EP2477970A1 - Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable - Google Patents

Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

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Publication number
EP2477970A1
EP2477970A1 EP10773114A EP10773114A EP2477970A1 EP 2477970 A1 EP2477970 A1 EP 2477970A1 EP 10773114 A EP10773114 A EP 10773114A EP 10773114 A EP10773114 A EP 10773114A EP 2477970 A1 EP2477970 A1 EP 2477970A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
viii
alkylation reaction
ivabradine
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.)
Withdrawn
Application number
EP10773114A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jean-Louis Peglion
Pascal Caignard
Jean-Michel Lerestif
Jean-Pierre Lecouve
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.)
Laboratoires Servier SAS
Original Assignee
Laboratoires Servier SAS
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 Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP2477970A1 publication Critical patent/EP2477970A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D223/00Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16Benzazepines; Hydrogenated benzazepines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63Esters of sulfonic acids
    • C07C309/64Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66Methanesulfonates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63Esters of sulfonic acids
    • C07C309/72Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings

Definitions

  • the present invention relates to a process for synthesizing ivabradine of formula (I)
  • Ivabradine as well as its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride, have very interesting pharmacological and therapeutic properties, especially bradycardic properties, which render these compounds useful in the treatment or prevention of different clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in various pathologies including rhythm disorders, especially supraventricular disorders, and in heart failure.
  • the present invention relates to a process for synthesizing ivabradine of formula (I), its addition salts with a pharmaceutically acceptable acid and their hydrates: characterized in that the compound of formula (VIII) is subjected to:
  • X represents a halogen atom, a mesylate group or a tosylate group
  • ivabradine of formula (I) a particular case of the compounds of formula (VII) and the product of the alkylation reaction of the compound of formula (VIII) with the compound of formula (IX), is isolated and purified and can be converted into its addition salts with a pharmaceutically acceptable acid, selected from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulphonic and camphoric, and in their hydrates,
  • a pharmaceutically acceptable acid selected from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane
  • ivabradine of formula (I) is subjected to a catalytic hydrogenation reaction to yield ivabradine of formula (I), which is isolated and purified and then can be converted into its addition salts with a pharmaceutically acceptable acid, chosen from the acids hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic and camphoric, and their hydrates.
  • a pharmaceutically acceptable acid chosen from the acids hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzene
  • the base preferentially used to carry out the alkylation reaction of the compound of formula (VIII) with the compound of formula (IX) is potassium tert-butoxide.
  • solvents that can be used to carry out the alkylation reaction of the compound of formula (VIII) with the compound of formula (IX)
  • the solvent preferentially used to carry out the alkylation reaction of the compound of formula (VIII) with the compound of formula (IX) is dimethylsulfoxide.
  • the compounds of formula (VIIIa), in particular cases of the compounds of formula (VIII) for which X represents a bromine or iodine atom, a mesylate group or a tosylate group, are novel products which are useful as synthesis intermediates in the art. chemical or pharmaceutical industry, especially in the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and their hydrates, and are therefore part of the present invention.
  • Step 1 3-Chloro-N - ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl ⁇ -N-methylpropan-1-amine
  • the organic phase obtained after extraction of the basic aqueous phase with dichloromethane, is washed with distilled water and then dried over MgSO 4 .
  • the residue obtained after concentration under pressure reduced is purified by chromatography on silica (dichloromethane / ethyl acetate: 80/20) and 7.7 g of title product are obtained in the form of crystals.
  • Step n 3- ⁇ 3 - [ ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl]
  • reaction medium After a night of contact at ambient temperature, the reaction medium is poured into distilled water (100 ml) and then the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with distilled water and then dried over MgSO 4 . After concentration under reduced pressure, 6.2 g of title product are obtained in the form of an oil (HPLC purity: 88%) and engaged in the next step.
  • Step 3 3- ⁇ 3 - [ ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl ⁇ (methyl) amino] propyl ⁇ -7 , 8-dimethoxy-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-one
  • the oil obtained after drying of the organic phase over MgSO 4 then concentration under pressure is purified by chromatography on silica (dichloromethane / ethanol / NH 4 OH 28%: 95/5 / 0.5) and 2.6 g of title product. are obtained in the form of an oil.
  • Step 4 3- ⁇ 3 - [ ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl ⁇ (methyl) amino] propyl hydrochloride ⁇ -7,8-dimethoxy-l, 3 5 4.5 out-tetrahydro-2 - r -3-benzazepin-2-one
  • Step 1 3-Chloro-N - ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl ⁇ -N-methylpropan-1-amine
  • the organic phase obtained after extraction of the basic aqueous phase with dichloromethane, is washed with distilled water and then dried over MgSO 4. After concentration under reduced pressure, the title product is obtained with a crude mass yield of 82% and a purity of 56%.
  • the reaction crude still contains 40% of (15) -4,5-dimethoxy-1- (methylaminomethyl) benzocyclobutane.
  • Step 2 3- ⁇ 3 - [ ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl]
  • Step 3 3- ⁇ 3 - [ ⁇ [(7S) -3,4-Dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl ⁇ (methyl) amino] propyl Hydrochloride ⁇ -7,8-dimethoxy-3 5 4,5-tetrahydro-2 / f-3-benzazepin-2- one to a solution of 5 g of crude product obtained in the preceding stage in acetonitrile (15 mL) , a solution of 6N hydrochloric acid in isopropanol is added. After a night of contact at room temperature, the hydrochloride of the title compound did not precipitate and is therefore not isolable. From the crude compound obtained in the preceding stage, it was impossible to obtain the title product following the procedure described in application WO 2008/065681.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP10773114A 2009-09-18 2010-09-17 Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable Withdrawn EP2477970A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0904463A FR2950343B1 (fr) 2009-09-18 2009-09-18 Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
PCT/FR2010/000625 WO2011033194A1 (fr) 2009-09-18 2010-09-17 Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

Publications (1)

Publication Number Publication Date
EP2477970A1 true EP2477970A1 (fr) 2012-07-25

Family

ID=42245545

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10773114A Withdrawn EP2477970A1 (fr) 2009-09-18 2010-09-17 Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

Country Status (20)

Country Link
US (1) US20120172589A1 (pt)
EP (1) EP2477970A1 (pt)
JP (1) JP2013505225A (pt)
KR (1) KR101416595B1 (pt)
CN (1) CN102498102A (pt)
AR (1) AR078179A1 (pt)
AU (1) AU2010297176B2 (pt)
BR (1) BR112012005834A2 (pt)
CA (1) CA2773064C (pt)
EA (1) EA019380B1 (pt)
FR (1) FR2950343B1 (pt)
GE (1) GEP20146019B (pt)
MA (1) MA33580B1 (pt)
MX (1) MX2012002818A (pt)
MY (1) MY169295A (pt)
NZ (1) NZ598354A (pt)
SG (1) SG178532A1 (pt)
UA (1) UA106386C2 (pt)
WO (1) WO2011033194A1 (pt)
ZA (1) ZA201201329B (pt)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2471780E (pt) 2007-05-30 2015-02-24 Ind Swift Lab Ltd Sais oxalato de ivabradina cristalinos e seus polimorfos
US9120755B2 (en) 2011-11-14 2015-09-01 Cadila Healthcare Limited Polymorphic forms of ivabradine hydrochloride
FR2988720B1 (fr) * 2012-03-27 2014-03-14 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
CN102827019B (zh) * 2012-09-12 2014-12-10 江苏宇田生物医药科技有限公司 一组新的苯并环丁烷化合物及其在化学合成中的应用
CN103848789B (zh) * 2012-11-29 2016-05-18 江苏恒瑞医药股份有限公司 一种伊伐布雷定的制备方法
CN104447553B (zh) * 2013-09-22 2017-02-01 广东众生药业股份有限公司 伊伐布雷定及其中间体的制备方法
CN103772281B (zh) * 2013-12-31 2015-10-21 南京正大天晴制药有限公司 伊伐布雷定的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2681862B1 (fr) * 1991-09-27 1993-11-12 Adir Cie Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent.
EP2097383B1 (en) * 2006-11-30 2012-02-08 Cadila Healthcare Limited Process for preparation of ivabradine hydrochloride
PT2471780E (pt) * 2007-05-30 2015-02-24 Ind Swift Lab Ltd Sais oxalato de ivabradina cristalinos e seus polimorfos
FR2956401B1 (fr) * 2010-02-17 2012-02-03 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011033194A1 *

Also Published As

Publication number Publication date
BR112012005834A2 (pt) 2015-09-08
AU2010297176A1 (en) 2012-03-15
JP2013505225A (ja) 2013-02-14
KR101416595B1 (ko) 2014-07-08
MA33580B1 (fr) 2012-09-01
CA2773064C (fr) 2014-09-02
UA106386C2 (ru) 2014-08-26
FR2950343A1 (fr) 2011-03-25
CA2773064A1 (fr) 2011-03-24
NZ598354A (en) 2013-03-28
US20120172589A1 (en) 2012-07-05
WO2011033194A1 (fr) 2011-03-24
ZA201201329B (en) 2013-05-29
CN102498102A (zh) 2012-06-13
EA019380B1 (ru) 2014-03-31
AR078179A1 (es) 2011-10-19
GEP20146019B (en) 2014-01-27
FR2950343B1 (fr) 2011-11-18
MX2012002818A (es) 2012-04-19
EA201200498A1 (ru) 2012-10-30
MY169295A (en) 2019-03-21
SG178532A1 (en) 2012-03-29
KR20120064708A (ko) 2012-06-19
AU2010297176B2 (en) 2013-05-16

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