WO2007069271A2 - Procede de purification d'une (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine - Google Patents

Procede de purification d'une (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine Download PDF

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WO2007069271A2
WO2007069271A2 PCT/IN2006/000426 IN2006000426W WO2007069271A2 WO 2007069271 A2 WO2007069271 A2 WO 2007069271A2 IN 2006000426 W IN2006000426 W IN 2006000426W WO 2007069271 A2 WO2007069271 A2 WO 2007069271A2
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carboxy
tetrazol
amine
methyl
ylmethyl
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PCT/IN2006/000426
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English (en)
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WO2007069271A3 (fr
Inventor
Pandurang Balwant Deshpande
Parven Kumar Luthra
Anand Kumar Pandey
Kamlesh Sanmukhbhai Soni
Ravindra Charudatta Ghotikar
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Alembic Limited
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Publication of WO2007069271A2 publication Critical patent/WO2007069271A2/fr
Publication of WO2007069271A3 publication Critical patent/WO2007069271A3/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

Definitions

  • the present invention relates to process for purification of (S)-N-(I -Carboxy-2-methyl- prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biplienyl-4-ylmethyl]-amine. Moreover it provides process for preparation of amorphous form of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4 ⁇ ylmethyl]-amine.
  • Present invention also provides process for preparation of various salts of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine. It also provides novel salts of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine.
  • Valsartan belongs to group of angiotensin II antagonists which are useful in the treatment of hypertension, anxiety, glaucoma and cardiac attacks. Valsartan is an orally active specific angiotensin II antagonist acting on the ATI receptor subtype. It is useful in regulating high blood pressure and cardiac insufficiency.
  • Valsartan is first disclosed in US Patent No. 5,399,578 which also discusses its process for preparation. The final product is recrystallized from ethyl acetate. Another example in same patent recites recrystallization from diisopropyl ether. However these processes for purification do not give Valsartan with high purity. Journal of Labelled Compounds and Radiopharmaceuticals 2000, 43, 1245-1252 reports recrystallization of Valsartan a (1:1) mixture of ethyl acetate-hexane. However, it does not provide any enabling disclosure with respect to the crystallization i.e. crystallization by precipitation or slurrying or any the process. Moreover it also remains silent about the resultant form of Valsartan.
  • the primary object of the present invention is to provide an improved process for the purification of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine.
  • Another object of the present invention is to provide process for preparing amorphous (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4- ylmethyl]-amine.
  • Yet another object of the present invention is to provide novel salts of (S)-N-(l-Carboxy- 2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • present invention provides process for purification of (S)-N-(I -Carboxy-2- methyl- ⁇ rop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine which results in high purity of product as well as overall increase in the yield.
  • Another aspect of the present invention provides process for preparation of amorphous form of (S)-N-(I -Carboxy-2-methyl-pro ⁇ - 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5-yl) biphenyl-4-ylmethy 1] -amine .
  • Yet another aspect of the present invention provides process for preparing salts of (S)-N- ( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl)biphenyl-4- ylmethyl]-amine.
  • step (c) treating the salt obtained in step (b) with acid to obtain pure (S)-N-(l-Carboxy- 2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]- amine
  • mixing refers to create or form by combining ingredients or to combine or blend into one mass or mixture.
  • treating refers to simple dictionary meaning: "To subject to a process, action, or change, especially to a chemical or physical process or application”.
  • high purity refers to Valsartan having D-isomer in an amount less than about 0.25%
  • the alkali and alkaline earth metal carbonate, bicarbonate or hydroxide is selected from group comprising of sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, barium carbonate, lithium carbonate, cesium carbonate, strontium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, barium bicarbonate, lithium bicarbonate, cesium bicarbonate, strontium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, lithium hydroxide, cesium hydroxide, strontium hydroxide and like, preferably calcium hydroxide, cesium carbonate, lithium hydroxide and strontium hydroxide .
  • Suitable solvent can be selected from group comprising of water, C 3-6 ketone, C 1-6 alkanol, C 1-6 nitrile, C 1-6 esters or mixtures thereof, preferably water, acetone, ethanol, acetonitrile, ethyl acetate or mixtures thereof.
  • Acid can be mineral acid selected from group comprising of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and like.
  • Salts of (S)-N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine can be prepared by mixing (S)-N-(I -Carboxy-2 -methyl - prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with suitable alkali and alkaline earth metal carbonate, bicarbonate or hydroxide to obtain solid mass.
  • This mixture is dissolved in suitable solvent at about ambient temperature to about reflux temperature of the solvent. After complete dissolution the reaction mixture is stirred for about 1 hour to about 10 hours. Further it is cooled to about 0°C to about 25°C to obtain the desired salt.
  • the desired salt can be isolated by conventional methods like filtration or centrifugation and dried.
  • the salt is further treated with acid in the presence of solvent preferably water, ethyl acetate, methylenedichloride or like and mixtures thereof.
  • solvent preferably water, ethyl acetate, methylenedichloride or like and mixtures thereof.
  • Another aspect of the present invention is to provide a process for the preparation of amorphous form of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl] -amine comprising steps of;
  • Another aspect of the present invention is to provide a process for the preparation of amorphous form of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine comprising steps of; (a) preparing a slurry of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N- [2'-
  • Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4- ylmethyl] -amine The slurry is prepared by stirring, suspending or contacting (S)-N-(I -Carboxy-2-methyl- prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in a suitable organic solvent, preferably ethyl acetate and a solvent selected from group comprising of alkanes or ether.
  • a suitable organic solvent preferably ethyl acetate and a solvent selected from group comprising of alkanes or ether.
  • alkanes and ether solvents include but are not limited to n-pentane, n- heptane, hexane, diisopropyl ether and like.
  • the stirring is preferably carried out at ambient temperature.
  • the amorphous form thus obtained can be isolated by conventional methods such as centrifugation or filtration and dried.
  • Another aspect of the present invention is to provide a process for the preparation of salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl- 4-ylmethyl] -amine comprising steps of,
  • Another aspect of the present invention is to provide cesium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • the crystalline cesium salt of (S)-N-(l-Carboxy-2-methyl-prop ⁇ l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD peaks at 9.7, 21.6, 24.3, 27.9, 29.2 ⁇ 0.2°-2 ⁇ .
  • cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine can be prepared by mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine with cesium carbonate and dissolving this solid mass in acetone.
  • reaction mixture is stirred at about ambient temperature for about 1 to 10 hours and then cooled to obtain cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • Another aspect of the present invention is to provide lithium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • Lithium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine is substantially amorphous. It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 3.
  • Lithium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N- ⁇ entanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine can be prepared by process comprising steps of;
  • lithium salt of (S)-N-(I -Carboxy-2 -methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine can be prepared by mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine with lithium hydroxide and dissolving this solid mass in mixture of ethanol-water.
  • reaction mixture is stirred at about ambient temperature for about 1 to 10 hours and then cooled to obtain lithium salt of (S)-N-(I- Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]- amine.
  • Another aspect of the present invention is to provide strontium salt of (S)-N-(I -Carboxy- 2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • the crystalline strontium salt of (S)-N-(I -Carboxy-2 -methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD peaks at 6.2, 8.4, 9.2, 9.8, 19.6, 20.5 ⁇ 0.2°-2 ⁇ . It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 4.
  • Strontium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol- 5-yl)biphenyl-4-ylmethyl]-amine can be prepared by process comprising steps of; (a) mixing (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with carbonate, bicarbonate or hydroxide salt of strontium to form a reaction mass
  • strontium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine can be prepared by mixing (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine with strontium hydroxide and dissolving this solid mass in mixture of water-acetonitrile.
  • reaction mixture is stirred at about 50-55°C for about 1 to 10 hours and then cooled to obtain strontium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • Another aspect of the present invention is to provide calcium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • the crystalline calcium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD peaks at 5.6, 11.1, 12.7, 15.2, 19.6, 20.6 ⁇ 0.2°-2 ⁇ . It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 5.
  • calcium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine can be prepared by mixing (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine with calcium hydroxide and dissolving this solid mass in mixture of acetone-water.
  • reaction mixture is stirred at about reflux temperature for about 1 to 10 hours and then cooled to obtain calcium salt of (S)-N-(I- Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]- amine.
  • Valsartan prepared in accordance with processes know in prior art contained D-isomer as impurity in amount greater than about 1.5% by HPLC method.
  • the inventors of the present invention have accidentally found that it is possible to obtain Valsartan substantially free from D-isomer by carrying out process of purification comprising steps of; (a) preparing a slurry of (S)-N-(I -Carboxy-2 -methyl-prop- 1 -yl)-N-pentanoyl -N-
  • step (b) stirring the slurry obtained in step (a) to obtain (S)-N-(I -Carboxy-2 -methyl- prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine substantially free from D-isomer
  • the slurry is prepared by stirring, suspending or contacting (S)-N-(I -Carboxy-2-methyl- prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in ethyl acetate and diisopropyl ether.
  • substantially free refers to (S)- N-(l-Carboxy-2-methyl-prop-l-yl)-N- ⁇ entanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4- ylmethyl] -amine containing impurity of D-isomer in amount less than about 0.25% preferably by HPLC method.
  • Another aspect of the present invention is to provide a process for the preparation of amorphous form of (S)-N-(I -Carboxy-2 -methyl-prop- l-yl)-N-pentanoyl-N- [2'-(I H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine substantially free from D-isomer comprising steps of; (a) preparing a slurry of (S)-N-(I -Carboxy-2 -methyl-prop- l-yl)-N ⁇ pentanoyl-N-
  • the slurry is prepared by stirring, suspending or contacting (S)-N-(I -Carboxy-2 -methyl - prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in ethyl acetate and diisopropyl ether.
  • FIGURE-I represents PXRD of amorphous form of (S)-N-(I -Carboxy-2-methyl-prop-l- yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • FIGURE-2 represents PXRD of Cesium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N- pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • FIGURE-3 represents PXRD of lithium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N- pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • FIGURE-4 represents PXRD of strontium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)- N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.
  • FIGURE-5 represents PXRD of calcium salt of (S)-N-(I -Carboxy-2-methyl- ⁇ rop-l-yl)- N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé destiné à la purification d'une (S)-N-(1-Carboxy-2-méthyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tétrazol-5-yl)biphényl-4-ylméthyl]-amine.
PCT/IN2006/000426 2005-10-31 2006-10-19 Procede de purification d'une (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine WO2007069271A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7880015B2 (en) 2006-07-03 2011-02-01 Aurobindo Pharma Ltd. Process for the preparation of angiotensin II antagonist
WO2012016969A1 (fr) * 2010-08-03 2012-02-09 Novartis Ag Valsartan hautement cristallin
CN102617497A (zh) * 2012-02-27 2012-08-01 浙江新赛科药业有限公司 一种缬沙坦的精制方法
WO2015124102A1 (fr) * 2014-02-21 2015-08-27 浙江华海药业股份有限公司 Procédé de raffinage de valsartan comportant plus de 10 % d'isomères d

Citations (2)

* 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
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle

Patent Citations (2)

* 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
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7880015B2 (en) 2006-07-03 2011-02-01 Aurobindo Pharma Ltd. Process for the preparation of angiotensin II antagonist
WO2012016969A1 (fr) * 2010-08-03 2012-02-09 Novartis Ag Valsartan hautement cristallin
CN102617497A (zh) * 2012-02-27 2012-08-01 浙江新赛科药业有限公司 一种缬沙坦的精制方法
WO2015124102A1 (fr) * 2014-02-21 2015-08-27 浙江华海药业股份有限公司 Procédé de raffinage de valsartan comportant plus de 10 % d'isomères d
CN105683170A (zh) * 2014-02-21 2016-06-15 浙江华海药业股份有限公司 一种含10％以上d型异构体的缬沙坦的精制方法
US9815801B2 (en) 2014-02-21 2017-11-14 Zhejiang Huahai Pharmaceutical Co., Ltd. Method of refining valsartan comprising more than or equal to 10% D-isomers
CN105683170B (zh) * 2014-02-21 2019-04-26 浙江华海药业股份有限公司 一种含10％以上d型异构体的缬沙坦的精制方法

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