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WO2007096724A1 - Procédé amélioré de synthèse du bésylate d'amlodipine - Google Patents

Procédé amélioré de synthèse du bésylate d'amlodipine Download PDF

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Publication number
WO2007096724A1
WO2007096724A1 PCT/IB2007/000293 IB2007000293W WO2007096724A1 WO 2007096724 A1 WO2007096724 A1 WO 2007096724A1 IB 2007000293 W IB2007000293 W IB 2007000293W WO 2007096724 A1 WO2007096724 A1 WO 2007096724A1
Authority
WO
WIPO (PCT)
Prior art keywords
amlodipine
process according
preparation
toluene
solvent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2007/000293
Other languages
English (en)
Inventor
Mahender Rao Siripragada
Unni Santhosh
Thirumurugan Kunchithapatham
Chinnam Naidu Kundrappu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and Pharmaceuticals Ltd
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 Orchid Chemicals and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Publication of WO2007096724A1 publication Critical patent/WO2007096724A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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 the preparation of anti- ischemic and anti-hypertensive compound amlodipine.
  • Amlodipine 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl- 5-methoxycarbonyl-6-methyl-l,4-dihydropyridine having formula (I), is a long-term calcium-channel blocker useful for treating cardiovascular diseases such as angina, hypertension etc.
  • Amlodipine and its salt were first reported in EP 89167, which also describes its preparation from the precursor phthalimido derivative. Phthaloyl amlodipine of formula II is stirred in 33% ethanoHc methylamine solution at room temperature. After evaporation of solvent the residue is slurried in industrial methylated spirits and filtered. The filtrate is washed and crystallized with industrial methylated spirits to obtain amlodipine base.
  • US patent 6,784,297 describes a process for the preparation of amlodipine from phthaloyl amlodipine of formula II. Phthaloyl amlodipine purified in acetone and water is hydrolyzed with monomethylamine in the presence of protic solvent such as ethanol, denatured spirit, methanol, isopropyl alcohol, chloroform or dioxane preferably denatured spirit at room temperature for 8 hours. This process involves an additional step of purification, which increases the manufacturing cost.
  • protic solvent such as ethanol, denatured spirit, methanol, isopropyl alcohol, chloroform or dioxane preferably denatured spirit at room temperature for 8 hours.
  • WO 2005/023769 describes a one pot process for the preparation of Amlodipine salts from the phthaloyl amlodipine of formula II by a process involving deprotection of the phthalimido group and converting the free base thus obtained to the desired salt without isolating the Amlodipine free base.
  • Phthaloyl amlodipine is treated with aqueous solution of methylamine in a water immiscible solvent such as methylene dichloride, ethylene dichloride, chloroform, ethyl acetate, toluene, or is treated with alcoholic solution of methylamine at room temperature.
  • DE 20201878 describes the process of preparation of Amlodipine by hydrolyzing Phthaloyl amlodipine of formula II using 40% aq. methylamine. This process uses toluene for the extraction of Amlodipine base.
  • the object of the present invention is to provide an improved process for the preparation of Amlodipine free base of formula (I), which is easy to handle at industrial scale.
  • Another objective of the present invention is to provide a process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts in good yield and high purity.
  • the present invention provides a process for the preparation of Amlodipine, which comprises hydrolyzing phthaloyl amlodipine using monomethylamine gas in an organic solvent.
  • the process can be represented schematically as below.
  • the present invention provides a process by which amlodipine is prepared from phthaloyl amlodipine using monomethylamine gas and an organic solvent.
  • the organic solvent is selected from the group consisting of aromatic hydrocarbon and alcoholic solvent.
  • the aromatic hydrocarbon solvent may be selected from the group consisting of toluene, xylene, benzene and the like.
  • the alcoholic solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA) and the like.
  • the hydrolysis of the phthaloyl amlodipine with monomethylamine gas is carried out in presence of toluene or isopropyl alcohol preferably toluene.
  • the hydrolysis is carried out at a temperature in the range of room temperature to reflux temperature preferably in the range of 40 to 70° C.
  • Phthaloyl amlodipine which is the starting material for this invention is prepared according to the known processes in the prior art.
  • Amlodipine free base (100 g) was dissolved in IPA (600 mL) upon heating at 55-60 0 C. The temperature was slowly reduced to 45 0 C. Activated charcoal (5 g) was added and was stirred for 30 minutes at 55-60 0 C. The hot solution obtained was filtered through hyflo bed. Benzene sulfonic acid (40.6 g) in IPA (200 mL) was added slowly (30-45 min) to the above solution at 45-50 0 C. and was stirred for 2 hrs. The reaction mixture was cooled to 25 0 C and stirred for 1 h. The solid obtained was filtered and the residue was washed using IPA (400 mL). The product obtained was further purified by recrystallisation from IPA: methanol (1 :7) to get 85-95 g of amlodipine besylate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un procédé de synthèse de l'amlodipine qui consiste à faire barboter de la méthylamine gazeuse sous agitation dans de l'amlodipine de phtaloyle en présence d'un solvant organique sélectionné au sein du groupe constitué par le toluène et l'isopropanol.
PCT/IB2007/000293 2006-02-21 2007-02-08 Procédé amélioré de synthèse du bésylate d'amlodipine Ceased WO2007096724A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN278/CHE/2006 2006-02-21
IN278CH2006 2006-02-21

Publications (1)

Publication Number Publication Date
WO2007096724A1 true WO2007096724A1 (fr) 2007-08-30

Family

ID=38436989

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/000293 Ceased WO2007096724A1 (fr) 2006-02-21 2007-02-08 Procédé amélioré de synthèse du bésylate d'amlodipine

Country Status (1)

Country Link
WO (1) WO2007096724A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117876A1 (fr) * 2010-03-26 2011-09-29 Fdc Limited Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci
CN102659673A (zh) * 2012-05-07 2012-09-12 山东新华制药股份有限公司 氨氯地平自由碱的制备方法
CN102993083A (zh) * 2012-12-21 2013-03-27 王学军 一种苯磺酸氨氯地平的制备方法
CN108640868A (zh) * 2018-04-26 2018-10-12 山东新华制药股份有限公司 一种苯磺酸氨氯地平的精制方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2385268A (en) * 2000-12-29 2003-08-20 Bioorg Bv Amlodipine free base
WO2006003672A1 (fr) * 2004-07-02 2006-01-12 Matrix Laboratories Ltd Procede de preparation d'amlodipine pure

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2385268A (en) * 2000-12-29 2003-08-20 Bioorg Bv Amlodipine free base
WO2006003672A1 (fr) * 2004-07-02 2006-01-12 Matrix Laboratories Ltd Procede de preparation d'amlodipine pure

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117876A1 (fr) * 2010-03-26 2011-09-29 Fdc Limited Procédé amélioré pour la préparation de base libre d'amlodipine et des sels d'addition d'acide de celle-ci
CN102659673A (zh) * 2012-05-07 2012-09-12 山东新华制药股份有限公司 氨氯地平自由碱的制备方法
CN102993083A (zh) * 2012-12-21 2013-03-27 王学军 一种苯磺酸氨氯地平的制备方法
CN108640868A (zh) * 2018-04-26 2018-10-12 山东新华制药股份有限公司 一种苯磺酸氨氯地平的精制方法

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