KR20160112423A - Aripiprazole salt and process for preparing the same - Google Patents
Aripiprazole salt and process for preparing the same Download PDFInfo
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- KR20160112423A KR20160112423A KR1020150038136A KR20150038136A KR20160112423A KR 20160112423 A KR20160112423 A KR 20160112423A KR 1020150038136 A KR1020150038136 A KR 1020150038136A KR 20150038136 A KR20150038136 A KR 20150038136A KR 20160112423 A KR20160112423 A KR 20160112423A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
본 발명은 아리피프라졸 염 및 이의 제조 방법에 관한 것으로, 구체적으로는 아리피프라졸 무기염 및 이를 고순도 및 고수율로 제조하는 방법에 관련된다.The present invention relates to aripiprazole salts and processes for their preparation, and more particularly to aripiprazole inorganic salts and processes for their preparation in high purity and yield.
아리피프라졸(7-4-[4-(2,3-디클로로페닐)-1-피페라지닐]-부톡시-3,4-디히드로 카르보스티릴 또는 7-4-[4-(2,3-디클로로페닐)-1-피페라지닐]-부톡시-3,4-디히드로-2(1H)-퀴놀리논)은 하기 구조식을 갖는 항정신성 약물로, 도파민성 신경전달물질 길항제로서 정신분열증 등의 치료에 유용하다.Aripiprazole (7-4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy-3,4-dihydrocarbostyril or 7-4- [ Dichlorophenyl) -1-piperazinyl] -butoxy-3,4-dihydro-2 (1H) -quinolinone) is a psychotropic drug having the following structural formula and is used as a dopaminergic neurotransmitter antagonist: schizophrenia . ≪ / RTI >
아리피프라졸은 다양한 형태를 취하며 일수화물 형태(아리피프라졸 수화물 A), 수많은 무수물 형태, 즉, 무수물 결정 B, 무수물 결정 C, 무수물 결정 D, 무수물 결정 E, 무수물 결정 F, 및 무수물 결정 G로 존재하는 것으로 알려져 있다. 미국 특허 제5,006,528호 및 일본 특허 공개 제02-191256호에서는 에탄올로부터 아리피프라졸 무수물을 재결정화시키거나, 80 ℃의 온도에서 아리피프라졸 수화물을 가열함으로써 무수물 결정이 제조된다고 개시하고 있다.Aripiprazole takes various forms and is present in the form of a monohydrate (aripiprazole hydrate A), in the form of numerous anhydrides, namely, anhydrous crystal B, anhydrous crystal C, anhydrous crystal D, anhydrous crystal E, anhydrous crystal F, and anhydrous crystal G It is known. U.S. Patent No. 5,006,528 and Japanese Patent Publication No. 02-191256 disclose that anhydride crystals are prepared by recrystallizing aripiprazole anhydride from ethanol or heating aripiprazole hydrate at a temperature of 80 ° C.
US 20080287677 A1은 아리피프라졸의 산부가염 및 이의 제조방법, 그리고 산부가염을 이용하여 아리피프라졸을 유리 염기 또는 약제학적으로 허용되는 염의 형태로 제조 또는 정제하는 방법에 관한 것으로, 산부가염으로서 요오드화수소산, 브롬화수소산, 테트라플루오로붕산, 인산 및 옥살산과 아리피프라졸의 염을 개시하고 있다. US 20080287677 A1 relates to an acid addition salt of aripiprazole, a process for producing the acid addition salt, and a process for preparing or purifying aripiprazole in the form of a free base or a pharmaceutically acceptable salt using an acid addition salt, wherein the acid addition salt is hydroiodic acid, Tetrafluoroboric acid, phosphoric acid, and oxalic acid and salts of aripiprazole.
일본 특허공개 제2003212852호는 아리피프라졸의 저흡습성 형태 및 이의 제조방법에 관한 것으로, 아리피프라졸의 수화물 형태에 대하여 개시하고 있으며, 국제특허공개 WO 2004/106322호에서는 아리피프라졸의 여러 가지 다형 (polymorphism)을 소개하고 있다.Japanese Patent Application Laid-Open No. 2003212852 discloses a low hygroscopic form of aripiprazole and a method for preparing the same, discloses a hydrate form of aripiprazole, and International Patent Publication No. WO 2004/106322 discloses various polymorphisms of aripiprazole have.
또한, 미국특허공개 US 2009111829호에서는 아리피프라졸의 신규 염으로서 이염기 유기산, 캄포설폰산, 인산과의 염 및 이들의 제조방법, 그리고 이들 아리피프라졸의 신규 염을 포함하는 약제학적 조성물을 개시하고 있다. 여기에서 이들 염은 아리피프라졸 염기와 당해 산 성분을 적절한 유기 용매 중에서 아리피프라졸 몰량을 기준으로 0.5 내지 3 의 몰 비율로 반응시키는 것에 의해 제조된다.In addition, U.S. Patent Publication No. 2009111829 discloses a pharmaceutical composition comprising a salt of a dibasic organic acid, a camphorsulfonic acid, a salt thereof with phosphoric acid as a novel salt of aripiprazole, a process for their preparation, and a novel salt of these aripiprazole. Wherein these salts are prepared by reacting the aripiprazole base and the acid component in a suitable organic solvent in a molar ratio of from 0.5 to 3 based on the molar amount of aripiprazole.
그러나, 이들 개시된 대부분의 아리피프라졸 결정형과 염은 물에 대한 용해성이 거의 없거나 매우 낮기 때문에, 주사제로 개발하는 데 문제가 있다. 즉, 아리피프라졸 또는 그 염과 같이 물에 대해서 난용성인 약물을 유효 성분으로서 포함한 현탁액은 시간이 경과함에 따라 유효 성분 입자가 침강하고, 케이킹 형성 등으로 현탁액의 재분산이 어렵게 되므로 주사제로 만들기 어렵게 된다. 이에 따라, 물에 대한 용해도가 좀 더 우수한 아리피프라졸 염을 만들어 주사제 개발에 활용하고자 하는 요구가 커지고 있다.However, most of these disclosed aripiprazole crystalline forms and salts have little or no solubility in water and thus are problematic for development with injectables. That is, the suspension containing the drug resistant to water, such as aripiprazole or a salt thereof, as an active ingredient becomes difficult to be made into an injection because the active ingredient particles precipitate with time and redispersion of the suspension becomes difficult due to formation of a caking or the like . Accordingly, there is a growing demand for the use of aripiprazole salt having superior solubility in water for use in the development of injectable solutions.
본 발명의 목적은 물에 대한 용해도를 증가시켜 주사제 제조가 용이한 아리피프라졸의 무기염 및 이의 제조방법을 제공하고자 하는 것이다.It is an object of the present invention to provide an inorganic salt of aripiprazole which is easy to prepare an injectable solution by increasing solubility in water and a method for producing the same.
상기 목적을 달성하기 위하여, 본 발명에서는 아리피프라졸을 아세톤 또는 테트라하이드로퓨란에 용해시키고, 무기산을 가하여 염을 생성시키고, 생성된 염을 결정화하여 분리하는 단계를 포함하는 아리피프라졸 무기염의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a method for preparing aripiprazole inorganic salt, which comprises dissolving aripiprazole in acetone or tetrahydrofuran, adding a mineral acid to produce a salt, and crystallizing and separating the resulting salt.
여기에서, 무기산은 염산 가스 또는 황산인 것이 바람직하고, 이에 의해 아리피프라졸 염산염 또는 황산염을 제조할 수 있다.Here, the inorganic acid is preferably hydrochloric acid gas or sulfuric acid, whereby aripiprazole hydrochloride or sulfate can be produced.
바람직하게는, 아세톤을 용매로 사용하고 1 당량의 황산을 가하거나, 테트라하이드로퓨란을 용매로 사용하고 2 당량의 황산을 사용하여 아리피프라졸 황산염을 고수율로 제조할 수 있다.Preferably, the aripiprazole sulfate can be prepared in high yield by using acetone as a solvent and adding 1 equivalent of sulfuric acid, or using tetrahydrofuran as a solvent and 2 equivalents of sulfuric acid.
한편, 염을 생성시키는 온도는 -5 내지 80 ℃, 바람직하게는 -5 내지 50 ℃일 수 있으며, 결정화 온도는 -20 내지 30 ℃, 바람직하게는 -20 내지 10 ℃일 수 있다.On the other hand, the temperature for producing the salt may be -5 to 80 ° C, preferably -5 to 50 ° C, and the crystallization temperature may be -20 to 30 ° C, preferably -20 to 10 ° C.
본 발명에서는 또한 위의 방법에 따라 제조된 아리피프라졸의 무기염, 바람직하게는 아리피프라졸 염산염 또는 황산염을 제공한다. The present invention also provides an inorganic salt of aripiprazole, preferably aripiprazole hydrochloride or sulfate, prepared according to the above process.
이하, 본 발명을 더욱 구체적으로 설명한다.Hereinafter, the present invention will be described more specifically.
기존의 특허에서는 이염기 유기산 등으로 아리피프라졸의 여러 가지 유기산염을 만든 예를 개시하고 있으나, 간단한 무기산을 사용하여 효율적으로 제조한 아리피프라졸의 무기산 염은 보고되어 있지 않다. 본 발명에서는 무기산 중에서 염산과 황산을 사용하여 아라피프라졸의 염산염과 황산염을 고순도 및 고수율로 제조하였다.In the existing patents, various organic acid salts of aripiprazole have been disclosed using dibasic organic acids and the like, but inorganic salts of aripiprazole, which is efficiently produced using simple inorganic acids, have not been reported. In the present invention, hydrochloric acid and sulfuric acid salt of arapiprazole were prepared in high purity and high yield using hydrochloric acid and sulfuric acid in inorganic acids.
아리피프라졸은 화학 구조상 물에 대한 용해성이 매우 낮다. 유기산 염에 비해 무기산으로 된 아리피프라졸 염은 상대적으로 극성이 증가하고 물에 대한 용해성도 증가하게 되어 주사제로의 전환이 좀 더 용이하게 된다.Aripiprazole has very low solubility in water of chemical structure. Compared to organic acid salts, aripiprazole salts of inorganic acids are relatively polar and have increased solubility in water, making them easier to switch to injections.
아리피프라졸 염산염의 생성시 유기용매 하에 진한 염산 또는 묽은 염산 용액을 사용하면 고체가 생성되지 않는다. 유기용매와 물의 혼합용매에서는 아리피프라졸의 용해도가 우수하여 용해된 상태로 존재하므로 용액으로부터 분리가 용이하지 않고 고순도의 물질을 기대할 수가 없다. 그러나, 아세톤 또는 테트라하이드로퓨란 등의 유기용매에서 염산가스를 주입할 경우에는 아리피프라졸이 고체로 석출되므로 간단히 석출된 고체를 필터링하여 고순도, 고수율의 아리피프라졸의 염산염을 얻을 수 있다.In the production of aripiprazole hydrochloride, the use of concentrated hydrochloric acid or dilute hydrochloric acid solution in an organic solvent does not produce a solid. In a mixed solvent of an organic solvent and water, aripiprazole is excellent in solubility and exists in a dissolved state, so separation from a solution is not easy and a high purity substance can not be expected. However, when hydrochloric acid gas is injected into an organic solvent such as acetone or tetrahydrofuran, aripiprazole precipitates as a solid, so that a precipitated solid can be filtered to obtain a hydrochloride of aripiprazole of high purity and yield.
아세톤 또는 테트라하이드로퓨란 등의 유기용매 하에 진한 황산을 사용할 경우에는 고체가 쉽게 된다. 아세톤을 용매로 사용시 1 당량의 황산을 사용하는 것이 2 당량의 황산을 사용하는 것보다 수율이 더 높고, 테트라하이드로퓨란을 용매로 사용시에는 1 당량의 황산을 사용하는 것보다 2 당량의 황산을 사용하는 것이 수율이 더 높은 것이 주목된다.When concentrated sulfuric acid is used in an organic solvent such as acetone or tetrahydrofuran, a solid becomes easy. When acetone is used as a solvent, the use of 1 equivalent of sulfuric acid is higher than that of 2 equivalents of sulfuric acid. When tetrahydrofuran is used as a solvent, 2 equivalents of sulfuric acid is used instead of 1 equivalent of sulfuric acid It is noted that the yield is higher.
아리피프라졸의Aripiprazole 염 제조 Salt manufacture
본 발명에 따르면, 비교적 간단한 공정을 통해 아리피프라졸의 무기염을 고순도 및 고수율로 제조할 수 있다.According to the present invention, inorganic salts of aripiprazole can be produced with high purity and high yield through a relatively simple process.
이하, 실시예를 통해 본 발명을 더욱 구체적으로 설명한다. 단, 다음 실시예는 본 발명의 예시일 뿐, 본 발명의 범위가 이들만으로 제한되는 것은 아니다.Hereinafter, the present invention will be described more specifically by way of examples. However, the following examples are only illustrative of the present invention, and the scope of the present invention is not limited thereto.
실시예Example 1: 염산염의 제조 1: Preparation of hydrochloride salt
아리피프라졸 4 g(8.92 mmol)을 400 mL의 아세톤에 녹이고, 실온에서 이 용액에 HCl 가스를 서서히 주입하였다. 2 당량 이상의 HCl 주입 후 용액을 약 50 mL 까지 감압 농축하고 0 내지 5 ℃로 냉각하여 1시간 동안 교반하였다. 생성된 고체를 여과하고 아세톤 20 mL로 세척한 후 고체를 40 ℃에서 3시간 진공 건조하여 아리피프라졸 염산염의 흰색 고체 4.12 g (수율 95.2%)을 얻었다.4 g (8.92 mmol) of aripiprazole was dissolved in 400 mL of acetone, and HCI gas was slowly added to the solution at room temperature. After the addition of at least 2 equivalents of HCl, the solution was concentrated under reduced pressure to about 50 mL, cooled to 0-5 DEG C and stirred for 1 hour. The resulting solid was filtered and washed with 20 mL of acetone, and the solid was vacuum-dried at 40 DEG C for 3 hours to obtain 4.12 g (yield: 95.2%) of a white solid of aripiprazole hydrochloride.
C23H27Cl2N3O2 HClC 23 H 27 Cl 2 N 3 O 2 HCl
1H NMR(DMSO-d6, 400MHz): 11.18(brs, 1H), 10.03(s, 1H), 7.36(m, 2H), 7.20(m,1H), 7.05(d, J=8.0Hz, 1H), 6.50(dd, J1= 2.4Hz, J2= 8.0Hz, 1H), 6.45(d, J=2.4Hz, 1H), 3.93(t, J=6.4Hz, 2H), 3.58(m, 2H), 3.40(m, 6H), 2.78(t, J=7.2Hz, 2H), 2.41(t, J=8.0Hz, 2H), 1.90(m, 2H), 1.76(m, 2H)
1H NMR (DMSO-d 6, 400MHz): 11.18 (brs, 1H), 10.03 (s, 1H), 7.36 (m, 2H), 7.20 (m, 1H), 7.05 (d, J = 8.0Hz, 1H) , 6.50 (dd, J 1 = 2.4Hz, J 2 = 8.0Hz, 1H), 6.45 (d, J = 2.4Hz, 1H), 3.93 (t, J = 6.4Hz, 2H), 3.58 (m, 2H) , 3.40 (m, 6H), 2.78 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 8.0 Hz, 2H)
실시예Example 2: 염산염의 제조 2: Preparation of hydrochloride salt
아리피프라졸 4 g(8.92 mmol)을 100 mL의 테트라하이드로퓨란에 녹이고, 실온에서 이 용액에 HCl 가스를 서서히 주입하였다. 2 당량 이상의 HCl 주입 후 용액을 약 30 mL로 감압 농축하고 0 내지 5 ℃로 냉각하여 1 시간 동안 교반하였다. 생성된 고체를 여과하고 테트라하이드로퓨란 10 mL로 세척한 후 고체를 40 ℃에서 3 시간 진공 건조하여 아리피프라졸 염산염 고체 3.93g (수율 90.9%)을 얻었다.
4 g (8.92 mmol) of aripiprazole was dissolved in 100 mL of tetrahydrofuran, and HCl gas was gradually introduced into the solution at room temperature. After the addition of at least 2 equivalents of HCl, the solution was concentrated under reduced pressure to about 30 mL, cooled to 0 to 5 DEG C and stirred for 1 hour. The resulting solid was filtered, washed with 10 mL of tetrahydrofuran, and then the solid was vacuum-dried at 40 DEG C for 3 hours to obtain 3.93 g (yield: 90.9%) of aripiprazole hydrochloride solid.
실시예Example 3: 황산염의 제조 3: Preparation of sulfate
아리피프라졸 4 g(8.92 mmol)을 400 mL의 아세톤에 녹였다. 여기에 황산 0.44 g(4.46 mmol)을 4 mL 아세톤에 녹인 용액을 실온에서 서서히 주입한 후 혼액을 50 mL로 감압 증류하고 0 내지 5 ℃로 냉각하였다. 1 시간 동안 교반 후 생성된 고체를 여과하고 아세톤 20 mL로 세척한 후 고체를 40 ℃에서 3 시간 진공 건조하여 아리피프라졸 황산염 고체 4.52g(수율 92.7%) 을 얻었다.
4 g (8.92 mmol) of aripiprazole was dissolved in 400 mL of acetone. A solution of 0.44 g (4.46 mmol) of sulfuric acid in 4 mL of acetone was slowly added thereto at room temperature, and the mixture was distilled under reduced pressure to 50 mL and cooled to 0 to 5 ° C. After stirring for 1 hour, the resulting solid was filtered and washed with 20 mL of acetone, and the solid was vacuum-dried at 40 ° C for 3 hours to obtain 4.52 g of aripiprazole sulfate solid (92.7% yield).
실시예Example 4: 황산염의 제조 4: Preparation of sulfate
아리피프라졸 4 g(8.92 mmol)을 400 mL의 아세톤에 녹였다. 여기에 황산 0.88 g(8.92 mmol)을 4 mL 아세톤에 녹인 용액을 실온에서 서서히 주입한 후 혼액을 약 50 mL로 감압 증류하고 0 내지 5 ℃로 냉각하였다. 1 시간 동안 교반 후 생성된 고체를 여과하고 아세톤 20 mL로 세척한 후 고체를 40 ℃에서 3 시간 진공 건조하여 아리피프라졸 황산염 고체 4.31g(수율 88.4 %)을 얻었다.4 g (8.92 mmol) of aripiprazole was dissolved in 400 mL of acetone. A solution of 0.88 g (8.92 mmol) of sulfuric acid in 4 mL of acetone was slowly added thereto at room temperature, and the mixture was distilled under reduced pressure to about 50 mL and cooled to 0 to 5 ° C. After stirring for 1 hour, the resulting solid was filtered and washed with 20 mL of acetone, and the solid was vacuum-dried at 40 ° C for 3 hours to obtain 4.31 g (yield: 88.4%) of aripiprazole sulfate solid.
C23H27Cl2N3O2 H2SO4 C 23 H 27 Cl 2 N 3 O 2 H 2 SO 4
1H NMR(DMSO-d6, 400MHz): 10.01(s, 1H), 9.50(brs, 1H), 7.37(m, 2H), 7.22(m,1H), 7.05(d, J=8.0Hz, 1H), 6.50(dd, J1= 2.4Hz, J2= 8.4Hz, 1H), 6.44(d, J=2.4Hz, 1H), 3.93(t, J=6.0Hz, 2H), 3.62(d, J= 11.6Hz, 2H), 3.46(d, J=12.4Hz, 2H), 3.24(m, 4H), 2.78(t, J=7.2Hz, 2H), 2.41(t, J=8.0Hz, 2H), 1.86(m, 2H), 1.78(m, 2H)
1H NMR (DMSO-d 6, 400MHz): 10.01 (s, 1H), 9.50 (brs, 1H), 7.37 (m, 2H), 7.22 (m, 1H), 7.05 (d, J = 8.0Hz, 1H) , 6.50 (dd, J 1 = 2.4 Hz, J 2 = 8.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H) J = 8.0 Hz, 2H), 1.86 (m, 2H), 3.46 (d, J = 12.4 Hz, 2H), 3.24 (m, 2 H), 1.78 (m, 2 H)
실시예Example 5: 황산염의 제조 5: Preparation of sulfate
아리피프라졸 4 g(8.92 mmol)을 100 mL의 테트라하이드로퓨란에 녹였다. 여기에 황산 0.44 g(4.46 mmol)을 2 mL 테트라하이드로퓨란에 녹인 용액을 실온에서 서서히 주입한 후 혼액을 20 mL로 감압 농축하고 0 내지 5 ℃로 냉각하였다. 1 시간 동안 교반 후 생성된 고체를 여과하고 테트라하이드로퓨란 10 mL로 세척한 후 고체를 40 ℃에서 3 시간 진공 건조하여 아리피프라졸 황산염 고체 4.53g (수율 92.9%)을 얻었다.
4 g (8.92 mmol) of aripiprazole was dissolved in 100 mL of tetrahydrofuran. A solution of 0.44 g (4.46 mmol) of sulfuric acid in 2 mL of tetrahydrofuran was slowly added thereto at room temperature, and the mixture was concentrated under reduced pressure to 20 mL and cooled to 0 to 5 ° C. After stirring for 1 hour, the resulting solid was filtered and washed with 10 mL of tetrahydrofuran, and the solid was vacuum-dried at 40 ° C for 3 hours to obtain 4.53 g of aripiprazole sulfate solid (yield 92.9%).
실시예Example 6: 황산염의 제조 6: Preparation of sulfate
아리피프라졸 4 g(8.92 mmol)을 100 mL의 테트라하이드로퓨란에 녹였다. 여기에 황산 0.88 g(8.92 mmol)을 4 mL 테트라하이드로퓨란에 녹인 용액을 실온에서 서서히 주입한 후 혼액을 약 20 mL로 감압 농축하고 0 내지 5 ℃로 냉각하였다. 1 시간 동안 교반 후 생성된 고체를 여과하고 테트라하이드로퓨란 10 mL로 세척한 후 고체를 40 ℃에서 3 시간 진공 건조하여 아리피프라졸 황산염 고체 4.71g (수율 96.6%) 을 얻었다.
4 g (8.92 mmol) of aripiprazole was dissolved in 100 mL of tetrahydrofuran. A solution of 0.88 g (8.92 mmol) of sulfuric acid in 4 mL of tetrahydrofuran was slowly added thereto at room temperature, and the mixture was concentrated under reduced pressure to about 20 mL and cooled to 0 to 5 ° C. After stirring for 1 hour, the resulting solid was filtered and washed with 10 mL of tetrahydrofuran, and the solid was vacuum-dried at 40 ° C for 3 hours to obtain 4.71 g (yield: 96.6%) of aripiprazole sulfate solid.
위에 언급한 미국특허공개 US 2009111829호에 개시된 아리피프라졸 옥살산염의 수율은 91.3%, 주석산염의 수율은 93.2%, 헤미숙신산염의 수율은 80.8%, 캄포설폰산염의 수율은 86.4%, 그리고 인산염 일수화물의 수율은 65.0%인 반면, 본 발명에 따르면 아리피프라졸 무기염을 대체로 90% 이상의 높은 수율로 얻을 수 있다는 것이 확인된다.The yield of the aripiprazole oxalate salt was 91.3%, the yield of the stannate salt was 93.2%, the yield of the hemisuccinate salt was 80.8%, the yield of the camphosulfonate salt was 86.4%, and the yield of the phosphate monohydrate Is 65.0%, whereas it is confirmed that the present invention can obtain the inorganic salt of aripiprazole with a yield of 90% or higher in general.
이상에서 살펴본 바와 같이, 본 발명의 방법에 의하면 비교적 간단한 공정을 통해 아리피프라졸의 무기염을 고순도 및 고수율로 제조할 수 있다.As described above, according to the method of the present invention, inorganic salts of aripiprazole can be produced with high purity and high yield through a relatively simple process.
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| CN108069900B (en) * | 2016-11-08 | 2022-09-23 | 齐鲁制药有限公司 | Preparation method and application of aripiprazole hydrochloride |
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