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WO2008007391A2 - Procédé amélioré de préparation du valsartan - Google Patents

Procédé amélioré de préparation du valsartan Download PDF

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Publication number
WO2008007391A2
WO2008007391A2 PCT/IN2007/000279 IN2007000279W WO2008007391A2 WO 2008007391 A2 WO2008007391 A2 WO 2008007391A2 IN 2007000279 W IN2007000279 W IN 2007000279W WO 2008007391 A2 WO2008007391 A2 WO 2008007391A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
chloride
valsartan
gives
Prior art date
Application number
PCT/IN2007/000279
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English (en)
Other versions
WO2008007391A3 (fr
Inventor
Manne Satyanarayana Reddy
Muppa Kishore Kumar
Karamala Rama Subba Reddy
Original Assignee
Manne Satyanarayana Reddy
Muppa Kishore Kumar
Karamala Rama Subba Reddy
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 Manne Satyanarayana Reddy, Muppa Kishore Kumar, Karamala Rama Subba Reddy filed Critical Manne Satyanarayana Reddy
Publication of WO2008007391A2 publication Critical patent/WO2008007391A2/fr
Publication of WO2008007391A3 publication Critical patent/WO2008007391A3/fr

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Classifications

    • 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

Definitions

  • the present invention relates to an improved process for the preparation of valsartan compound of formula-1, chemically known as N-(l-Oxopentyl)-N-[[2'-(lH- tetrazol-5-yl)[l, 1 '-biphenyl]-4-yl]methyl]-L-valine.
  • This invention also relates to a novel process for the preparation of amorphous form of valsartan compound of formula-1.
  • Valsartan is an orally active specific angiotension II antagonist acting on the
  • Valsartan is prescribed for the treatment of hypertension.
  • Valsartan is marketed as the free acid under the name DIOVAN.
  • DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.
  • angiotension II has strong vasoconstrictor properties, additionally stimulates aldosterone secretion and thus causes distinct sodium/water retention.
  • the consequence of angiotensin II activity is manifested, inter alia, in an increase in blood pressure.
  • the importance of angiotensin II antagonists is in suppressing the vasoconstrictor and aldosterone secretion stimulating effects caused by angiotension II by competitive inhibition of the binding of angiotension II to the receptors.
  • the angiotension II antagonist properties of the compounds of the formula I and their pharmaceutically acceptable salts can be detected in the angiotensin II binding test.
  • the present invention relates to an improved process for the preparation of valsartan compound of formula-1, chemically known as N-(l-Oxopentyl)-N-[[2'-(lH- tetrazol-5-yl)[l , 1 '-biphenyl]-4-yl]methyl]-L-valine.
  • the first aspect of the present invention is to provide an improved process for the preparation of valsartan compound of formula-1 which comprises of the following steps; a) Reacting the compound of formula-2 with a mixture of metal azide and alkyl tin halide in a suitable solvent gives the compound of formula-3, b) Reacting the 5-chlorovaleric acid compound of formula-4 with suitable thiophenol derivative compound in presence of a base in a suitable solvent gives corresponding 5 -phenyl thio valeric acid compound of general formula-5, which upon chlorination in presence of a suitable chlorinating reagent in a suitable solvent gives corresponding acid chloride compound of formula-5 followed by condensation with either the compound of formula-3 or optionally with silyl protected compound of formula-3 a in presence of a base in a suitable solvent gives corresponding compound of general formula-6, c) Desulfurisation of the compound of general formula-6 with a mixture of transition metal halide hydrate and reducing agent in presence of a base in a suitable organic solvent gives the following
  • the second aspect of the present invention is to provide an improved process for the preparation of valsartan compound of formula- 1 through novel imidazole intermediate compounds, which comprises of the following steps, a) Reacting the compound of formula-2 with a mixture of metal azide and alkyl tin halide in a suitable solvent gives the compound of formula-3, b) Reacting the 5-chlorovaleric acid compound of formula-4 with suitable imidazole derivative compound of general formula-7 in presence of a base in a suitable solvent gives corresponding 5-imidazolo valeric acid compound of general formula-S, which upon chlorination in presence of a suitable chlorinating reagent in a suitable solvent gives corresponding acid chloride compound of formula-8 followed by condensation with either the compound of formula-3 or optionally silyl protected compound of formula-3 a in presence of a base in a suitable solvent gives the compound of general formula-9, c) Desulfurisation of the compound of general formula-9 with a mixture of transition metal halide hydrate and reducing agent in presence of a
  • the third aspect of the present invention is to provide a novel process for the preparation of amorphous form of valsartan compound of formula- 1 which comprises of the following steps, a) Dissolving the valsartan compound of formula- 1 in a suitable ester solvent, b) Heating the reaction mixture to reflux, c) Stirring the reaction mixture at reflux temperature for 10-60 minutes, d) Bringing down the temperature of the reaction mixture to about 10-50°C and stirring for 1-5 hours, e) Cooling down the reaction mixture to 0-5 0 C and stirring for 2-3 hours, f) Isolating the product by filtration, g) Drying the compound under reduced pressure at 10-40 0 C for 1-6 hours followed by 30-65 0 C for 1-6 hours and finally at 40-80 0 C for 20-25 hours gives amorphous valsartan.
  • the present invention relates to an improved process for the preparation of valsartan compound of formula-1, chemically known as N-(l-Oxopentyl)-N-[[2'-(lH- tetrazol-5-yl)[l, 1 '-biphenyl]-4-yl]methyl]-L-valine.
  • the first aspect of the present invention is to provide an improved process for the preparation of valsartan compound of formula- 1, which comprises of the following steps; a) Reacting the compound of formula-2
  • Formula-4 with suitable thiophenol derivative in presence of a base like sodium methoxide, potassium tertiary butoxide, sodium hydride, preferably potassium tertiary butoxide in a suitable polar solvent like dimethyl sulfoxide, dimethylformamide, dimethylacetamide, preferably dimethylformamide gives
  • R is H or C 1 -C 4 alkyl or haloalkyl or halogen or aryl which upon chlorination in presence of a suitable chlorinating reagent like thionyl chloride, oxalyl chloride, phosphorous halides preferably oxalyl chloride in a suitable solvent selected from chloro solvents like methylene chloride, carbon tetrachloride, chloroform, preferably methylene chloride and catalytic amount of dimethylformamide gives an acid chloride compound, which upon condensation with compound of formula-3,
  • R is H or C 1 -C 4 alkyl or haloalkyl or halogen or aryl c) Desulfurisation of the compound of general formula-6 with a mixture of transition metal halide hydrate like Nickel chloride hexahydrate and reducing agent like sodium borohydride in presence of a base like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide or activated Raney-Nickel in presence of a base, in a suitable organic solvent selected from alcoholic solvents like methanol, ethanol, preferably methanol gives the compound of formula- 1,
  • Formula- 1 d) Purification of valsartan compound of formula- 1 in a suitable chloro solvent like methylene chloride followed by in a suitable ester solvent like ethyl acetate, propyl acetate, methyl acetate, tertiary butyl acetate, preferably ethyl acetate or in chloro solvent alone or in ester solvent alone or mixture of both chloro and ester solvents gives high pure compound of formula- 1.
  • a suitable chloro solvent like methylene chloride
  • a suitable ester solvent like ethyl acetate, propyl acetate, methyl acetate, tertiary butyl acetate, preferably ethyl acetate or in chloro solvent alone or in ester solvent alone or mixture of both chloro and ester solvents gives high pure compound of formula- 1.
  • the second aspect of the present invention is to provides an improved process for the preparation of valsartan compound of formula- 1 through novel imidazole intermediate compounds,
  • Formula- 1 which comprises of the following steps a) Reacting the compound of formula-2 with a mixture of metal azide like sodium azide and alkyl tin halide like tributyl tin chloride in a suitable solvent selected from non polar solvents like Cyclohexane, n-Hexane, ortho xylene, para xylene, meta xylene, mixture of xylenes, xylene, toluene, n-Heptane, preferably xylene gives the compound of formula-3, b) Reacting the 5-chlorovaleric acid compound of formula-4 with suitable imidazole thiol derivative compound of general formula-7 in presence of a base like sodium methoxide, potassium tertiary butoxide, sodium hydride, preferably potassium tertiary butoxide in a suitable polar solvent like dimethyl sulfoxide, dimethylformamide, dimethylacetamide, preferably dimethylformamide to give corresponding 5-imidazol
  • the third aspect of the present invention is to provide a novel process for the preparation of amorphous form of valsartan compound of formula- 1 which comprises of the following steps; a) Dissolving the valsartan compound of formula- 1 in a suitable ester solvents like ethyl acetate, methyl acetate, propyl acetate, preferably ethyl acetate, b) Heating the solution to reflux temperature, c) Stirred the reaction mixture at reflux temperature for 10-60 minutes, d) Bringing the reaction mixture temperature to about 20-50 0 C and stirring for 1-5 hours, e) Cooling down the reaction mixture temperature to -10 to 5 0 C and stirring for
  • the compound of general formula-5, formula-6, formula-7 arid formul-8 are novel intermediate which are used in the preparation of valsartan.
  • the process of the present invention is simple, environment friendly and suitable over the prior art references.
  • the present invention is schematically represented by the following schemes.
  • a solution of 100 grams of 5-Chlorovaleric acid compound of formula-4, 82.6 ml of thiophenol and 2000 ml of dimethylformamide is slowly added to a suspension of 120 grams of sodium hydride and 700 ml of dimethyl formamide at 25-35°C. Stirred the reaction mixture for 3 hours at 25-35°C. Quenched the reaction mixture with water slowly at a temperature of 25-35°C. Added 2400 ml of 20% sodium hydroxide solution drop wise at 25-35°C. Cooled the reaction mixture to 10-15 0 C. Adjusted pH of the reaction mixture 2.5 with hydrochloric acid. Stirred the reaction mixture at 25-35°C for 90 minutes. Filtered the solid and washed with water.
  • a solution of 50 grams of valsartan compound of formula-1 and 850 ml of methylene chloride is heated to reflux. Stirred the reaction mixture for 45 minutes at reflux temperature. Treated the above obtained solution with carbon. Cooled the reaction mixture to 0-5 0 C and stirred for 2 hours. Filtered the precipitated solid and the semi dried solid was taken in 330 ml of ethyl acetate. Heated to reflux temperature and treated the obtained solution with carbon. Cooled the reaction mixture to 34-36°C and stirred for 2 hours followed by cooled the reaction mixture to 10-15 0 C and stirred the reaction mixture for 60 minutes. Further cooled the reaction to 0-5 0 C. Stirred the reaction mixture for 3 hours at 0-5 0 C.

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

Abstract

L'invention concerne un procédé de préparation amélioré d'un composé de valsartan représenté par la formule (1) au moyen de nouveaux composés intermédiaires. L'invention concerne également un nouveau composé pour préparer une forme amorphe du valsartan.
PCT/IN2007/000279 2006-07-10 2007-07-09 Procédé amélioré de préparation du valsartan WO2008007391A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1204/CHE/2006 2006-07-10
IN1204CH2006 2006-07-10

Publications (2)

Publication Number Publication Date
WO2008007391A2 true WO2008007391A2 (fr) 2008-01-17
WO2008007391A3 WO2008007391A3 (fr) 2010-02-18

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000279 WO2008007391A2 (fr) 2006-07-10 2007-07-09 Procédé amélioré de préparation du valsartan

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WO (1) WO2008007391A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125416A2 (fr) 2008-04-07 2009-10-15 Hetero Research Foundation Procédé de préparation d'un intermédiaire de valsartan
WO2012056294A1 (fr) 2010-10-29 2012-05-03 Jubilant Life Sciences Ltd. Procédé amélioré de préparation de n-pentanoyl-n-[[2'-(1h-tétrazol-5-yl)[1,1'-biphényl]-4-yl]méthyl]-l-valine
CN102702118A (zh) * 2012-06-11 2012-10-03 吉林三善恩科技开发有限公司 一种缬沙坦有机药物共晶及其制备方法
CN104072433A (zh) * 2014-07-16 2014-10-01 南京正大天晴制药有限公司 一种缬沙坦的水解杂质化合物及其制备方法、检测方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094391A2 (fr) * 2003-04-21 2004-11-04 Teva Pharmaceutical Industries Ltd. Procede de preparation du valsartan et de ses intermediaires
WO2005102987A1 (fr) * 2004-04-20 2005-11-03 Inke, S.A. Methode de production d'un compose pharmaceutiquement actif et d'intermediaires de synthese dudit compose
EP1661891A1 (fr) * 2004-11-30 2006-05-31 KRKA, D.D., Novo Mesto Procédé de prépartion de valsartan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094391A2 (fr) * 2003-04-21 2004-11-04 Teva Pharmaceutical Industries Ltd. Procede de preparation du valsartan et de ses intermediaires
WO2005102987A1 (fr) * 2004-04-20 2005-11-03 Inke, S.A. Methode de production d'un compose pharmaceutiquement actif et d'intermediaires de synthese dudit compose
EP1661891A1 (fr) * 2004-11-30 2006-05-31 KRKA, D.D., Novo Mesto Procédé de prépartion de valsartan

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125416A2 (fr) 2008-04-07 2009-10-15 Hetero Research Foundation Procédé de préparation d'un intermédiaire de valsartan
US8492577B2 (en) 2008-04-07 2013-07-23 Hetero Research Foundation Process for preparation of valsartan intermediate
WO2012056294A1 (fr) 2010-10-29 2012-05-03 Jubilant Life Sciences Ltd. Procédé amélioré de préparation de n-pentanoyl-n-[[2'-(1h-tétrazol-5-yl)[1,1'-biphényl]-4-yl]méthyl]-l-valine
CN102702118A (zh) * 2012-06-11 2012-10-03 吉林三善恩科技开发有限公司 一种缬沙坦有机药物共晶及其制备方法
CN102702118B (zh) * 2012-06-11 2014-04-16 吉林三善恩科技开发有限公司 一种缬沙坦有机药物共晶及其制备方法
CN104072433A (zh) * 2014-07-16 2014-10-01 南京正大天晴制药有限公司 一种缬沙坦的水解杂质化合物及其制备方法、检测方法和用途

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WO2008007391A3 (fr) 2010-02-18

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