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WO2006059332A1 - Intermédiaires de synthèse de la lercanidipine - Google Patents

Intermédiaires de synthèse de la lercanidipine Download PDF

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Publication number
WO2006059332A1
WO2006059332A1 PCT/IL2005/001290 IL2005001290W WO2006059332A1 WO 2006059332 A1 WO2006059332 A1 WO 2006059332A1 IL 2005001290 W IL2005001290 W IL 2005001290W WO 2006059332 A1 WO2006059332 A1 WO 2006059332A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
dimethyl
nitrophenyl
pyridine
dihydro
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/IL2005/001290
Other languages
English (en)
Inventor
Zvulun Tomer
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.)
MOTIVAN Ltd
Original Assignee
MOTIVAN 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 MOTIVAN Ltd filed Critical MOTIVAN Ltd
Priority to EP05812950A priority Critical patent/EP1824824A1/fr
Publication of WO2006059332A1 publication Critical patent/WO2006059332A1/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 invention is directed to novel intermediates for preparing Lercanidipine hydrochloride, to a processes for the manufacture of these intermediates and their use in preparing Lercanidipine.
  • Lercanidipine (methyl 1 , 1 ,N-trimethyl-N-(3 ,3-diphenylpropyl)-2- aminoethyl l,4-dmydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5- dicarboxylate) is a calcium channel blocker of the Dihydropyridine class used mainly in medicines as an antihypertensive medicament in the form of tablets or capsules. It is a highly lipophilic dihydropyridine with long duration of action and high vascular selectivity. Its mechanism of antihypertensive activity is attributed to a direct relaxant effect on vascular smooth muscle, which lowers total peripheral resistance.
  • Lercanidipine has been described along with methods for making it in Israel Patents Nos. 74238 and 118143 and in U.S. Patents Nos. 4,705,797; 5,767,136; 4,968,832 and 5,696,139. Processes for preparing lercanidipine are described in U.S. Pats. Nos. 4,705,797, 4,705,797. US Pat. No.
  • 5,912,351 describes a process for the preparation of lercanidipine hydrochloride by first preparing an intermediate by reacting 1,4-dihydro- 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid with thionyl chloride in dichloromethane and dimethylformamide at a temperature between -4 and +1 0 C. and subsequent esterification of the obtained acid chloride with 2,N-dimethyl-N-(3,3-diphenylpropyl)-l- amino-2-propyl alcohol at a temperature between -10 and 0° C.
  • the invention related to a novel intermediates for the preparation of
  • Lercanidipine HCl (methyl 1 , 1 ,N-trimethyl-N-(3 ,3 -diphenylpropyl)-2-aminoethyl 1 ,4- dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride) which is known by its generic name Lercanidipine HCl, and their use in preparing Lercanidipine HCl.
  • novel intermediates are l-Chloro-2-methyl-2-propyl methyl 1,4- dihydro-2,6-dimethyl-4-(3 -nitrophenyl)- 1 -pyridine-3 ,5-dicarboxylate and 1 -Bromo-2-methyl-2- ⁇ ropyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)-l-pyridine-3,5-dicarboxylate.
  • These intermediates when reacted with N-methyl-3,3-diphenylpropylamine produce Lercanidipine.
  • the method for performing the HPLC was as follows:
  • the buffer pH 4.0 was prepared by dissolving 5.14g potassium di- hydrogen phosphate and 2.4 ml triethylamine in 980 ml water with mixing. The pH of the solution was adjusted to 4.0 with phosphoric acid and distilled water was added to make 1 liter, and the solution was mixed.
  • the filtrate was concentrated to about half of its volume and 3,95 g (0.108 moles) of gaseous HCl. was bubbled into the solution aasO-5°C under nitrogen. After 24 hours the suspension was filtered to give 45 g crude methyl l,l,N-trimethyl-N-(3,3- diphenylpropyl)-2-aminoethyl 1 ,4-dihydro-2,6-dimethyl-4-(3 - nitrophenyl)-pyridine-3 ,5-dicarboxylate hydrochloride (Lercanidipine HCL).
  • the crude Lercanidipine HCl. is recrystallized from absolute ethanol to give pure Lercanidipine HCl. suitable for pharmaceutical purposes. Lercanidipine HCl. obtained thus may be formulated into tablets in a conventional manner.
  • the Lercanidipine HCl can be formulated into a medicine as is known in the art, preferably it is formulated as a tablet.
  • the process of the invention is illustrated by the scheme in Figure 2.

Landscapes

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

Abstract

LA présente invention a pour objet des intermédiaires de synthèse de la Lercarnidipine, incluant le 1-halo-2-méthyl-2-propylméthyl-1,4-dihydro-2,6-diméthyl-4-(3-nitrophényl)-1-pyridine-3,5-dicarboxylate de formule suivante.
PCT/IL2005/001290 2004-12-02 2005-12-01 Intermédiaires de synthèse de la lercanidipine Ceased WO2006059332A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05812950A EP1824824A1 (fr) 2004-12-02 2005-12-01 Intermédiaires de synthèse de la lercanidipine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL16552504A IL165525A0 (en) 2004-12-02 2004-12-02 Intermediates and a process for the manufacturing for antihypertensive dihydropyridine derivative suitable for pharmaceutical compositions
IL165525 2004-12-02

Publications (1)

Publication Number Publication Date
WO2006059332A1 true WO2006059332A1 (fr) 2006-06-08

Family

ID=35945255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2005/001290 Ceased WO2006059332A1 (fr) 2004-12-02 2005-12-01 Intermédiaires de synthèse de la lercanidipine

Country Status (3)

Country Link
EP (1) EP1824824A1 (fr)
IL (1) IL165525A0 (fr)
WO (1) WO2006059332A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007031865A3 (fr) * 2005-09-16 2007-08-30 Glenmark Pharmaceuticals Ltd Forme polymorphique d'hydrochlorure de lercanidipine et son procede de preparation
CN102020602B (zh) * 2009-09-18 2013-12-25 深圳信立泰药业股份有限公司 盐酸乐卡地平晶型及其制备方法和含有该晶型的药物组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4705797A (en) * 1984-02-14 1987-11-10 Recordati S.A., Chemical And Pharmaceutical Company N-(3,3-diphenylpropyl) aminoethyl esters of 1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid, compositions and use
US5912351A (en) * 1995-05-12 1999-06-15 Recordati, S.A. Chemical And Pharmaceutical Company Anhydrous 1,4-Dihydropyridines and salts thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4705797A (en) * 1984-02-14 1987-11-10 Recordati S.A., Chemical And Pharmaceutical Company N-(3,3-diphenylpropyl) aminoethyl esters of 1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid, compositions and use
US5912351A (en) * 1995-05-12 1999-06-15 Recordati, S.A. Chemical And Pharmaceutical Company Anhydrous 1,4-Dihydropyridines and salts thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007031865A3 (fr) * 2005-09-16 2007-08-30 Glenmark Pharmaceuticals Ltd Forme polymorphique d'hydrochlorure de lercanidipine et son procede de preparation
US8097729B2 (en) 2005-09-16 2012-01-17 Glenmark Generics Ltd. Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof
CN102020602B (zh) * 2009-09-18 2013-12-25 深圳信立泰药业股份有限公司 盐酸乐卡地平晶型及其制备方法和含有该晶型的药物组合物

Also Published As

Publication number Publication date
EP1824824A1 (fr) 2007-08-29
IL165525A0 (en) 2006-01-15

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