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WO2013171643A1 - Procédé amélioré pour la préparation d'irbésartan - Google Patents

Procédé amélioré pour la préparation d'irbésartan Download PDF

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Publication number
WO2013171643A1
WO2013171643A1 PCT/IB2013/053794 IB2013053794W WO2013171643A1 WO 2013171643 A1 WO2013171643 A1 WO 2013171643A1 IB 2013053794 W IB2013053794 W IB 2013053794W WO 2013171643 A1 WO2013171643 A1 WO 2013171643A1
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WO
WIPO (PCT)
Prior art keywords
formula
irbesartan
compound
reaction mixture
cyano
Prior art date
Application number
PCT/IB2013/053794
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English (en)
Inventor
Shashikant KADAM
Akbar Ali SHEIKH
Ashili SRINIVAS
Dadasaheb CHAVAN
Original Assignee
Piramal Enterprises Limited
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 Piramal Enterprises Limited filed Critical Piramal Enterprises Limited
Publication of WO2013171643A1 publication Critical patent/WO2013171643A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to a process for preparing 2-butyl-3-[[2'-(2H-tetrazol5yl[l,l'- biphenyl]-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one (Irbesartan or the compound of formula I).
  • the present invention provides an improved process for the conversion of 4'-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]-[l,l'-biphenyl]-2- carbonitrile ("referred to herein as "cyano Irbesartan” or the compound of formula II) to the compound of formula I (Irbesartan).
  • Irbesartan is a non-peptide angiotensin-II antagonist (blocker).
  • Angiotensin is an important participant in the rennin angiotensin-aldosterone system (RAAS) and has a strong influence on blood pressure.
  • RAAS rennin angiotensin-aldosterone system
  • Irbesartan inhibits the action of angiotensin-II as its receptors and thus prevents the increase in blood pressure produced by the hormone -receptor interactions. It is therefore useful in the treatment of hypertension and complications of heart failure.
  • the compound of formula I (Irbesartan) is disclosed in US Patent No. 5,270,317.
  • This patent also discloses a process for the preparation of tetrazole moiety of the compound of formula I (Irbesartan) comprising cyclization of cyano group using trialkyltin azide in the presence substituted benzenes, such as xylene as a solvent to obtain the reaction mixture.
  • the resulting reaction mixture is then refluxed for 110 hours and then cooled to room temperature.
  • the reaction mixture is then diluted with toluene and extracted with sodium hydroxide solution; the separated aqueous layer is then washed with xylene. Further, the aqueous layer is acidified with concentrated hydrochloric acid to precipitate the product.
  • trialkyltin azide as a reagent for cyclization of cynide compound, handling of such hazardous reagent is difficult on commercial scale.
  • trialkyltin azide is an expensive reagent and therefore, use of the same in manufacturing renders the whole process costly.
  • the process requires long reaction time of 36 hours to 110 hours, which renders the process industrially nonviable.
  • the Indian patent application no. 1426/MUM/2008 discloses a process for the preparation of sartans involving reaction of cyano group with sodium azide in the presence of triethylamine as a catalyst and triethylamine hydrochloride in an organic solvent such as chlorobenzene at a temperature of 60-130°C for 15-18 hours. After completion of the reaction, the reaction mass is cooled to room temperature and quenched with sodium nitrite solution. The pH of the reaction mixture is then adjusted to 3.6 to 3.9 by using aqueous hydrochloric acid to precipitate the solid product. The use of sodium nitrite during workup renders the whole process less safe and less eco friendly.
  • the Indian patent application no. 1615/MUM/2008 discloses a process for the preparation of the compound of formula I (Irbesartan) by reacting the compound of formula II (cyano Irbesartan) with sodium azide in the presence of an organic base and sulphuric acid in n- butanol as a solvent, and the resulting reaction mixture is heated at reflux temperature till the reaction completes. After completion of the reaction, the reaction mass is cooled to room temperature and washed with water. The organic layer is then concentrated under reduced pressure to obtain an oily residue. The traces of the solvent are removed by azeotropic distillation to obtain a solid, which is dissolved in water and the product, the compound of formula I (Irbesartan) is isolated at pH of 4.2 to 7.5.
  • the process for the preparation of Irbesartan generally involves cyclization of the compound of formula II (cyano Irbesartan) using trialkyltin azide or sodium azide in the presence of a base such as triethylamine, triethylamine hydrochloride to yield the compound of formula I (Irbesartan).
  • a base such as triethylamine, triethylamine hydrochloride.
  • the processes hitherto reported in the prior art involve carrying out the reaction at a high temperature and also require long duration of time. Also these processes involve tedious workup procedures as well as separations by column chromatography results in excessive production time, which in turn render the process more costly and less eco-friendly and therefore, such processes are not viable for industrial manufacturing.
  • the inventors of the present invention have now found that the compound of formula I (Irbesartan) can be obtained in good yield and purity from the compound of formula II (cyano Irbesartan) through an improved process involving use of l,8-Diazabicyclo[5.4.0]undec-7- ene (DBU) as a catalyst.
  • DBU l,8-Diazabicyclo[5.4.0]undec-7- ene
  • An object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) from the compound of formula II (cyano Irbesartan), using l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst.
  • DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
  • Another object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) with 98% conversion of the compound of formula II (cyano Irbesartan) to the compound of formula I (Irbesartan).
  • Another object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) by avoiding the use of toxic reagents such as trialkyltin azide and sodium nitrite thereby rendering the process environment friendly.
  • Yet another object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) involving carrying out the reaction at a shorter duration of time.
  • Further object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan), by avoiding any chromatographic purification method for intermediates or final product and providing the compound of formula I (Irbesartan) with good yield and purity > 99.0%.
  • an improved process for the preparation of the compound of formula I comprising the steps of, a. reacting the compound of formula II (cyano Irbesartan) with sodium azide in the presence of l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine hydrochloride in an organic solvent at a temperature of 120-140°C for 15-40 hours and isolating the compound of formula I (Irbesartan) from the resulting reaction mixture;
  • DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
  • step (b) optionally, purifying the compound of formula I (Irbesartan) obtained in step (a) using a polar solvent to yield the pure compound of formula I (Irbesartan).
  • the process for the preparation of the compound of formula I (Irbesartan) from the compound of formula II (cyano Irbesartan) results with 98% conversion with good yield and purity > 99.0%.
  • the present invention relates to an improved process for the preparation of the compound of formula I (Irbesartan).
  • the improved process for the preparation of the compound of formula I involves use of readily available raw materials and reagents.
  • Formula I comprises the steps of, a. reacting the compound of formula II (cyano Irbesartan),
  • the organic solvent used in step (a) of the process is substituted benzene, selected from toluene, xylenes (o-, m- or p-xylene) or chlorobenzene.
  • o-xylene may be used as the organic solvent in step (a) of the process.
  • the organic solvent used in step (a) ranges from 4 to 6 volumes based on the compound of formula II (cyano Irbesartan).
  • the step (a) of the process is carried out at a temperature of 120 -140°C.
  • the step (a) of the process may be carried out at a temperature of 125-130°C.
  • the step (a) of the process is carried out over a time period of 15-40 hours.
  • the step (a) of the process may be carried out over a time period of 20-30 hours.
  • the sodium azide used in the step (a) ranges from 2.5 to 4 molar equivalents based on the compound of formula II (cyano Irbesartan).
  • the sodium azide may be used in an amount ranging from 3 to 3.5 molar equivalent based on the compound of formula II (cyano Irbesartan).
  • the triethyl amine hydrochloride used in the step (a) ranges from 2.5 to 4 molar equivalents based on the compound of formula II (cyano Irbesartan).
  • the triethyl amine hydrochloride may be used in an amount ranging from 3 to 3.5 molar equivalents based on the compound of formula II (cyano Irbesartan).
  • 1,8-Diazabicyclo [5.4.0]undec- 7-ene (DBU) used in the step (a) ranges from 0.15-0.5 molar equivalents based on the compound of formula II (cyano Irbesartan).
  • l,8-Diazabicyclo[5.4.0]undec-7-ene may be used in an amount ranging from 0.2 to 0.3 molar equivalents based on the compound of formula II (cyano Irbesartan).
  • the crude compound of formula I (Irbesartan), obtained in the step (a) is isolated from the reaction mixture using sodium hydroxide (NaOH) at a temperature of 25-30°C.
  • isolation of the compound of formula I (Irbesartan) from the reaction mixture of the step (a) described above comprises the steps of:
  • step (i) charging sodium hydroxide solution to the reaction mixture obtained in step (a) at a temperature of 25-30°C,
  • the pH of the reaction mixture adjusted in the step (iii) is to 2.0 to 4.5.
  • the compound of formula I (Irbesartan) obtained in the step (a) of the present invention is of pharmaceutically acceptable purity; however, optionally the compound of formula I (Irbesartan) may be further purified to yield the pure compound of formula I (Irbesartan).
  • the purification of the compound of formula I (Irbesartan) carried out using a polar solvent selected from methanol, ethanol, n-propyl alcohol or isopropyl alcohol.
  • the purification of the compound of formula I (Irbesartan) is preferably carried out using isopropyl alcohol.
  • the starting material of the process i.e. the compound of formula II (cyano Irbesartan) is a known compound and can be prepared by a person skilled in the art by following methods described in the literature.
  • process described in US 5270317 can be used for the preparation of the compound of formula II.
  • the said compound of formula II (cyano Irbesartan) can be prepared by the condensation of a 2-n-butyl-l,3-diazaspiro-[4,4]non-en-4- one hydrochloride with a halomethyl-cyanobiphenyl using a phase transfer catalyst such as tetrabutyl ammonium bromide and a base in an organic solvent such as dichromethane.
  • the reaction mixture was stirred for 1-2 hours at a room temperature followed by addition of water; separated organic layer was distilled completely to obtain the crude compound of formula II (cyano Irbesartan).
  • the crude compound of formula II (cyano Irbesartan) was optionally crystallized to obtain the pure compound of formula II (cyano Irbesartan).
  • the process for the preparation of the compound of formula I involves charging of the compound of formula II (cyano Irbesartan), sodium azide, triethylamine hydrochloride, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and substituted benzene such as o-xylene as a solvent to the reaction flask and the reaction mixture heated to a temperature of 120-140°C for 15 to 40 hours. To the reaction mixture then water and 30% sodium hydroxide solution were charged at a room temperature. The two layers formed were separated and ethyl acetate was added to the aqueous layer.
  • DBU diethylamine hydrochloride
  • substituted benzene such as o-xylene
  • the pH of the reaction mixture was then adjusted to 2.0-4.5 with aqueous hydrochloric acid to precipitate the solid.
  • the resulting solid was filtered, and washed with water and then with ethyl acetate.
  • the solid was dried under vacuum at 60-65 °C to produce the compound of formula I (Irbesartan).
  • the product, the compound of formula I (Irbesartan) optionally crystallized using aqueous isopropyl alcohol (IPA) to yield the pure compound of formula I (Irbesartan).
  • the inventors of the present invention have observed that the process for the preparation of the compound of formula I (Irbesartan) when carried out in the presence of 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst, it promotes the reaction in which more basic, bulkier base catalyst such as triethylamine (TEA) and N,N-Diisopropylethylamine (DIPEA) have not been found to be effective.
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • the process for the preparation of the compound of formula I (Irbesartan) involving use of l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst results in a product which is off white to white in color and thus, avoids the further charcolisation and subsequent yield loss.
  • the process according to the present invention does not involve any chromatographic purification for final product i.e. the compound of formula I (Irbesartan) thereby avoiding any loss resulting in the final product in higher yield.
  • Example- 1 a) Preparation of 2-butyl-3-[[2'-(2H-tetrazol5yl[l,l'-biphenyl]-4-yl]methyl]-l,3- diazaspiro[4.4]non-l-en-4-one (Irbesartan)
  • the reaction mixture was cooled to room temperature and water (30ml) and 30% sodium hydroxide solution (10ml) were added to the reaction mixture. The two layers formed were separated. To the aqueous layer was then added ethyl acetate (70 ml) and the pH of the reaction mixture was adjusted to 2.0-4.5 using aqueous hydrochloric acid to precipitate a solid. The precipitated solid was filtered and washed with water (40ml) and then with ethyl acetate (40 ml). The solid was dried under vacuum at a temperature of 60-65°C to yield the compound of formula I (Irbesartan). Yield 95%, HPLC purity 99%.
  • the compound of formula I (Irbesartan) obtained was crystallized using aqueous isopropyl alcohol and dried under vacuum at 60-65 °C to yield pure white the compound of formula I (Irbesartan). Yield 85%, Purity 99.95%.
  • the reaction mixture was cooled to room temperature and water (30ml) and 30% sodium hydroxide solution (10ml) was added to the reaction mixture. The two layers formed were separated. To the aqueous layer was then added ethyl acetate (70 ml) and the pH of the reaction mixture was adjusted to 2.0-4.5 using aqueous hydrochloric acid. The precipitated solid was filtered and washed with water (40ml) and then with ethyl acetate (40 ml). The solid was dried under vacuum at a temperature of 60-65°C to yield the compound of formula I (Irbesartan). Yield 95%, HPLC purity 99%.
  • the crude compound of formula I (Irbesartan) obtained was crystallized using aqueous isopropyl alcohol and dried under vacuum at 60-65°C to yield pure white the compound of formula I (Irbesartan) Yield 85%, Purity 99.95%.

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 2-butyl-3-[[2'-(2H-tétrazol5yl[1,1'-biphényl]-4-yl]méthyl]-1,3-diazaspiro[4.4]non-1-én-4-one, le composé de formule I (irbésartan), comprenant la mise en réaction de 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-én-3-yl)méthyl]-[1,1'-biphényl]-2-carbonitrile, le composé de formule II (cyano-irbésartan), avec de l'azide de sodium, du 1,8-diazabicyclo[5.4.0]undéc-7-ène (DBU) en tant que catalyseur et du chlorhydrate de triéthylamine dans un solvant organique à une température de 120 à 140 °C.
PCT/IB2013/053794 2012-05-14 2013-05-10 Procédé amélioré pour la préparation d'irbésartan WO2013171643A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1457/MUM/2012 2012-05-14
IN1457MU2012 2012-05-14

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WO2013171643A1 true WO2013171643A1 (fr) 2013-11-21

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111551652A (zh) * 2020-06-28 2020-08-18 珠海润都制药股份有限公司 一种厄贝沙坦中溴丁烷的检测方法
CN113866300A (zh) * 2021-09-26 2021-12-31 山东建筑大学 一种药物或其中间体中叠氮化钠的检测方法
US11649226B2 (en) 2017-03-30 2023-05-16 Bristol-Myers Squibb Company Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl- D3)pyridazine-3-carboxamide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080214830A1 (en) * 2005-07-27 2008-09-04 Jubilant Organosys Limited Process for Producing 2-(N-Butyl)-3-[[2'-(Tetrazol-5-Yl)Biphenyl-4-Yl]Methyl]-I,3-Diazaspiro[4,4] Non-1-En-4-One
US20100063299A1 (en) * 2007-03-06 2010-03-11 Udhaya Kumar Process for Preparing Irbesartan
WO2011061996A1 (fr) * 2009-11-17 2011-05-26 田辺三菱製薬株式会社 Procédé de fabrication d'un dérivé de biphényle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080214830A1 (en) * 2005-07-27 2008-09-04 Jubilant Organosys Limited Process for Producing 2-(N-Butyl)-3-[[2'-(Tetrazol-5-Yl)Biphenyl-4-Yl]Methyl]-I,3-Diazaspiro[4,4] Non-1-En-4-One
US20100063299A1 (en) * 2007-03-06 2010-03-11 Udhaya Kumar Process for Preparing Irbesartan
WO2011061996A1 (fr) * 2009-11-17 2011-05-26 田辺三菱製薬株式会社 Procédé de fabrication d'un dérivé de biphényle

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11649226B2 (en) 2017-03-30 2023-05-16 Bristol-Myers Squibb Company Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl- D3)pyridazine-3-carboxamide
CN111551652A (zh) * 2020-06-28 2020-08-18 珠海润都制药股份有限公司 一种厄贝沙坦中溴丁烷的检测方法
CN113866300A (zh) * 2021-09-26 2021-12-31 山东建筑大学 一种药物或其中间体中叠氮化钠的检测方法

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