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WO2011030213A8 - Procédé amélioré de préparation du 7-(4-bromobutoxy)-3,4-dihydrocarbostyrile, un précurseur de l'aripiprazole - Google Patents

Procédé amélioré de préparation du 7-(4-bromobutoxy)-3,4-dihydrocarbostyrile, un précurseur de l'aripiprazole Download PDF

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Publication number
WO2011030213A8
WO2011030213A8 PCT/IB2010/002276 IB2010002276W WO2011030213A8 WO 2011030213 A8 WO2011030213 A8 WO 2011030213A8 IB 2010002276 W IB2010002276 W IB 2010002276W WO 2011030213 A8 WO2011030213 A8 WO 2011030213A8
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WO
WIPO (PCT)
Prior art keywords
process according
formula
dihydrocarbostyril
solvent
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2010/002276
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English (en)
Other versions
WO2011030213A1 (fr
Inventor
Jayant Srivastava
Vijay Shankar Gupta
Bharat Vithalbhai Varu
Pramod Kumar
Dharam Vir
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jubilant Pharmova Ltd
Original Assignee
Jubilant Life Sciences Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jubilant Life Sciences Ltd filed Critical Jubilant Life Sciences Ltd
Publication of WO2011030213A1 publication Critical patent/WO2011030213A1/fr
Publication of WO2011030213A8 publication Critical patent/WO2011030213A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • the present invention relates to an improved process for the preparation of 7-(4- bromobutoxy) 3,4-dihydrocarbostyril, a key intermediate used in the preparation of Aripiprazole.
  • Schizophrenia is a common type of psychosis characterized by the symptoms like delusions, hallucination, excitations and the like. Schizophrenia generally occurs between the age of 16-25 years and affects one percent individuals worldwide. It is considered as more prevalent than Alzheimer's disease, multiple sclerosis, insulin- dependent diabetes and muscular dystrophy. Schizophrenia is the most common type of psychosis caused by an excessive neurotransmission activity of the dopaminergic nervous system in the central nervous system.
  • a number of drugs, having the activities for blocking the neurotransmission of dopaminergic receptor in the central nervous system such as chlorpromazine, haloperidol and sulpiride have been developed. However, many of these drugs are considered not effective for improving the negative symptoms, which are observed in the chronic period of schizophrenia.
  • 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.
  • the main drawback of the said process is the use of dimethylformamide, which is not only harmful by inhalation but also acts as carcinogen and its long-term exposure may result in kidney or liver damage.
  • 7-BBQ obtained by the said process involves the formation of dimer impurity in the range of 5-8%, which causes low yield and affect the purity of 7-BBQ as well as final Aripiprazole product.
  • US 7,361 ,756 discloses the process for the preparation of 7-BBQ by mixing 7HQ and dibromobutane and at least one base to form a reaction mixture, heated the said mixture at temperature between 50-140°C, cooled the reaction mixture and isolated 7-BBQ from the reaction mixture.
  • US '756 also disclose the use of phase transfer catalyst during the reaction.
  • the main drawback of the process disclosed in the US'756 patent is the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (7- BBQ) at high reaction temperature (140°C or above), which not only increases the formation of dimer impurity but also difficult to handle on the commercial scale, thus make the process tedious and uneconomical.
  • the inventor of the present invention observed that once the dimer impurity is formed during the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, it is difficult to remove completely even after multiple purifications. This not only increases the number of operational steps, but also increases the production cost and makes the process unsuitable and unviable on commercial scale.
  • WO2008146156 A2 discloses a process for the preparation of 7-[4-[4-(2,3- dichlorophenyl)- 1 -piperazinyl]butoxy]-3 ,4-dihydro-2-(l H)-quinolinone by reacting 7- hydroxy-3,4-dihydro-2(lH)-quinolinone with 1 ,4-dibromobutane in the presence of base and solvent at temperature 75-100°C to form 7-[4-bromobutoxy]-3,4-dihydro- 2(l H)-quinolinone, treating the resulting compound with silica gel in a solvent to produce pure 7-[4-bromobutoxy]-3,4-dihydro-2(lH)-quinolinone, reacting the resulting compound with l-(2,3-dichlorophenyl)piperazine or its salt to produce Aripiprazole.
  • the main drawback is 7-[4-bromobutoxy]-3,4-dihydro-2(lH)- quinolinone prepared by the said process is contaminated by 5 to 10% dimer impurity, thus removal of said dimer impurity require extra purification step. This not only increases the number of steps, but also increases the production cost on commercial scale.
  • the reaction of 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) of Formula III with 1 ,4-dibromobutane is carried out in presence of a base in an organic solvent, at temperature 45°C or below in order to reduce the formation of dimer impurity.
  • the base can be selected from organic or inorganic.
  • the organic base can be selected from diethylamine, triethylamine, pyridine, diisopropylamine, diisopropylethyl amine and the like.
  • the inorganic base can be selected from alkali metal or alkaline earth metal carbonate, bicarbonates, hydroxide, alkoxides, hydride and the like or mixture thereof.
  • the solvent used herein can be selected from lower alcohols, nitriles, ethers, esters, chlorinated hydrocarbons, ketone, and the like and mixture thereof.
  • the solvent is selected from methanol, ethanol, propanol, butanol, acetonitrile, propionitrile tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, chloroform, acetone, or mixture thereof.
  • phase transfer catalyst wherein the phase transfer catalyst is selected from quaternary ammonium and phosphonium compound, crown ethers or polyethylene glycols.
  • the phase transfer catalyst is selected from quaternary ammonium and phosphonium compound, crown ethers or polyethylene glycols.
  • the phase transfer catalyst is selected from quaternary ammonium and phosphonium compound, crown ethers or polyethylene glycols.
  • the phase transfer catalyst is selected from quaternary ammonium and phosphonium compound, crown ethers or polyethylene glycols.
  • the phase transfer catalyst can be present in an amount of about 0.1 to about 5 mole equivalent with respect to the 7-hydroxy-3,4- dihydrocarbostyril. Preferably, the phase transfer catalyst is present in an amount of about 0.1 to about 1 mole equivalent with respect to the 7-hydroxy-3,4- dihydrocarbostyril.
  • the reaction is carried at temperature 45°C or below, preferably between 20-45°C more preferably between 25-45°C.
  • the reaction time depends on the scale and the mixing procedure as is commonly known to the person skilled in the art. Typically the reaction time is from about 20 to about 50 hours.
  • reaction mixture After the completion of the reaction, the reaction mixture is cooled to room temperature, filtered, followed by distillation of filtrate.
  • the resultant mass was cooled to room temperature and non-polar solvent such as cyclohexane was added, as a result solid was precipitated off, which was filtered, washed with water and dried to obtain 7-(4-bromobutoxy) ⁇ 3,4-dihydrocarbostyril, having low dimer content.
  • the base can be selected from organic or inorganic.
  • the inorganic base can be selected from alkali metal or alkaline earth metal carbonate, bicarbonates, hydroxide, alkoxides, hydride and the like or mixture thereof.
  • the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and the like.
  • the organic base can be selected from diethylamine, triethylamine, pyridine, diisopropylamine, diisopropylethyl amine and the like.
  • the solvent used herein can be selected from lower alcohols, nitriles, esters, chlorinated solvents, ketone, amides, sulfoxides and the like or mixture thereof.
  • the solvent is selected from methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, chloroform, dimethylsulphoxide, dimethylformamide or mixture thereof.
  • the reaction is carried at temperature of about 35-90°C, preferably between 75-85°C more preferably between 80-85°C for 5 to 10 hours, preferably between 6-8 hours.
  • the aripiprazole so obtained is crystallized employing the suitable solvent such aliphatic alcohol and water, wherein alcohol is selected from methanol, ethanol, propanol, butanol and the like to obtain pure aripiprazole having dimer impurity content less than 0.1 %, preferably less than 0.05%.
  • suitable solvent such aliphatic alcohol and water, wherein alcohol is selected from methanol, ethanol, propanol, butanol and the like to obtain pure aripiprazole having dimer impurity content less than 0.1 %, preferably less than 0.05%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation du 7-(4-bromobutoxy)-3,4-dihydrocarbostyrile, un intermédiaire clé utilisé dans la préparation de l'aripiprazole.
PCT/IB2010/002276 2009-09-14 2010-09-14 Procédé amélioré de préparation du 7-(4-bromobutoxy)-3,4-dihydrocarbostyrile, un précurseur de l'aripiprazole Ceased WO2011030213A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1892DE2009 2009-09-14
IN1892/DEL/2009 2009-09-14

Publications (2)

Publication Number Publication Date
WO2011030213A1 WO2011030213A1 (fr) 2011-03-17
WO2011030213A8 true WO2011030213A8 (fr) 2011-05-19

Family

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Application Number Title Priority Date Filing Date
PCT/IB2010/002276 Ceased WO2011030213A1 (fr) 2009-09-14 2010-09-14 Procédé amélioré de préparation du 7-(4-bromobutoxy)-3,4-dihydrocarbostyrile, un précurseur de l'aripiprazole

Country Status (1)

Country Link
WO (1) WO2011030213A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105367491A (zh) * 2015-11-26 2016-03-02 苏州黄河制药有限公司 一种以间氨基苯酚为原料合成阿立哌唑的方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54130587A (en) 1978-03-30 1979-10-09 Otsuka Pharmaceut Co Ltd Carbostyryl derivative
US5006528A (en) 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
MXPA06008829A (es) * 2004-02-05 2007-04-25 Teva Pharma Metodo de fabricar 7-(4-bromobutoxi)-3,4-dihidrocarboestirilo.
DE102005048695A1 (de) * 2004-10-12 2006-05-18 Chemagis Ltd. Verfahren zur Herstellung und Reinigung von Carbostyrilverbindungen wie beispielsweise Aripiprazol und 7-(4-Halobutoxy)-3,4-dihydro-2(1H)-quinolinonen
US20070213535A1 (en) * 2006-03-07 2007-09-13 Chemagis Ltd. Process for the manufacture of aripiprazole by using purified carbostyril compounds such as 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinones
WO2007118923A1 (fr) * 2006-04-13 2007-10-25 Fermion Oy Procédé de préparation d'aripiprazole et intermédiaires correspondants
WO2008001188A2 (fr) * 2006-06-29 2008-01-03 Cadila Pharmaceuticals Limited Procédé amélioré de synthèse d'aripiprazole sensiblement pur
US20100130744A1 (en) 2007-06-01 2010-05-27 Mahesh Nagarimadugu Process for the preparation of aripiprazole

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WO2011030213A1 (fr) 2011-03-17

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