cas 129722-12-9, Aripiprazole | Articles data

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Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole
The invention discloses a synthesis method of high-purity aripiprazole and a preparation method of hydrate particles of aripiprazole. The method comprises the following steps: step (1), carrying out Williamson etherification on 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-dibromobutane under the action of potassium carbonate to obtain 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone; step (2), synthesizing 2,3-dichlorophenyl piperazine hydrochloride from 2,3-dichloroaniline and bis(2-chloroethyl) amine hydrochloride; step (3), carrying out an alkylation coupling reaction of nitrogen on 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 1-(2,3-dichlorophenyl) piperazine hydrochloride, so as to prepare aripiprazole; (4) refining: recrystallizing aripiprazole by using ethyl acetate to obtain high-purity anhydrous aripiprazole; and (5) preparation of aripiprazole hydrate particles: refluxing and dissolving anhydrous aripiprazole in an ethanol-water system, and controlling the stirring rate and the cooling rate to obtain the aripiprazole hydrate particles.
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Paragraph 0035; 0054; 0135-0143

(2021/08/07)

The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH
Based on the SAR of both α1-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C6min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α1-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.
Chen, Kaixuan,Jiang, Zhenzhou,Liu, Shuwen,Xi, Baomin,Yang, Fubiao,Zeng, Li-Yan,Zeng, Yunong
(2020/09/18)

Synthesis method of aripiprazole
The invention discloses a synthesis method of aripiprazole. 7-(4-hydroxybutyloxy)-3,4-dihydro-2(1H)-quinolone as a raw material is subjected to reaction with 1-(2,3-dichlorophenyl)piperazine hydrochloride in the presence of (cyanomethyl)trialkylphosphonium iodide and diisopropylethylamine to generate aripiprazole. Alkyl in (cyanomethyl)trialkylphosphonium iodide can be any one of methyl, ethyl, propyl or butyl. The raw materials and reagents in the method are cheap and commercially available, and high-quality aripiprazole can be obtained by two-step reaction. The process has good reaction selectivity and does not produce dimer by-products; intermediates in all the steps can be purified by recrystallization, and single impurities can reach the intermediate index of raw material drugs; the total yield of the finally prepared qualified-purity raw material drug can reach 60-70%, the process is obviously improved, and the synthesis method has a good industrial application prospect.
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Paragraph 0027; 0032-0043

(2019/02/04)

Preparation method of aripiprazole
The invention relates to a preparation method of aripiprazole, and belongs to the technical field of preparation of raw material medicines. The preparation method comprises the following steps: carrying out a coupling reaction on 2,3-dichlorobromobenzene ued as a starting material and bis(2-chloroethyl)amine, carrying out a cyclization reaction on the obtained coupling reaction product and 4-amino-1-butanol, carrying out a substitution reaction on the obtained cyclization reaction product and thionyl chloride to obtain a chlorobutyl-substituted intermediate III, and further reacting the intermediate III with 3,4-dihydro-7-hydroxyl-2(1H)-quinolinone to form the aripiprazole. The preparation method has great advantages in reducing the use equivalent of every material and controlling the formation of a dimer, so the finished aripiprazole product with a high purity is well obtained.
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(2019/01/21)

Preparation method of aripiprazole
The invention discloses a preparation method of aripiprazole. The method comprises the following steps: dissolving 1-(2,3-dichlorophenyl)piperazine or a salt thereof in a polar solvent, adding 1,4-dibromobutane and an acid binding agent, carrying out a reaction under a first heating condition, performing first cooling and first filtration to obtain a first filtrate, distilling the solvent out of the first filtrate, adding a weakly polar solvent for crystallization, performing second filtration to obtain a second filtrate, performing drying to obtain 1-(2,3-dichlorophenyl)piperazine azacyclopentamine salt, adding the 1-(2,3-dichlorophenyl)piperazine azacyclopentamine salt, 7-hydroxyl-3,4-dihydroquinolone, and an alcohol base in an anhydrous alcohol, carrying out a reaction under a second heating condition, performing second cooling, performing dispersing by pouring the cooled system into ice water, performing third filtration, performing washing with water, and performing crystallization to obtain aripiprazole. According to the provided method, the process raw materials are easy to obtain, the route is simple and short, and the high-purity target product can be obtained. Compared with a method of the prior art, the method optimizes the process conditions, reduces the production cost, has good product quality, has high yield, and is favorable for industrialized production.
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Paragraph 0068-0074

(2019/10/01)

Preparation method of aripiprazole crystal form B
The invention discloses a preparation method of an aripiprazole crystal form B. The preparation method comprises the following steps: dissolving an aripiprazole crude product in dichloromethane, and carrying out refluxing and separating water to obtain a dichloromethane solution of aripiprazole; and dropwise adding the dichloromethane solution of aripiprazole into n-hexane, evaporating out dichloromethane, then evaporating out a part of the solvent, stopping performing distillation, and carrying out cooling, filtering and drying to obtain the aripiprazole crystal form B. According to the preparation method provided by the invention, purification and crystallization of the aripiprazole crude product are completed in one step, operation is simple and convenient, the process is stable, the quality is good, the yield is high, purity of aripiprazole is further improved, and the impurity content is further reduced. The obtained crystal form meets the requirement of medicinal-grade purity, has good stability, and facilitates industrial production.
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Paragraph 0064-0066

(2019/10/01)

Method for synthesizing aripiprazole
The invention discloses a method for synthesizing aripiprazole. The method comprises making 4-halogenated-3-nitrophenol react with an ethylenation reagent under palladium catalysis conditions to obtain 3-nitro-4-vinylphenol; making the 3-nitro-4-vinylphenol and 1,4-dihalogenated butane reacting with alkali to obtain 4-(4-halobutoxy)-2-nitro-1-styrene; making the 4-(4-halobutoxy)-2-nitro-1-styreneand 1-(2,3-dichlorophenyl)piperazine salt reacting with the alkali to obtain 1-(2,3-dichlorophenyl)-4-(4-(3-nitro-4-vinylphenoxy)butyl)piperazine; making the 1-(2,3-dichlorophenyl)-4-(4-(3-nitro-4-vinylphenoxy)butyl)piperazine reacting with CO to form the aripiprazole. The method for synthesizing the aripiprazole has the total yield of up to 77% and is simple in post treatment.
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(2019/01/16)

Enabling CO Insertion into o-Nitrostyrenes beyond Reduction for Selective Access to Indolin-2-one and Dihydroquinolin-2-one Derivatives
The transition metal-catalyzed reductive cyclization of o-nitrostyrene in the presence of carbon monoxide (CO) has been developed to be a general synthetic route to an indole skeleton, wherein CO was used as a reductant to deoxidize nitroarene into nitrosoarene and/or nitrene with CO2 release, but the selective insertion of CO into the heterocyclic product with higher atom economy has not yet been realized. Herein, the Pd-catalyzed reduction of o-nitrostyrene by CO and its regioselective insertion were efficiently achieved to produce synthetically useful five- and six-membered benzo-fused lactams. Detailed investigations revealed that the chemoselectivity to indole or lactam was sensitive to the nature of the counteranions of Pd2+ precursors, whereas ligands significantly decided the carbonylative regioselectivity by different reaction pathways. Using PdCl2/PPh3/B(OH)3 (condition A), an olefin hydrocarboxylation was primarily initiated followed by partial reduction of the NO2 moiety and cyclization reaction to give N-hydroxyl indolin-2-one, which was further catalytically reduced by CO to afford the indolin-2-one as the final product with up to 95% yield. When the reaction was conducted under the Pd(TFA)2/BINAP/TsOH·H2O system (condition B), complete deoxygenation and carbonylation of the NO2 group occurred initially to yield the corresponding isocyanate followed by internal hydrocyclization to generate 3,4-dihydroquinolin-2-one with up to 98% yield. Importantly, the methodology could be efficiently applied in the synthesis of marketed drug Aripiprazole.
Yang, Li,Shi, Lijun,Xing, Qi,Huang, Kuo-Wei,Xia, Chungu,Li, Fuwei
p. 10340 - 10348
(2018/10/20)

Novel Polymorphic DH Form of Aripiprazole Anhydride and Preparing Method of the Same
The present invention relates to novel polymorphism of aripiprazole, which are DH-1, DH-2, and DH-3. The present invention further relates to a method for producing the polymorphism. The novel polymorphism of aripiprazole provided in the present invention ensures excellent physicochemical properties such as stability and non-hygroscopicity, and can be useful for producing aripiprazole-containing drugs.COPYRIGHT KIPO 2018
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Paragraph 0047-0049

(2018/08/22)

A process for preparing aripiprazole crystalline B method
A method of preparing a B-type aripiprazole crystal is provided. The method includes heating to dissolve aripiprazole into dichloromethane, cooling for crystallizing, filtering and drying to obtain the B-type aripiprazole crystal. The method is simple and convenient in operation and stable in process. The prepared product has characteristics of good crystal form oneness, easy drying and good crystal form stability and is suitable for industrial production.
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Paragraph 0025; 0026; 0027

(2017/08/25)

IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE WITH REDUCED PARTICLE SIZE
The present invention relates to process for preparation of Aripiprazole with reduced particle size having dehydro impurity less than 0.1 %.
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Page/Page column 7

(2016/12/01)

Method for synthesizing aripiprazole using m-amino phenol as raw material
The present invention discloses a method for synthesizing aripiprazole using m-amino phenol as a raw material. The synthesis method comprises: step 1, performing a substitution reaction on the m-amino phenol and 3-methoxy propionyl chloride in an aqueous solution of a strong base; step 2, performing electrophilic substitution on the product obtained in the first step using boron trifluoride diethyl ether as a catalyst; step 3, performing a substitution reaction on the product obtained in the second step and 4-bromine-1-butyl iodide under catalysis of the strong base in solvent composed of DMSO, DMF and water; and step 4, performing a substitution reaction on the product obtained in the third step and 1-(2, 3-dichloro phenyl) piperazine under catalysis of the strong base in solvent composed of DMSO, DMF and water; Tert-butyl benzenesulfonic acid 4-chloro butyl ester and 7-hydroxy-3, 4-2 (1H) dihydroquinolinone are used for a substitution reaction. Since tert-butyl benzenesulfonyloxy and chlorine respectively in 1, 4-position carbon atoms in 4-bromine-1-butyl iodide have different substitution activity, iodine is preferably substituted by hydroxy, and in this way dimerized quinolinone by-products are reduced, thereby improving the purity of the product and ensuring the yield.
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(2016/10/08)

Process for preparing aripiprazole
The invention provides a preparation method of aripiprazole shown in the formula (I). The method comprises the following steps of: 1) enabling 7-hydroxy-3,4-dihydro-2(1H) quinolinone shown in the formula (II) to react with a compound represented by the formula (III) in a mixed solvent formed by amide and/or a sulfoxide solvent and water in the presence of an inorganic alkaline compound, thereby preparing a quinolinone compound shown in the formula (IV); and 2) enabling the quinolinone compound represented by the formula (IV) to react with a piperazine compound represented by the formula (V) and/or a salt thereof in the mixed solvent formed by the amide and/or the sulfoxide solvent and the water in the presence of the inorganic alkaline compound, thereby preparing the aripiprazole, wherein a product obtained by the step 1) can be separated from the reaction system or is not separated from the reaction system.
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Paragraph 0081; 0084; 0085

(2017/02/23)

Carbostyril derivatives and serotonin reuptake inhibitors for treatment of mood disorders
The pharmaceutical composition of the present invention comprises (1) a carbostyril derivative and (2) a serotonin reuptake inhibitor in a pharmaceutically acceptable carrier. The carbostyril derivative may be aripiprazole or a metabolite thereof, which is a dopamine-serotonin system stabilizer. The serotonin reuptake inhibitor may be fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine, paroxetine, sertraline or escitalopram. The pharmaceutical composition of the present invention is useful for treating patients with mood disorders, particularly depression or major depressive disorder.
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Page/Page column 17

(2016/08/10)

The method of producing crystals B aripiprazole anhydride (by machine translation)
PROBLEM TO BE SOLVED: aripiprazole anhydride of B-type crystal in an easy and safe operation, without using a solvent of high toxicity, without being mixed with other crystalline form of high-purity, high yield. SOLUTION: 2 θ = 16.3 °, 21.8 °, 22.2 °, in X-ray diffraction spectrum 23.3 ° and 24.5 ° shows a peak having a powder, a melting point of 148 ±3 °C, aripiprazole 0.05-0.30% moisture content in the crystal, and benzyl alcohol dissolved in a mixed solvent of amyl acetate, recrystallization to aripiprazole anhydride-B. Selected drawing: fig. 2 (by machine translation)
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Paragraph 0019; 0021

(2017/01/31)

Novel Crystal form of aripiprazole and the method of preparing the same
The present invention relates to novel crystal form 1 to 8 of aripiprazole and a preparation method thereof. The new crystal form 1 to 8 of aripiprazole have uniform and fine particle sizes to show excellent workability. The new crystal forms of aripiprazole have a low moisture absorption rate not to be converted into hydrates or lose the original solubility even if pharmaceutical formulations containing the new crystal forms are stored for more than the storage period. Accordingly, the present invention has excellent storage stability. The new crystal forms are single crystal forms, have stable physical properties, and do not include impurities such as metal.COPYRIGHT KIPO 2015
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Paragraph 0098-0108

(2016/12/16)

LOW HYGROSCOPIC ARIPIPRAZOLE DRUG SUBSTANCE AND PROCESSES FOR THE PREPARATION THEREOF
The present invention provides low hygroscopic forms of aripiprazole and processes for the preparation thereof which will not convert to a hydrate or lose their original solubility even when a medicinal preparation containing the anhydrous aripiprazole crystals is stored for an extended period.
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Paragraph 0274

(2015/09/22)

Modular C-H Functionalization Cascade of Aryl Iodides
We report the first example of ipso-borylation for the modular 1,2-bisfunctionalization of aryl iodides via C-H functionalization. The carbon-boron bond is used as a lynchpin to access ipso carbon-carbon, carbon-nitrogen, carbon-oxygen, and carbon-halogen (Cl, Br, I) bonds. The utility of our methodology is illustrated through quick, modular syntheses of the pharmaceuticals Abilify and Flunixin.
Shi, Hang,Babinski, David J.,Ritter, Tobias
supporting information
p. 3775 - 3778
(2015/04/14)

Carbostyril derivatives and mood stabilizers for treating mood disorders
The pharmaceutical composition of the present invention comprises a carbostyril derivative which is a dopamine-sero-tonin system stabilizer and a mood stabilizer in a pharmaceutically acceptable carrier. The carbostyril derivative may be aripiprazole or a metabolite thereof. The mood stabilizer may include but is not limited to lithium, valproic acid, divalproex sodium, carbamaza-pine, oxcarbamazapine, zonisamide, lamotragine, topiramate, gabapentin, levetiracetam or clonazepam. These compositions are used to treat patients with mood disorders, particularly bipolar disorder with or without psychotic features, mania or mixed episodes. Methods are provided for separate administration of a carbostyril derivative and a mood stabilizer to a patient with a mood disorder.
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Page/Page column 16; 17

(2015/09/28)

ORAL SOLID PREPARATION COMPRISING ARIPIPRAZOLE AND METHOD FOR PRODUCING ORAL SOLID PREPARATION COMPRISING ARIPIPRAZOLE
[Object] An object of the present invention is to provide an oral solid preparation that can be produced in a simpler manner than conventional methods, that exhibits high bioavailability and high dissolubility even in persons having low stomach acid, and that can also ensure dissolubility after being allowed to stand for a certain period of time. Another object is to provide a simple method for producing the oral solid preparation. [Means for Achieving the Object] The present invention relates to an oral solid preparation comprising, as an active ingredient, a finely milled crystal obtained by milling an aripiprazole hydrate crystal, and a pharmaceutically acceptable carrier, the finely milled crystal having a mean particle size of 15 μm or less; and a method for producing an oral solid preparation comprising the steps of (1) milling an aripiprazole hydrate crystal into a finely milled crystal having a mean particle size of 15 μm or less, and (2) mixing the obtained finely milled crystal with a pharmaceutically acceptable carrier.
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Paragraph 0092; 0093

(2014/11/11)

METHOD FOR PRODUCING FINE PARTICLES OF ARIPIPRAZOLE ANHYDRIDE CRYSTALS B
The present invention provides a novel method for producing fine particles of aripiprazole anhydride crystals B. The method for producing fine particles of aripiprazole anhydride crystals B comprises the steps of: (1) heating and dissolving crude aripiprazole in a lower alcohol, and subsequently cooling the resulting mixture to precipitate crystals to obtain crystals of aripiprazole lower alcohol solvate; (2) subjecting the crystals of aripiprazole lower alcohol solvate to wet-milling in the form of a slurry containing the lower alcohol; and (3) subjecting the dispersion of the wet-milled crystals to solid-liquid separation to obtain the crystals, and heating the crystals.
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Page/Page column 11-12

(2013/03/26)

PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
The present invention relates to an improved process for the preparation of high pure crystalline Aripiprazole of formula (I) having low residue ethanol content. The process comprises slurrying Aripiprazole obtained from the reaction mixture with water.
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Page/Page column 6

(2013/03/26)

An efficient synthesis of aripiprazole, buspirone and NAN-190 by the reductive alkylation of amines procedure
The reductive alkylation of amines procedure was applied for the synthesis of aripiprazole 1a, buspirone 1b, and NAN-190 1c. The reductive alkylation of amines procedure was applied for the synthesis of aripiprazole 1a, buspirone 1b, and NAN-190 1c. Copyright
Kowalski, Piotr,Jaskowska, Jolanta
p. 81 - 85
(2012/04/10)

PROCESS FOR PRODUCING ARIPIPRAZOLE IN ANHYDROUS TYPE I CRYSTALS
Disclosed herein is an improved process for the preparation of anpiprazole in anhydrous Type I crystals, substantially free of other polymorphic forms of aripiprazole via improved drying technique.
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Page/Page column 7

(2012/10/18)

IMPROVED PROCESS FOR THE PREPARATION OF 7.(4-BROMOBUTOXY) 3,4-DIHYDROCARBOSTYRIL, A PRECURSOR OF ARIPIPRAZOLE
Disclosed herein is an improved process for the preparation of 7-(4-bromobutoxy) 3,4-dihydrocarbostyril, a key intermediate used in the preparation of Aripiprazole.
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Page/Page column 9

(2011/04/18)

ARIPIPRAZOLE SALTS
Aripiprazole salts, consisting of aripiprazole and tricarboxylic acid derivative, wherein one carboxyl group of an acid forms ester with C1-C4-aliphatic alcohol, represented by formula (1), wherein is double bond and R is H, or is single bond and R is -O (C=O) R2, R2 is Ci-C4-aliphatic group or phenyl, optionally substituted by -CH3 or - OCH3 group in position 4 of the phenyl ring, n = 1 - 2, are new derivatives of antipsychotic effect. Aripiprazole salts are prepared in the reaction of aripiprazole free base and bicarboxylic acid anhydride in C1-C4 aliphatic alcohol as a solvent.
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Page/Page column 16

(2010/10/03)

PROCESS FOR PREPARING CRYSTALLINE ARIPIPRAZOLE
The present invention relates the process for preparation of stable polymorph of aripiprazole and in particular the present invention is related to an improved process for the preparation of crystalline anhydrous aripiprazole and its hydrochloride salt.
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Page/Page column 5

(2010/05/13)

Optimization of aripiprazole synthesis
A series of aripiprazole (AR3) syntheses were performed at laboratory scale (10 mmol of the AR1 substrate) in order to optimize the amount of another substrate AR2, as well as Na2CO3, ethanol and varying the reaction time. The reaction parameters were chosen according to the D-optimal plans. A high conversion ratio, about 90-99 %, was obtained. Purity of crude product (AR3) was determined by HPLC. Molar content of crude reaction product was predicted theoretically with the use of the mass balance and the corresponding HPLC parameters. The theoretical predictions were verified with the potentiometric and thermogravimetric analysis of selected samples. Based on the predicted molar content of reaction mixtures, a series of reaction response surfaces was calculated and optimal set of reaction parameters for aripiprazole synthesis was determined.
Les, Andrzej,Badowska-Roslonek, Katarzyna,Laszcz, Marta,Kamienska-Duda, Agata,Baran, Piotr,Kaczmarek, Lukasz
experimental part
p. 151 - 157
(2011/08/05)

PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
The present invention relates to an improved process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)-1-piper-azinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone of Formula (I).
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Page/Page column 3

(2010/06/14)

ARYLPIPERAZINE MODULATORS OF D2 RECEPTORS, 5-HT1A RECEPTORS, AND/OR 5-HT2A RECEPTORS
The present invention relates to new arylpiperazine modulators of D2 receptors, 5-HT1A receptors, and/or 5-HT2A receptors, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 26

(2010/04/23)

Novel intermediates useful for the preparation of aripiprazole and methods for the preparation of the novel intermediates and aripiprazole
An improved process for the preparation of aripiprazole (1) which comprises (i) reacting 6-hydroxy-l-indanone (11) with 1,4-dihalobutane (12) in the presence of a base and a solvent at a temperature in the range of 90 to 110 deg C. to form the novel intermediate 6-(4-halo butoxy)-indan-1-one (3), (ii) reacting the novel intermediate with 1-(2,3-clichlorophenyl)-piperazine (9) to get another novel intermediate 6-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-indan-l-one (2) and (iii) reacting the resulting novel compound with sodium azide. The invention also relates to the novel intermediates of the formulae (2) and (3) and processes for their preparation. The invention also includes intermediate compounds useful for the preparation of aripiprazole.
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Page/Page column 5; 6

(2009/08/18)

ARIPIPRAZOLE HEMIFUMARATE AND PROCESS FOR ITS PREPARATION
The present invention relates to aripiprazole hemifumarate, a crystalline and amorphous form thereof, a process for its preparation, a pharmaceutical composition comprising it as well as its use for preparing a pharmaceutical dosage form.
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Page/Page column 14-15

(2008/06/13)

PROCESS FOR PREPARING ANHYDROUS ARIPIRAZOLE TYPE I
Type I anhydrous aripiprazole is prepared by dissolving aripiprazole (or an acid salt thereof) in an alcoholic solvent, optionally containing water, at elevated temperature, adding seed crystals of Type 1 anhydrous aripiprazole to the solution, cooling the mixture, and isolating crystals aripiprazole and drying the isolated crystals to obtain low moisture Type 1 anhydrous aripiprazole.
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Page/Page column 6-8

(2008/12/05)

AN IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
The present invention relates to an improved process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone of Formula (I).
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Page/Page column 7-8; 10

(2009/01/20)

AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE ARIPIPRAZOLE
The invention relates to an improved process for preparing substantially pure aripiprazole (HPLC >99.8 %), wherein 7,7'-[tetramethylenebis(oxy)]bis(3,4- dihydroquinolin-2(lH)-one) is present in pure aripiprazole in 0.01 % (w/w).
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Page/Page column 11

(2008/06/13)

SYNTHESES AND PREPARATIONS OF POLYMORPHS OF CRYSTALLINE ARIPIPRAZOLE
The invention relates to polymorphic crystalline forms of aripiprazole, synthetic processes for their preparation and pharmaceutical compositions containing the same. These crystalline forms of aripiprazole can be readily milled and can be easily combined with various pharmaceutical adjuvants without effecting changes to their crystalline structure when, for example, pressed into tablet or capsule form.
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Page/Page column 25

(2008/06/13)

A NOVEL PROCESS FOR PREPARATION OF ARIPIPRAZOLE AND ITS INTERMEDIATES
A process for the preparation of 7-hydroxy-3,4-dihydro carbostyril (II) by intramolecular Fridel-Craft alkylation of N-(3-methoxyphenyl)-3-chloropropionamide (I) in which an equivalent of N-(3-methoxyphenyl)-3-chloropropionamide (I) is contacted with a Lewis acid (e.g. aluminium chloride) in dimethyl acetamide (DMA), at an elevated temperature of from about 120°C to about 160°C, is provided. The process produces 7-hydroxy-3,4- dihydro carbostyril (II) in high yield and a high state of purity such that it may be used in subsequent .reaction towards the preparation of aripiprazole (IV). Thus 7-hydroxy-3,4- dihydro carbostyril (II) was treated with l-bromo-4-chlorobutane under phase transfer catalyst (PTC) conditions using solvents like acetone or n-butanol at temperature ranging 25°C to 45°C to afford 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III). The PTC conditions described in this patent afford 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III) in high purity and high yield with the corresponding dimmer formation is considerably low as compared with the other literature methods of preparing 7-(4-chlorobutoxy)-3,4- dihydro carbostyril (III). Compound (III) was treated with l-(2,3-dichlorophenyl)piperazine, at temperature ranging from 50°C to 100°C, and sodium iodide, potassium carbonate, dimethyl formamide (DMF) as a solvent to afford aripiprazole in high purity and high yield.
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Page/Page column 7-8

(2010/11/28)

New crystalline aripiprazole salts and processes for preparation and purification thereof
Provided are novel crystalline carboxylic acid salts of aripiprazole [7-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)-butoxy)-3,4-dihydro-2(1H)-quinolinone], methods of using such salts, and processes for producing such salts.
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Page/Page column 13-14

(2008/06/13)

An improved process for the preparation of aripipirazole
The present invention provides a process for the preparation of aripiprazole of Formula I comprising condensing a carbostyril compound of Formula II wherein X is a leaving group with dichlorophenyl piperazine or its salts of Formula III wherein Y is an organic or inorganic acid in water in the presence of an organic base.
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Page/Page column 5

(2008/06/13)

PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
The present invention provides a process for the preparation of aripiprazole of Formula I comprising condensing a carbostyril compound of Formula II wherein X is a leaving group with dichlorophenyl piperazine or its salts of Formula III wherein Y is an organic or inorganic acid in water in the presence of an organic base.
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Page/Page column 2

(2008/06/13)

Process for the manufacture of aripiprazole by using purified carbostyril compounds such as 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinones
The present invention provides a process for purifying carbostyril derivatives such as 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone and aripiprazole by passing a solution of the material in an organic solvent through a suitable absorbing material.
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Page/Page column 4-5

(2008/06/13)

Methods of preparing a crystalline form of 7-(4-chlorobutoxy)-3,4-dihydro-2(1h)-quinolinone and the use thereof in the synthesis of Aripiprazole
The present invention relates to methods of preparing a highly pure crystalline form of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone, which is a chemical intermediate useful in the preparation of Aripiprazole thereof in high quality and yield, and provides data that characterizes the crystalline form of 7-(4-chlorobutoxy)-3,4-dihydro-(1H)-quinolinone.
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Page/Page column 5

(2008/06/13)

AN IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
The present invention relates to an improved process for the preparation of Aripiprazole of formula (I), which is useful in the treatment of Schizophrenia. More particularly, the present invention relates to an improved process for the preparation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula (III) by reacting 7-hydroxy-3,4- dihydrocarbostyril of formula (II) with 1,4-dichlorobutane, in presence of inorganic base and solvent dimethylacetamide.
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Page/Page column 6

(2008/06/13)

A PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE AND INTERMEDIATES THEREOF
The present invention is related to the process for the preparation aripiprazole and intermediates thereof. The process comprises reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1-bromo-4-chlorobutane in aqueous solvent in the presence of a phase transfer catalyst and a base.
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Page/Page column 8-9

(2010/11/28)

PROCESS FOR THE PREPARATION OF POLYMORPHS, SOLVATES OF ARIPIPRAZOLE USING ARIPIPRAZOLE ACID SALTS
The present invention relates to Aripiprazole, a useful agent for antipsychotic. The present invention also provides new acid addition salts of Aripiprazole and process for the preparation of polymorphs and solvates of Aripiprazole using Aripiprazole acid salts, their interconversion and the process for preparation of Aripiprazole acid salts.
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Page/Page column 24-27; 28-29

(2008/06/13)

Polymorph and solvates of aripiprazole
The present invention relates to novel polymorphic forms of aripiprazole and processes for producing them. It further relates to pharmaceutical compositions comprising the novel forms and to the use of the novel forms in the treatment of schizophrenia.
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Page/Page column 9

(2008/06/13)

CRYSTALLINE ARIPIPRAZOLE SOLVATES
Alcoholates of aripiprazole are useful as pharmaceuticals and/or as intermediates in making aripiprazole Form A or Form B.
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Page/Page column 21

(2008/06/13)

Process for the preparation of aripiprazole
The present invention relates to an improved process for the preparation of 7-[4[-(2,3-dichlorophenyl) -1-piperazinyl]butoxy]3,4-dihydro-2-(1H) quinolinone (Aripiprazole) having dimer impurity less than 0.15%, particularly, the present invention relates to an improved process for the preparation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula (I) having dimer impurity less than 0.5% comprising a step of, reacting 7-hydroxy-tetrahydroquinolinone of formula (III) with 1-bromo-4-chlorobutane in the presence of a base in a solvent.
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Page/Page column 3; 5

(2008/06/13)

Crystalline aripiprazole salts and processes for preparation and purification thereof
Provided are novel crystalline carboxylic acid salts of aripiprazole, methods of using such salts, and processes for producing such salts.
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Page/Page column 9

(2008/06/13)

ARIPIPRAZOLE CRYSTALINE FORMS AND ASSOCIATED METHODS
A crystal form of anhydrous aripiprazole having good stability, which can be prepared by simple and economical processes, including such processes are disclosed and described. In one aspect, such a process may include dissolving aripiprazole in an appropriate solvent by heating, and then rapidly cooling with agitation of high speed, to cause the anhydrous aripiprazole of crystal a to swiftly and uniformly precipitate.
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Page/Page column 8-9

(2010/02/15)