydroxybutoxy) -3,4-dihydrocarbostyryl.

MS (m / z); Theoretical 235.28 / found 235

¹ H-NMR (δ, CDCl ₃ ): 8.4 (NH, s), 7.0 (1H, d), 6.5 (1H, d), 6.3 (1H, s), 3.9 (2H, t), 3.7 (2H , m), 2.9 (2H, t), 2.6 (2H, t), 1.8 (2H, m), 1.7 (2H, m)

Purity: 99.1%

[ Example  3] 7- (4- (4- Toluenesulfonyl ) Butoxy ) -3,4- Of dihydrocarbostyryl Produce

72.0 g (0.30 mol) of 7- (4-hydroxybutoxy) -3,4-dihydrocarbostyryl obtained in Example 2 was diluted in 700 ml of dichloromethane. The solution was cooled to 10 ° C., 87.5 g (0.46 mol) of 4-toluenesulfonyl chloride and 22.5 g of 4-dimethylaminopyridine were added thereto, and 64 ml of triethylamine was added thereto. The solution is cooled to 5 ° C. and stirred for 6 hours. 500 ml of purified water was added to the solution and stirred for 30 minutes. After the solution was allowed to stand for 30 minutes, the resulting layer was separated to collect a dichloromethane layer. 5.0 g of magnesium sulfate was added to the dichloromethane layer, the mixture was stirred for 30 minutes, and then filtered through a Buchner funnel (Coors). The filtrate was distilled under reduced pressure at 40 ° C. to remove all dichloromethane to give 119 g (yield 100%) of 7- (4- (4-toluenesulfonyl) butoxy) -3,4-dihydrocarbostyryl. It was.

MS (m / z); Theoretical 389.47 / found 389

¹ H-NMR (δ, CDCl ₃ ): 9.1 (NH, s), 7.8 (1H, 1H, d), 7.3 (1H, 1H, d), 7.0 (1H, d), 6.4 (1H, d) , 6.3 (1H, s), 4.0 (2H, t), 3.8 (2H, m), 2.8 (2H, t), 2.6 (2H, t), 2.4 (3H, s), 1.8 (2H, m), 1.7 (2H, m)

Purity: 98.2%

[ Example  4] Aripiprazole  Produce

119 g of 7- (4- (4-toluenesulfonyl) butoxy) -3,4-dihydrocarbostyryl obtained in Example 3 was diluted in 600 ml of acetonitrile and 1- (2,3-dichlorophenyl Add 90 g of piperazine and 63.4 g of potassium carbonate. The external temperature was raised to 60 ° C and reacted for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and 1,200 ml of purified water was added thereto. After cooling the temperature to 10 ℃ and stirred for 1 hour, the resulting solid was filtered through a Buchner funnel (Coors) and washed with 300 ml of purified water. The filtered crystals were recrystallized from ethanol and dried at 70 ℃ to give 120.0 g (87.6% yield) of white aripiprazole.

-M.P. : 139 ℃

MS (m / z); Theoretical 448.39 / found 447

¹ H-NMR (δ, CDCl ₃ ): 9.4 (NH, s), 7.1 (1H, 1H, m), 7.0 (1H, d), 6.9 (1H, d), 6.5 (1H, d), 6.4 (1H, s), 3.9 (2H, t), 3.0 (2H, m), 2.8 (2H, t), 2.6 (6H, m), 2.4 (2H, t) 1.8 (2H, m (2H, m)

Purity: 99.9%

[ Example  5] 7- (4- Bromobutoxy ) -3,4- Of dihydrocarbostyryl  Produce

72.0 g of 7- (4-hydroxybutoxy) -3,4-dihydrocarbostyryl obtained in Example 3 was diluted in 700 ml of chloroform. The solution is cooled to 5 ° C., 870.5 g of tribromophosphate and 22.5 g of pyridine are slowly injected and stirred for 2 hours. 500 ml of purified water was added to the solution and stirred for 30 minutes. After the solution was allowed to stand for 30 minutes, the resulting layer was separated to collect a chloroform layer. 5.0 g of magnesium sulfate was added to the chloroform layer, the mixture was stirred for 30 minutes, and then filtered through a Buchner funnel (Coors). The filtrate was distilled under reduced pressure at 40 ° C. to remove all chloroform to give 119 g (yield 95%) of 7- (4-bromobutoxy) -3,4-dihydrocarbostyryl.

MS (m / z); Theoretical 298.18 found 297

¹ H-NMR (δ, CDCl ₃ ): 9.4 (NH, s), 7.0 (1H, d), 6.5 (1H, d), 6.4 (1H, s), 3.9 (2H, t), 3.4 (2H , t), 2.8 (2H, t), 2.6 (2H, t) (2H, m) (2H, m)

Purity: 97.6%

[ Example  6] Aripiprazole  Produce

119 g of 7- (4-bromobutoxy) -3,4-dihydrocarbostyryl obtained in Example 5 was diluted in 600 ml of acetonitrile, 90 g of 1- (2,3-dichlorophenyl) piperazine and carbonic acid Add 63.4 g of potassium. The external temperature was raised to 60 ° C and reacted for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and 1,200 ml of purified water was added thereto. After cooling the temperature to 10 ℃ and stirred for 1 hour, the resulting solid was filtered through a Buchner funnel (Coors) and washed with 300 ml of purified water. The filtered crystals were recrystallized from ethanol and dried at 70 ° C. to obtain 120.0 g of white aripiprazole (yield 92.6%).

-M.P. : 139 ℃

MS (m / z); Theoretical 448.39 / found 447

¹ H-NMR (δ, CDCl ₃ ): 9.4 (NH, s), 7.1 (1H, 1H, m), 7.0 (1H, d), 6.9 (1H, d), 6.5 (1H, d), 6.4 (1H, s), 3.9 (2H, t), 3.0 (2H, m), 2.8 (2H, t), 2.6 (6H, m), 2.4 (2H, t), 1.8 (2H, m), 1.7 ( 2H, m)

Purity: 99.9%

Claims (14)

7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of formula (4):
[Chemical Formula 4]

7-hydroxy-3,4-dihydrocarbostyryl of formula (2) and 4-halobutane acetate of formula (3) in the presence of a base and a solvent to react 7- (4-acetoxybutoxy) of formula (4) Method for preparing -3,4-hydrocarbostyryl.
(2)

(3)

(In Formula 3, X is Br or Cl)
[Chemical Formula 4]

The method of claim 2, wherein the 4-halobutane acetate of Chemical Formula 3 is added in an amount of 1.0 to 2.0 molar equivalents based on 1.0 molar equivalent of 7-hydroxy-3,4-dihydrocarbostyryl of Chemical Formula 2. The process according to claim 2, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate or triethylamine. The method of claim 2, wherein the solvent is at least one selected from the group consisting of purified water, hexane, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, dimethylformamide or dimethyl sulfoxide. Manufacturing method. The method of claim 2, wherein the reaction proceeds at a temperature of 10 ° C. to 30 ° C. 4. 7- (4-hydroxybutoxy) -3,4-dihydrocarbostyryl of formula (5):
[Chemical Formula 5]

7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of formula (4) is reacted with a base in a solvent to make 7- (4-hydroxybutoxy) -3,4- of formula (5) Method for preparing dihydrocarbostyryl.
[Chemical Formula 4]

[Chemical Formula 5]

The method according to claim 8, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. The method of claim 8, wherein the base is added in an amount of 1.0 to 5.0 molar equivalents based on 1.0 molar equivalent of 7- (4-acetoxybutoxy) -3,4-dihydrocarbostyryl of Chemical Formula 4. The method of claim 8, wherein the solvent is a mixed solvent of purified water and alcohol. The method of claim 8, wherein the reaction proceeds at a temperature of 10 ° C. to 70 ° C. 10. (1) preparing 7- (4-acetoxybutoxy) -3,4-hydrocarbostyryl of the following formula (4) by the method of claim 2;
(2) preparing 7- (4-hydroxybutoxy) -3,4-dihydrocarbostyryl of formula 5 by the method of claim 8; And
(3) converting 7- (4-hydroxybutoxy) -3,4-hydrocarbostyryl of formula 5 to a carbostyryl derivative of formula 6;
Method for producing a carbostyryl derivative comprising a.
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(In Formula 6, X is a halogen atom, a C1 to C4 alkanesulfonyloxy group or an arylsulfonyloxy group) (I) preparing a carbostyryl derivative of Formula 6 by the method of claim 13; And
(II) reacting a carbostyryl derivative of Formula 6 with 1- (2,3-dichlorophenyl) piperazine of Formula 7 to prepare aripiprazole of Formula 1;
Method for producing aripiprazole comprising a.
[Formula 1]

[Chemical Formula 6]

(In Formula 6, X is a halogen atom, a C1 to C4 alkanesulfonyloxy group or an arylsulfonyloxy group)
(7)