WO2011117876A1 - Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci - Google Patents

Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci Download PDF

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Publication number
WO2011117876A1
WO2011117876A1 PCT/IN2010/000296 IN2010000296W WO2011117876A1 WO 2011117876 A1 WO2011117876 A1 WO 2011117876A1 IN 2010000296 W IN2010000296 W IN 2010000296W WO 2011117876 A1 WO2011117876 A1 WO 2011117876A1
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WO
WIPO (PCT)
Prior art keywords
amlodipine
free base
preparation
acid addition
addition salts
Prior art date
Application number
PCT/IN2010/000296
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English (en)
Inventor
Mohan Anand Chandavarkar
Suhas Vasant Sohani
Vijtkumar Gajanan Bhoir
Sameer Narayan Sawant
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Fdc 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.)
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Publication date
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Publication of WO2011117876A1 publication Critical patent/WO2011117876A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to an improved process for preparation of Amlodipine free base and acid addition salts thereof preferably Amlodipine Besilate.
  • Amlodipine free base in the present invention is prepared in good yield by deprotection of Phthaloyl Amlodipine using a total concentration of 25% aqueous monomethyl amine in reaction mixture. Amlodipine free base thus formed is treated with suitable acids in aqueous medium to form corresponding Amlodipine salts.
  • Amlodipine is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina. Like other calcium channel blockers, Amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing total peripheral resistance and hence reducing blood pressure; in angina it increases blood flow to the heart muscle. It also dilates coronary arteries, increasing blood flow to the heart. Its chemical name is (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-l ,4- dihydropyridine-3,5-dicarboxylate. The molecular structure of Amlodipine is represented as follows:
  • Amlodipine is used as a salt with pharmacologically acceptable acids wherein Amlodipine Besilate is used as most preferred salt.
  • US4572909 discloses Amlodipine as Amlodipine maleate in the treatment of ischaemic heart diseases and hypertension.
  • Amlodipine free base is prepared by deprotection of Phthaloyl Amlodipine either by using methylamine in ethanol at room temperature or hydrazine hydrate in ethanol at reflux temperature or potassium hydroxide at room temperature. Methylamine used for the deprotection is 33% ethanolic methyl amine.
  • WO 2002053135 discloses deprotection of Phthaloyl Amlodipine using 40% aqueous methylamine solution at temperature from ambient to 60 °C, and further extraction of resulting aqueous reaction mixture with water immiscible organic solvent like toluene, gives better yield then direct isolation of the free base of Amlodipine, however methylamine used in the reaction is in excess.
  • US 6784297 discloses hydrolysis of Phthaloyl Amlodipine using 40% monomethyl amine in protic solvent at 20 ° to 50° C to form Amlodipine base.
  • Protic solvent includes ethanol, denatured spirit, methanol, isopropanol, chloroform or dioxane.
  • Amlodipine base was treated with benzene sulfonic acid to form Amlodipine Besilate which was purified by dissolving it in an organic solvent at about 30°C and about 70° C and precipitating it by addition of an insoluble solvent preferably isopropyl alcohol.
  • US 5389654 describes a process for preparaing Amlodipine monobenzene sulfonate by reacting Amlodipine with benzene sulfonic acid in methanol at temperature of 20° C to reflux.
  • US 6608206 discloses a process for S (-) Amlodipine salts such as benzenesulphonic acid, oxalic acid, maleic acid, succinic acid and p-toluene sulfonic acid. The reaction is carried out in the presence of an organic solvent at room temperature. The acid to Amlodipine ratio is 1:1 and the water to organic solvent ratio is 5:1 to 8:1.
  • WO 2005023769 discloses a process for the preparation of salts of Amlodipine by the deprotection of Phthaloyl Amlodipine and converting free base thus obtained to a salt without isolating the free base. Phthaloyl Amlodipine is deprotected by using either 40% aq. monomethyl amine in water immisible solvent or 20% methanolic monomethyl amine followed by treatment of the organic phase with suitable organic acid to form Amlodipine salts.
  • WO 2006003672 discloses purification process of Phthaloyl Amlodipine.
  • Phthaloyl Amlodipine is purified by dissolving it in chlorinated solvents like methylene chloride, ethylene chloride, chloroform and tetrachloroethane, followed by removal of insoluble matter. Hydrocarbon was added to the filtrate under stirring at temperature 30° to 50° C, to precipitate Phthaloyl Amlodipine, which is further suspended in ethanolic methylamine at reflux temperature to form Amlodipine base.
  • US20070260065 discloses deprotection of Phthaloyl Amlodipine with 40% aq. methylamine at 30°C to form Amlodipine base which is then treated with benzene sulfonic acid in an organic solvent to give Amlodipine Besilate.
  • US 6518288 disclose process for preparation of Amlodipine hemifumarate and crystalline salts thereof.
  • Amlodipine fumarate was prepared by contacting Amlodipine as free base or its acid addition salts other than fumarate, with fumaric acid or its ammonium salts in a suitable solvent.
  • Preferred solvents used for the reaction includes ethanol, isopropanol, ethyl acetate and toluene.
  • the deprotection of Phthaloyl Amlodipine can be carried in aqueous medium i.e. without use of any organic solvent, using lower concentration/ molar quantity of monomethyl amine, which gives high yield Amlodipine free base in a short period of time compared to that of prior art processes.
  • the present invention also provides a process for preparation of acid addition salts of Amlodipine preferably Amlodipine Besilate, from the Amlodipine free base in aqueous medium, which makes the process environment friendly.
  • the process further involves direct precipitation and isolation of Amlodipine free base as well as Amlodipine Besilate from the reaction medium, while reducing the step of solvent extraction of the products as mentioned in both cases, thus making the process highly cost-effective for industrial scale preparation.
  • the main objective of the present invention is to provide a cost effective process for preparation of Amlodipine free base by deprotecting Phthaloyl Amlodipine in good yield using a total concentration of 25% aqueous monomethyl amine in reaction mixture, and subsequent preparation of Amlodipine Besilate from the free base in aqueous medium.
  • Further objective of the present invention is to provide a process for deprotection of Phthaloyl Amlodipine using lower concentration and molar quantity of monomethyl amine in aqueous medium.
  • the present invention discloses an improved process for preparation of Amlodipine free base and acid addition salts thereof preferably Amlodipine Besilate.
  • Amlodipine free base in the present invention is prepared by deprotection of Phthaloyl Amlodipine using a total concentration of 25% aqueous monomethyl amine in reaction mixture, and Amlodipine free base thus formed is treated with suitable acids in aqueous medium to form corresponding salts, which are then purified by treating with organic solvents.
  • the present invention provides a process for the preparation of Amlodipine free base of Formula 2 by deprotection of Phthaloyl Amlodipine of Formula 1 using aqueous monomethyl amine with a total concentration of 25%,in the reaction mixture and subsequently preparation of Amlodipine acid addition salts of Formula 3 by reacting Amlodipine free base with suitable acids in aqueous medium.
  • R is Benzenesulfonic acid
  • the starting material Phthaloyl Amiodipine of Formula 1 can be produced by general processes known in the art.
  • the process of the present invention comprises deprotection of Phthaloyl Amiodipine using 40% monomethyl amine and further diluting the reaction mixture with water in order to give a final concentration of 25% aqueous monomethyl amine in the reaction mixture, followed by heating the reaction to 40 - 50°C for 4 - 5hrs to form Amiodipine free base. This solution is cooled and the precipitate is filtered under vacuum.
  • the inventiveness of the present invention is attributed to the use of 25% aqueous monomethyl amine in order to precipitate out the amiodipine free base from the reaction mass with good amount of yield and purity.
  • decreasing the total concentration of monomethyl amine not only increases the yield but also avoids the solvent extraction work up.
  • the co-product water soluble phthalimide remains in aqueous phase.
  • the wet mass of Amlodipine free base was then treated with Benzenesulfonic acid (1.1M to 1.2M) in water at room temperature for 4 to 5 hrs.
  • the resulting crude Amlodipine Besilate was then filtered and dried. Crude Amlodipine Besilate was further mixed with 4 volumes of methanol at 50 to 55°C under stirring.
  • the wet Amlodipine Besilate crude was dried at 60-65 °C in hot air oven for 8.0 hr and further cooled to room temperature to obtain dry Amlodipine Besilate crude (50.58 gm) with water content (1.21%).

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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 pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci avec un bon rendement par la déprotection d'amlodipine phtaloyle au moyen d'une concentration totale de 25% de solution aqueuse de monoéthylamine dans le mélange réactionnel et la base libre d'amlodipine ainsi obtenue est traitée avec des acides appropriés dans un milieu aqueux pour obtenir des sels d'amlodipine correspondants.
PCT/IN2010/000296 2010-03-26 2010-05-06 Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci WO2011117876A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN877/MUM/2010 2010-03-26
IN877MU2010 2010-03-26

Publications (1)

Publication Number Publication Date
WO2011117876A1 true WO2011117876A1 (fr) 2011-09-29

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WO (1) WO2011117876A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107445889A (zh) * 2017-08-01 2017-12-08 东瑞（南通）医药科技有限公司 一种一锅法制备苯磺酸氨氯地平
CN108358833A (zh) * 2018-03-15 2018-08-03 上海峰林生物科技有限公司 一种马来酸氨氯地平的合成工艺
CN108456160A (zh) * 2018-03-15 2018-08-28 上海峰林生物科技有限公司 一种苯磺酸氨氯地平的合成工艺

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4572909A (en) 1982-03-11 1986-02-25 Pfizer Inc. 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents
US4879303A (en) 1986-04-04 1989-11-07 Pfizer Inc. Pharmaceutically acceptable salts
US5389654A (en) 1992-11-26 1995-02-14 Lek, Tovarna, Farmacevtskih In Kemicnih . . . 3-ethyl 5-methyl(±)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate
WO2002053135A1 (fr) 2000-12-29 2002-07-11 Pfizer Limited Base libre d'amlodipine
US6518288B2 (en) 2000-12-29 2003-02-11 Synthon Bv Amlodipine fumarate
US6608206B1 (en) 2002-10-30 2003-08-19 Council Of Scientific & Industrial Research Process for making S(-) Amlodipine salts
US20040044218A1 (en) * 2002-09-04 2004-03-04 Purohit Arun Kumar Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
WO2005023769A1 (fr) 2003-09-04 2005-03-17 Cipla Limited Procede pour l'elaboration de sels d'amlodipine
WO2006003672A1 (fr) 2004-07-02 2006-01-12 Matrix Laboratories Ltd Procede de preparation d'amlodipine pure
JP2007015978A (ja) * 2005-07-07 2007-01-25 Sagami Kasei Kogyo Kk アムロジピンベンゼンスルホン酸塩の製造方法
WO2007096724A1 (fr) * 2006-02-21 2007-08-30 Orchid Chemicals & Pharmaceuticals Limited Procédé amélioré de synthèse du bésylate d'amlodipine
US20070260065A1 (en) 2006-05-03 2007-11-08 Vijayabhaskar Bolugoddu Process for preparing amlodipine

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4572909A (en) 1982-03-11 1986-02-25 Pfizer Inc. 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents
US4879303A (en) 1986-04-04 1989-11-07 Pfizer Inc. Pharmaceutically acceptable salts
US5389654A (en) 1992-11-26 1995-02-14 Lek, Tovarna, Farmacevtskih In Kemicnih . . . 3-ethyl 5-methyl(±)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate
WO2002053135A1 (fr) 2000-12-29 2002-07-11 Pfizer Limited Base libre d'amlodipine
US6518288B2 (en) 2000-12-29 2003-02-11 Synthon Bv Amlodipine fumarate
US20040044218A1 (en) * 2002-09-04 2004-03-04 Purohit Arun Kumar Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
US6784297B2 (en) 2002-09-04 2004-08-31 Kopran Limited Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
US6608206B1 (en) 2002-10-30 2003-08-19 Council Of Scientific & Industrial Research Process for making S(-) Amlodipine salts
WO2005023769A1 (fr) 2003-09-04 2005-03-17 Cipla Limited Procede pour l'elaboration de sels d'amlodipine
WO2006003672A1 (fr) 2004-07-02 2006-01-12 Matrix Laboratories Ltd Procede de preparation d'amlodipine pure
JP2007015978A (ja) * 2005-07-07 2007-01-25 Sagami Kasei Kogyo Kk アムロジピンベンゼンスルホン酸塩の製造方法
WO2007096724A1 (fr) * 2006-02-21 2007-08-30 Orchid Chemicals & Pharmaceuticals Limited Procédé amélioré de synthèse du bésylate d'amlodipine
US20070260065A1 (en) 2006-05-03 2007-11-08 Vijayabhaskar Bolugoddu Process for preparing amlodipine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 9, 1986, pages 1696 - 1702

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107445889A (zh) * 2017-08-01 2017-12-08 东瑞（南通）医药科技有限公司 一种一锅法制备苯磺酸氨氯地平
CN108358833A (zh) * 2018-03-15 2018-08-03 上海峰林生物科技有限公司 一种马来酸氨氯地平的合成工艺
CN108456160A (zh) * 2018-03-15 2018-08-28 上海峰林生物科技有限公司 一种苯磺酸氨氯地平的合成工艺

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