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 acceptableInfo
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds 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
- C07C217/56—Compounds 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
- C07C217/58—Compounds 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters 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.
Landscapes
- 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)
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)
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)
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 |
-
2009
- 2009-09-18 FR FR0904463A patent/FR2950343B1/fr not_active Expired - Fee Related
-
2010
- 2010-09-16 AR ARP100103374A patent/AR078179A1/es unknown
- 2010-09-17 CA CA2773064A patent/CA2773064C/fr not_active Expired - Fee Related
- 2010-09-17 GE GEAP201012667A patent/GEP20146019B/en unknown
- 2010-09-17 EA EA201200498A patent/EA019380B1/ru not_active IP Right Cessation
- 2010-09-17 MY MYPI2012700035A patent/MY169295A/en unknown
- 2010-09-17 WO PCT/FR2010/000625 patent/WO2011033194A1/fr active Application Filing
- 2010-09-17 US US13/496,326 patent/US20120172589A1/en not_active Abandoned
- 2010-09-17 AU AU2010297176A patent/AU2010297176B2/en not_active Ceased
- 2010-09-17 SG SG2012012316A patent/SG178532A1/en unknown
- 2010-09-17 MX MX2012002818A patent/MX2012002818A/es active IP Right Grant
- 2010-09-17 EP EP10773114A patent/EP2477970A1/fr not_active Withdrawn
- 2010-09-17 BR BR112012005834A patent/BR112012005834A2/pt not_active Application Discontinuation
- 2010-09-17 KR KR1020127009706A patent/KR101416595B1/ko active IP Right Grant
- 2010-09-17 JP JP2012529319A patent/JP2013505225A/ja active Pending
- 2010-09-17 NZ NZ598354A patent/NZ598354A/xx not_active IP Right Cessation
- 2010-09-17 CN CN2010800412745A patent/CN102498102A/zh active Pending
- 2010-09-17 UA UAA201204572A patent/UA106386C2/ru unknown
-
2012
- 2012-02-22 ZA ZA2012/01329A patent/ZA201201329B/en unknown
- 2012-03-12 MA MA34682A patent/MA33580B1/fr unknown
Non-Patent Citations (1)
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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