Home > News > Chemical Synthesis of Aripiprazole

News

Chemical Synthesis of Aripiprazole
2015-05-10 07:08:00

Chemical Structure of Aripiprazole (brand names: Abilify, Japanese: エビリファイ, アリピプラゾール; Chinese: 安律凡, 阿立哌唑)

Chemical Strutcure of Aripirazole-Abilify-Antipsychotics-Otsuka-BMS-阿立哌唑-安律凡-大冢制药-エビリファイ

Originally discovered by Otsuka Pharmaceutical Co.(大塚製薬), the compound was jointly developed by Otsuka and Bristol Myers Squibb and was first marketed in the USA in 2002 under the trade name Abilify. The value of sales of Abilify preparations in the world in the years 2009 and 2010 was $6.5 and $6.7 billion, which provided the aripiprazole, manufactured by Otsuka company, third and second place respectively in the Top50 list of drugs acting on the central nervous system. According to IMS Health, Abilify was the fourth top-selling drug in the United States in 2011, with sales of $5.2 billion.

Chemical Synthesis of Aripiprazole(active ingredient for Abilify)

Chemical Synthesis of Abilify-Aripirazole-Atypical Antipsychotics-Otsuka-BMS-阿立哌唑-アリピプラゾール

Experimental Procedures for the preparation of Aripiprazole (Abilify, Japanese: エビリファイ, アリピプラゾール; Chinese: 安律凡, 阿立哌唑)

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps. The first step comprises synthesis of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield. The resulting 7-BBQ is further reacted with 1- (2,3-dichlorophenyl)-piperazine to obtain Aripiprazole.

Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)quinolinon (7-(4-bromobutoxy)-3,4-dihydrocarbostyril; 7-BBQ)

7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (aka 7-Hydroxy-3,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40- 45°C for 24 hours. Reaction mass was cooled upto room temperature and was filtered off. The resulting filtrate was distilled off under vacuum. The resultant mass was cooled to 25-30°C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The solid was filtered and dried under vacuum at 55-60°C for 20 hours to obtain title compound. mp 110.5-111 °C; 1H NMR (DMSO-d6) ä 1.81 (2H, m, -CH2-), 1.95 (2H, m, -CH2-), 2.41 (2H, t, J ) 7 Hz, -CH2CO-), 2.78 (2H, t, J) 7 Hz, -CH2-C-CO-), 3.60 (2H, t, J ) 6 Hz, -CH2Br), 3.93 (2H,t, J ) 6 Hz, O-CH2-), 6.43 (1H, d, J ) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz), 7.04 (1H, d, J ) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.

Yield: 73-75%; Purity: 93-95%

Preparation of Aripiprazole (7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one)

7-(4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30°C. To this potassium carbonate (67.2 gm) and l-(2,3- dichlorophenyl) piperazine hydrochloride (44.9gm) were added under stirring. The reaction mixture was refluxed at 80-85°C for 8 hours. The reaction mass was cooled to room temperature, filtered and the resulting solid was washed with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80°C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to obtain title compound. Yield: 75-80%; Dimer Impurity: <0.1%. 1H NMR: DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t, -CH2-O-]; 2.97 [4H, bb,2(-CH2-)]; 2.78 [2H, t, -CH2-N2-)]; 2.39 [4H, m, 2(-CH2-)]; 1.73 [2H, m, – CH2-]; 1.58 [2H, m, -CH2-]. IR:cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588.

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water
 
Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85°C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30°C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105°C for 6 hours to obtain title compound.
Yield: 87-89% HPLC Purity: 99.89
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1 %.
Particle size distribution: d10=15.83 m, d50=60.12 m, d90=144.99 m
 
Preparation of aripiprazole anhydrous Type I using ethanol and water
 
Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85°C for 1-2 hours. The resulting mixture was cooled to 25-30°C within 4 hours and stirred for 3 hours. The resulting solid was filtered and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105°C for 3 hours to obtain title compound. Yield: 90% HPLC Purity: 99.9%
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle size distribution: d10=22.01 m, d50=105.10 m, d90=232.97 m

References For the Process of Aripiprazole (Abilify, Japanese: エビリファイ, アリピプラゾール; Chinese: 安律凡, 阿立哌唑)

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori, Yasufumi Uwahodo, and Takao Nishi; Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties: Synthesis and Pharmacology of 7-[4-(4-Phenyl-1-piperazinyl)butoxy]- 3,4-dihydro-2(1H)-quinolinone DerivativesJ. Med. Chem. 1998, 41, 658-667

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi; Carbostyril derivatives, Otsuka Pharmaceutical Co., Ltd; US patent 5006528;Issue date: Apr 9, 1991

BANDO, Takuji, YANO, Katsuhiko, FUKANA, Makoto, AOKI, Satoshi ;Method for producing fine particles of aripiprazole anhydride crystals b; OTSUKA PHARMACEUTICAL CO., LTD., WO 2013002420 A1

袁秋慧,陈宏文,钱雯,柴雨柱,徐丹,杨治旻,田 舟山; 一种制备高纯度阿立哌唑的方法; 南京正大天晴制药有限公司;申请号:201210292382.0;公开号: CN102863377A; 公开日:2013.01.09 (本发明涉及医药化工领域,具体涉及一种制备高纯度阿立哌唑的方法。将阿立哌唑加入A溶剂中加热后,抽滤,滤液中加入B溶剂,低温搅拌后,抽滤,将滤饼悬 浮于水中,调节水溶液的pH值至碱性,抽滤,高温真空干燥,得到高纯度的阿立哌唑精制品。该方法操作简单,产品纯度高,适用于在工业上大规模应用)

ZHENG Siji, LIU Xiaoyi, FU Linyong, TAN Bo, ZHOU Min: ARIPIPRAZOLE MEDICAMENT FORMULATION AND PREPARATION METHOD THEREFOR. / FORMULATION DE MÉDICAMENT ARIPIPRAZOLE ET SON PROCÉDÉ DE PRÉPARATION. / 一种阿立哌唑药物制剂及其制备方法. SHANGHAI ZHONGXI PHARMACEUTICAL January 2013: WO 2013/000391

郑斯骥, 刘潇怡, 傅麟勇, 谭波, 周敏: 一种阿立哌唑药物制剂及其制备方法; 上海中西制药有限公司;公开日:2013.01.02 : 申请号:CN 201210235157.3;公开号:CN102846543A (本发明提供了一种阿立哌唑药物制剂的制备方法,其包括如下步骤:将阿立哌唑溶于含酸化剂的酸性溶液中,制得含药酸性溶液;之后,将所得含药酸性溶液与碱 化剂和辅料进行湿法制粒或制备混悬液,得到阿立哌唑药物制剂;所述的辅料包括抗氧剂)

郑斯骥;谭波;傅麟勇;刘潇怡;袁少卿;曹智慧;阿立哌唑Ⅰ型微晶、阿立哌唑固体制剂及制备方法;申请号:201110180032.0;公开号:CN102850268A;公开日:2013.01.02

蔡 付波,秦欣荣,杜小春,李凌; 一种合成阿立哌唑的改进方法; 成都康弘药业集团股份有限公司;申请号:200910058148.X;公开号:CN101781246A ;公开日:2010.07.21 (本发明提供了一种合成阿立哌唑的改进方法,根据本发明的改进方法,阿立哌唑分为醚化反应和缩合反应两步合成,在醚化反应中通过喹诺酮化合物和至少6倍摩 尔 当量的1,4-二卤代丁烷反应,用非极性溶剂将阿立哌唑醚化物析出,同时回收1,4-二卤代丁烷循环利用;缩合反应中以可共沸的酮/水混合物为溶剂,在碱 金属碘化物和碱性化合物存在条件下阿立哌唑醚化物与哌嗪化合物或其盐回流反应,反应结束后加入适量的水,降温析晶,过滤、干燥得到阿立派唑。改进后的合成 方法收率高、纯度高、步骤简单、成本低、适合工业化生产。)

GUPTA, Vijay Shankar, KUMAR, Pramod, VIR, Dharam ;Process for producing aripiprazole in anhydrous type i crystals;JUBILANT LIFE SCIENCES LIMITED;WO 2012131451 A1

SRIVASTAVA JAYANT GUPTA Vijay Shankar;Improved process for the preparation of 7.(4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole;wo2011030213 A1

No Generic Abilify in the US until April 2015

On May 7, 2012, The U.S. Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. in its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify®. (see the pdf file for the decision upholding the Otsuka patent here). The Federal Circuit affirmed a decision of the U.S. District Court for the District of New Jersey holding that the asserted claims of U.S. Patent No. 5,006,528 (pdf file here) covering aripiprazole, the active ingredient in Abilify®, are valid, thus maintaining patent and regulatory protection for Abilify® in the U.S. until at least April 20, 2015. The case is Otsuka Pharma Co. v. Sandoz Inc., 2011-1126 and 2011-1127, U.S. Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, U.S. District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole(active ingredient for Abilify): 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
CAS number 129722-12-9


Previous   [Return Home] [Print] [Go Back]   Next