WO2005051929A1 - Conversion de nitriles aromatiques en tetrazoles - Google Patents

Conversion de nitriles aromatiques en tetrazoles Download PDF

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Publication number
WO2005051929A1
WO2005051929A1 PCT/IB2004/003841 IB2004003841W WO2005051929A1 WO 2005051929 A1 WO2005051929 A1 WO 2005051929A1 IB 2004003841 W IB2004003841 W IB 2004003841W WO 2005051929 A1 WO2005051929 A1 WO 2005051929A1
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WIPO (PCT)
Prior art keywords
formula
chloride
grp
alkyl
salts
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PCT/IB2004/003841
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English (en)
Inventor
Yatendra Kumar
Kintali Venkata Ramana
Mohan Prasad
Asok Nath
Swargam Sathyanarayana
Bakthavathsalan Vijayaraghavan
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Ranbaxy Laboratories Limited
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Publication of WO2005051929A1 publication Critical patent/WO2005051929A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings

Definitions

  • the present invention relates to the conversion of aromatic nitriles into tetrazoles.
  • the tetrazoles thus formed can be pharmacologically useful compounds in treating a variety of ailments.
  • Background of the Invention Compounds belonging to the class of non-peptide angiotensin - II inhibitors such as irbesartan of Formula I (A), candesartan of Formula I (B), losartan of Formula I (C), and valsartan of Formula I (D)
  • angiotensin - II inhibitors are known for inhibiting the action of angiotensin - II on its receptors, prevent the increase in blood pressure produced by hormone-receptor interactions and are hence used in the treatment of cardiovascular complaints such as hypertension and heart failure.
  • a common structural feature in many non-peptide angiotensin - II inhibitors is the presence of an aromatic tetrazolyl moiety.
  • Compounds such as irbesartan, candesartan, losartan, valsartan and the like have a biphenyl tetrazolyl moiety present in their structure.
  • Various known processes provide a tetrazolyl moiety on the aromatic ring.
  • U. S. Patent No. 5,559,233 describes methods for preparing irbesartan and related compounds wherein the conversion of aromatic nitriles into tetrazole is carried out in presence of tributyltin azide in xylene followed by the protection of the tetrazolyl group with trityl chloride to give a trityl-protected aromatic tetrazole which, after deprotection, gives the desired spiro biphenyl derivative.
  • 5,399,578 and 5,196,444 describe similar procedures for the synthesis of some non-peptide angiotensin II inhibitors wherein the use of trimethyltin azide is reported in presence of toluene as a solvent for the conversion of aromatic nitriles into tetrazoles.
  • U.S. Patent No. 5,599,943 also describes a process for the preparation of candesartan and related molecules wherein the conversion of aromatic nitriles to tetrazoles is carried out with (R) 3 SnN 3 (wherein R is Cs-is) in toluene and dimethylformamide. All these processes require trialkyltin azide as a reagent which is not safe to handle and is costly.
  • Grp is a substituent group selected from residues of A, B, C or D
  • R, R a , Rb, R e , Rd, Re, Rf and R g are independently selected from -H, - CN, -NO 2 , -COOH, -COOC 1-4 alkyl, -CONHR', -OR" (R' and R" are independently C 1-4 alkyl, aryl, aralkyl, alkoxyalkyl, or amino alkyl), -OH, C 1- alkyl, C 1-4 alkoxy C 1- alkyl, C 1-4 alkylcarbonyl, halo, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C -8 cycloalkyl attached directly to the ring, C 3-8 heterocycloalkyl, C 1- alkoxy C 1- alkylamino; carboxy C 1-6 alkyl, into
  • FORMULA I wherein Grp is a substituent group selected from residues of Formula A, B, C or D as defined for Formula II, and P is hydrogen or a tetrazolyl protecting group, wherein the process comprises reacting a compound of Formula II with trialkyltin chloride and sodium azide optionally in the presence of a phase transfer catalyst.
  • the trialkyltin chlorides can be selected from tri CM S alkyltin chlorides, for example, trimethyltin chloride, triethyltin chloride, tributyltin chloride or trioctyltin chloride.
  • the optional phase transfer catalyst can be selected from crown ethers, quaternary ammonium salts (such as tetraalkyl ammonium halide or aryl and aralkyl trialkyl ammonium halide, e.g., tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium iodide, benzalkonium chloride, cetyl trimethyl ammonium chloride and benzyl trialkyl ammonium chloride), polyethylene glycols, diglyme and phosphoric acid derivatives.
  • quaternary ammonium salts such as tetraalkyl ammonium halide or aryl and aralkyl trialkyl ammonium halide, e.g., tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetra
  • the reaction can be carried out in the presence of an organic solvent, such as aromatic hydrocarbons (e.g., benzene, toluene, mono, di or tri-substituted benzenes and xylene), non-polar aprotic solvents (e.g., diisopropyl ether, methyl isobutyl ketone, diisobutyl ketone and substituted 2- ⁇ yrrolidones) and high boiling polar aprotic solvents (e.g., dioxane, dimethylformamide, dimethylacetamide and dimethylsulphoxide) and mixtures thereof.
  • aromatic hydrocarbons e.g., benzene, toluene, mono, di or tri-substituted benzenes and xylene
  • non-polar aprotic solvents e.g., diisopropyl ether, methyl isobutyl ketone, diisobutyl ketone and substitute
  • R is n-butyl and R e is a cyclopropyl ring directly attached to the imidazole ring, forming a spiro compound, with trialkyltin chloride and sodium azide to get irbesartan structural isomers, substituted derivatives or salts thereof.
  • R can be hydrogen, for example.
  • R f is 1 -oxo-pentyl and R g is an L-valyl amino acid residue, with trialkyltin chloride and sodium azide to give valsartan structural isomers or substituted derivatives thereof.
  • R can be hydrogen, for example.
  • a first aspect provides efficient processes for the conversion of aromatic nitriles of Formula II,
  • Grp is a substituent group selected from residues comprising A, B, C or D
  • a B C D wherein X, Y and Z are independently C, O, N or S; dotted line represents a single or a double bond; R, Ra, R , Re, Rd, Re, Rf and R g are independently selected from -H, -CN, - NO 2 , -COOH, -COOC ⁇ -4 alkyl, -CONHR', -OR" (R' and R" are independently C 1-4 alkyl, aryl, aralkyl, alkoxyalkyl, or amino alkyl), -OH, C 1-4 alkyl, C 1- alkoxy C 1-4 alkyl, C 1-4 alkylcarbonyl, halo, halo C 1- alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, C 3-8 cycloalkyl attached directly to the ring, C 3-8 heterocycloalkyl, C ⁇ -4 alkoxy C 1-4 alkylamino; carboxy C 1-6 alkyl, into
  • Grp is a substituent group selected from residues comprising Formula A, B, C or D as defined for Formula II, and P is hydrogen or tetrazolyl protecting group, wherein the process comprises reacting compound of Formula II with trialkyltin chloride and sodium azide optionally in presence of a phase transfer catalyst.
  • the point of attachment between the phenyl ring in Formula I or Formula II and Grp can be such that a biphenyl group is formed, with 1,4-disubstituion of the Grp phenyl ring, and 1,2-disubstitution of the Formula I or II phenyl ring.
  • Other isomers are also possible.
  • the conversion of the first aspect can be efficiently carried out in the presence of an organic solvent at a temperature of about 50 to about 250°C for about 10 to about 150 hours. In one of the embodiments, the reaction can be carried out at about 90 to about 130°C for about 20 to about 50 hours.
  • the organic solvent suitable for this conversion can be selected from aromatic hydrocarbons, non-polar aprotic solvents and high boiling polar aprotic solvents and mixtures thereof.
  • An aromatic hydrocarbon can be, for example, benzene, toluene, mono, di or tri-substituted benzenes, xylene and the like.
  • Non-polar aprotic solvent can be, for example, diisopropyl ether, methyl isobutyl ketone, and diisobutyl ketone and substituted 2-pyrrolidones and the like.
  • High boiling polar aprotic solvent can be, for example, dioxane, dimethylformamide, dimethylacetamide, dimethylsulphoxide and the like.
  • Trialkyltin chloride can be tri C 1-18 alkyltin chloride such as trimethyltin chloride, trimethyltin chloride, tributyltin chloride and trioctyltin chloride.
  • the phase transfer catalyst can be selected from crown ethers, quaternary ammonium salts, polyethylene glycols, diglyme and phosphoric acid derivatives.
  • Quaternary ammonium salts can be tetraalkyl ammonium halide or aryl and aralkyl trialkyl ammonium bromide such as tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium iodide, benzalkonium chloride, cetyl trimethyl ammonium chloride and benzyl trialkyl ammonium chloride or mixtures thereof.
  • the reaction mass After completion of the reaction, the reaction mass is cooled to ambient temperature and diluted with water and acetic acid.
  • the product is isolated by adding a non-solvent to the reaction mass and water sufficient to precipitate the product completely.
  • seeding with the product crystals can be also advantageously used wherever applicable.
  • the purification of the tetrazolyl compound can be carried out by treating it with a base in the presence of water and converting it to salt, followed by washing the salt with an organic solvent to remove impurities. The aqueous solution of the salt is then acidified to liberate free tetrazolyl compound.
  • the tetrazolyl compound can be protected with any suitable protecting group and further alterations can be achieved with a protected tetrazole group on the molecule.
  • Suitable protecting groups for tetrazole moiety are conventionally known.in the art and can be selected from, but are not limited to, trityl, monomethoxytrityl, dimethoxytrityl, benzhydryl and acyl.
  • a second aspect provides improved processes for the preparation of irbesartan structural isomers, or substituted derivatives of Formula I (A) or salts thereof
  • a third aspect provides improved processes for the preparation of candesartan structural isomers, or substituted derivatives of Formula I (B) or salts or esters thereof,
  • a fourth aspect provides improved processes for the preparation of losartan structural isomers, or substituted derivatives of Formula I (C) or salts thereof,
  • a fifth aspect relates to improved processes for the preparation of valsartan structural isomers, or substituted derivatives of Formula I (D),
  • Example 1 Preparation of 2-n-butyl-3-rr2'(tetrazol-5-yl biphenyl-4-yllmethyll-l,3- diazaspiro-[4.41non-l-ene-4-one (Irbesartan of Formula I A A mixture of 2-n-butyl-3 - [ [2 ' -cyanobiphenyl-4-yl]methyl] -1,3 -diazaspiro-
  • Step A) Preparation of 2-ethoxy-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyI]- lH-benzimidazole-7-carboxylic acid methyl ester
  • 2-ethoxy- 1 -[[2'-cyano[ 1 , 1 '-biphenyl]-4-yl]methyl]-lH-benzimidazole-7- carboxylic acid methyl ester of Formula IV (310 g) in toluene (2.48 L) added tributyltin chloride (737 g) and sodium azide (146 g) and tetrabutyl ammonium bromide (31 g).
  • the resultant mass was slowly heated to 110°C and maintained for 24 hours at 110-115°C.
  • the reaction was monitored by TLC and after completion of reaction, the reaction mass was cooled to 15°C.
  • the resultant mixture was stirred at 15-20°C for 1 hour to allow separation of the product.
  • Step B) Preparation of 2-ethoxy-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]- lH-benzimidazoIe-7-carboxylic acid (Candesartan of Formula I B)
  • methanol dissolved in methanol (1.17 L)
  • sodium hydroxide solution 93 g in 1.17 L water
  • the reaction mass was heated to reflux at 78-80°C and maintained for 1 hour.
  • methanol was completely removed under vacuum at 40-45°C and to the residue was added ethyl acetate (2.8 L) and water (3.50 L) at room temperature.

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

Abstract

L'invention concerne la conversion de nitriles aromatiques en tétrazoles par traitement du composé cyano avec du chlorure d'étain de trialkyle et de l'azoture de sodium, facultativement en présence d'un catalyseur du transfert de phase. Ce procédé est particulièrement utile pour préparer l'irbesartan, le candesartan, le losartan et le valsartan.
PCT/IB2004/003841 2003-11-28 2004-11-23 Conversion de nitriles aromatiques en tetrazoles WO2005051929A1 (fr)

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IN1495DE2003 2003-11-28
IN1495/DEL/2003 2003-11-28

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007020659A2 (fr) * 2005-08-16 2007-02-22 Matrix Laboratories Ltd Procede de preparation de l'irbesartan forme a
EP1764365A1 (fr) * 2005-09-20 2007-03-21 KRKA, D.D., Novo Mesto Méthode de préparation de dérivés de sartan et des intermédiaires servant à un tel procédé
WO2007054965A2 (fr) * 2005-09-23 2007-05-18 Alembic Limited Procede de preparation de tetrazoles a partir de derives cyano aromatiques
WO2008041957A1 (fr) * 2006-10-03 2008-04-10 Ulkar Kimya Sanayi Ve Ticaret As PROCÉDÉ SERVANT À PRODUIRE UNE FORME CRISTALLINE PURE DE LA 2-n-BUTYL-3-[(2-(1H-TÉTRAZOL-5-YL)(1,1'-BIPHÉNYL)-4-YL)MÉTHYL]-1,3-DIAZASPIRO-[4,4]-NON-1-ÉN-4-ONE
WO2008044244A2 (fr) * 2006-10-10 2008-04-17 Matrix Laboratories Ltd Processus en enceinte unique destiné à la préparation de candesartan
WO2010133909A2 (fr) * 2009-05-20 2010-11-25 Sms Pharmaceuticals Limited Procédés de préparation de tétrazoles substitués en 5
WO2009001375A3 (fr) * 2007-06-27 2011-01-20 Matrix Laboratories Ltd Procédé perfectionné pour préparer du valsartan pur
US8236843B2 (en) 2008-09-02 2012-08-07 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
US8541411B2 (en) 2010-10-06 2013-09-24 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8623928B2 (en) 2009-11-12 2014-01-07 National Research Council Of Canada Polymers of intrinsic microporosity containing tetrazole groups
CN103923069A (zh) * 2014-05-04 2014-07-16 青岛雪洁助剂有限公司 一种坎地沙坦c8的制备方法
WO2015056219A1 (fr) 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Procédé de séchage et de micronisation simultanés de valsartan
US11655220B2 (en) 2020-10-22 2023-05-23 Hetero Labs Limited Process for the preparation of angiotensin II receptor blockers
WO2023116515A1 (fr) * 2021-12-22 2023-06-29 浙江华海药业股份有限公司 Procédé de préparation de losartan de haute pureté

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DUNCIA J V ET AL: "Three synthesis routes to a sterically hindered tetrazole. A new one-step mild conversion of an amide into a tetrazole", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 56, 1991, pages 2395 - 2400, XP002243982, ISSN: 0022-3263 *
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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007020659A3 (fr) * 2005-08-16 2008-07-10 Matrix Lab Ltd Procede de preparation de l'irbesartan forme a
WO2007020659A2 (fr) * 2005-08-16 2007-02-22 Matrix Laboratories Ltd Procede de preparation de l'irbesartan forme a
EP1764365A1 (fr) * 2005-09-20 2007-03-21 KRKA, D.D., Novo Mesto Méthode de préparation de dérivés de sartan et des intermédiaires servant à un tel procédé
WO2007039117A2 (fr) * 2005-09-20 2007-04-12 Krka, D.D., Novo, Mesto Procede pour preparer des derives de sartan, et produits intermediaires pouvant etre utilises pour ce procede
WO2007039117A3 (fr) * 2005-09-20 2007-06-21 Krka D D Novo Mesto Procede pour preparer des derives de sartan, et produits intermediaires pouvant etre utilises pour ce procede
US7868180B2 (en) 2005-09-20 2011-01-11 Krka, D.D. Novo Mesto Process for the preparation of sartan derivatives and intermediates useful in such process
EA014691B1 (ru) * 2005-09-20 2010-12-30 КРКА, д.д., НОВО МЕСТО Способ получения производных сартана и промежуточных соединений, пригодных для этого способа
WO2007054965A2 (fr) * 2005-09-23 2007-05-18 Alembic Limited Procede de preparation de tetrazoles a partir de derives cyano aromatiques
WO2007054965A3 (fr) * 2005-09-23 2007-11-01 Alembic Ltd Procede de preparation de tetrazoles a partir de derives cyano aromatiques
WO2008041957A1 (fr) * 2006-10-03 2008-04-10 Ulkar Kimya Sanayi Ve Ticaret As PROCÉDÉ SERVANT À PRODUIRE UNE FORME CRISTALLINE PURE DE LA 2-n-BUTYL-3-[(2-(1H-TÉTRAZOL-5-YL)(1,1'-BIPHÉNYL)-4-YL)MÉTHYL]-1,3-DIAZASPIRO-[4,4]-NON-1-ÉN-4-ONE
WO2008044244A3 (fr) * 2006-10-10 2008-05-29 Matrix Lab Ltd Processus en enceinte unique destiné à la préparation de candesartan
WO2008044244A2 (fr) * 2006-10-10 2008-04-17 Matrix Laboratories Ltd Processus en enceinte unique destiné à la préparation de candesartan
US8258312B2 (en) 2007-06-27 2012-09-04 Mylan Laboratories Ltd Process for preparing pure valsartan
WO2009001375A3 (fr) * 2007-06-27 2011-01-20 Matrix Laboratories Ltd Procédé perfectionné pour préparer du valsartan pur
US8236843B2 (en) 2008-09-02 2012-08-07 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
WO2010133909A3 (fr) * 2009-05-20 2012-03-29 Sms Pharmaceuticals Limited Procédés de préparation de tétrazoles substitués en 5
WO2010133909A2 (fr) * 2009-05-20 2010-11-25 Sms Pharmaceuticals Limited Procédés de préparation de tétrazoles substitués en 5
US8623928B2 (en) 2009-11-12 2014-01-07 National Research Council Of Canada Polymers of intrinsic microporosity containing tetrazole groups
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8674090B2 (en) 2010-10-06 2014-03-18 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797B2 (en) 2010-10-06 2015-10-13 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8541411B2 (en) 2010-10-06 2013-09-24 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
WO2015056219A1 (fr) 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Procédé de séchage et de micronisation simultanés de valsartan
CN103923069A (zh) * 2014-05-04 2014-07-16 青岛雪洁助剂有限公司 一种坎地沙坦c8的制备方法
US11655220B2 (en) 2020-10-22 2023-05-23 Hetero Labs Limited Process for the preparation of angiotensin II receptor blockers
WO2023116515A1 (fr) * 2021-12-22 2023-06-29 浙江华海药业股份有限公司 Procédé de préparation de losartan de haute pureté

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