HRP20150906T1 - Postupak za enzimsku sintezu (7s)-1-(3,4-dimetoksibiciklo [4.2.0]okta-1,3,5-trien-7-il) n-metil metilamina, i uporaba za sintezu ivabradina i njihovih soli - Google Patents
Postupak za enzimsku sintezu (7s)-1-(3,4-dimetoksibiciklo [4.2.0]okta-1,3,5-trien-7-il) n-metil metilamina, i uporaba za sintezu ivabradina i njihovih soli Download PDFInfo
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- HRP20150906T1 HRP20150906T1 HRP20150906TT HRP20150906T HRP20150906T1 HR P20150906 T1 HRP20150906 T1 HR P20150906T1 HR P20150906T T HRP20150906T T HR P20150906TT HR P20150906 T HRP20150906 T HR P20150906T HR P20150906 T1 HRP20150906 T1 HR P20150906T1
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- Prior art keywords
- formula
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- lipase
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- 230000015572 biosynthetic process Effects 0.000 title claims 11
- 238000000034 method Methods 0.000 title claims 11
- 238000003786 synthesis reaction Methods 0.000 title claims 11
- 230000002255 enzymatic effect Effects 0.000 title claims 3
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims 3
- 229960003825 ivabradine Drugs 0.000 title claims 3
- 150000003839 salts Chemical class 0.000 title claims 2
- SAVVFXUMMFHSJC-SECBINFHSA-N 1-[(7s)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]-n-methylmethanamine Chemical compound COC1=C(OC)C=C2[C@@H](CNC)CC2=C1 SAVVFXUMMFHSJC-SECBINFHSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 9
- 108090001060 Lipase Proteins 0.000 claims 8
- 102000004882 Lipase Human genes 0.000 claims 7
- 239000004367 Lipase Substances 0.000 claims 7
- 235000019421 lipase Nutrition 0.000 claims 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 3
- 241000589513 Burkholderia cepacia Species 0.000 claims 3
- 150000001412 amines Chemical class 0.000 claims 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 239000003960 organic solvent Substances 0.000 claims 3
- 238000006268 reductive amination reaction Methods 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 230000010933 acylation Effects 0.000 claims 2
- 238000005917 acylation reaction Methods 0.000 claims 2
- 239000003125 aqueous solvent Substances 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 238000001308 synthesis method Methods 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims 1
- CZLMRJZAHXYRIX-UHFFFAOYSA-N 1,3-dioxepane Chemical group C1CCOCOC1 CZLMRJZAHXYRIX-UHFFFAOYSA-N 0.000 claims 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 102100031375 Endothelial lipase Human genes 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910010082 LiAlH Inorganic materials 0.000 claims 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- 241000589540 Pseudomonas fluorescens Species 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 230000002829 reductive effect Effects 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- 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
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- 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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/18—Carboxylic ester hydrolases (3.1.1)
- C12N9/20—Triglyceride splitting, e.g. by means of lipase
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/008—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving carbamates
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/01—Carboxylic ester hydrolases (3.1.1)
- C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Cardiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Analytical Chemistry (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Claims (11)
1. Postupak sinteze spoja formule (IX):
[image]
gdje R1 predstavlja ravni ili razgranani C1-C6alkil, alil ili benzilnu skupinu, naznačen time, da se postupak dobiva enantioselektivnom enzimskom acilacijom racemičnog amina formule (IV):
[image]
pomoću lipaze (EC 3.1.1.3 u međunarodnoj klasifikaciji enzima), s karbonatom formule R1O-(CO)-OR1, pri čemu je R1 kao što je gore definirano, u količini od 1 do 15 molarnih ekvivalenata u odnosu na amin formule (IV), u organskom ili vodenom otapalu, smjesi organskih otapala ili smjesi organskih i vodenih otapala, u koncentraciji od 5 do 500 g/L spoja formule (IV) po litri otapala ili smjesi otapala, sa E/S omjeru od 10/1 do 1/100, pri temperaturi od 25°C do 40°C.
2. Postupak sinteze u skladu s patentnim zahtjevom 1, naznačen time, da je lipaza odabrana iz lipaze Pseudomonas fluorescens, Pseudomonas cepacia, svinjske gušterače i lipaze PS ’Amano’ SD (Burkholderia cepacia) i IM (imobiliziranu na Dijatomitu - kremenoj zemlji).
3. Postupak sinteze u skladu s patentnim zahtjevom 2, naznačen time, da je lipaza - lipaza Pseudomonas cepacia ili lipaza PS’Amano’ IM.
4. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time, da je E/S odnos od 1/1 do 1/10.
5. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time, da je otapalo odbrano od TBME, THF, 2-MeTHF i 1,4-dioksana, samog ili u smjesi s puferom pH = 7.
6. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time, da je Ri etil, alil ili benzilna skupina.
7. Postupak za sintezu spoja formule (I):
[image]
naznačen time, da se dobiva enzimskom acilacijom racemičnog amina formule (IV) u skladu s bilo kojim od patentnih zahtjeva 1 do 6 kako bi se dobio karbamat formule (IX):
[image]
pri čemu R1 predstavlja ravni ili razgranani C1-C6alkil, alil ili benzilnu skupinu, koja se potom reducira uporabom sredstva za redukciju odabranog iz LiAlH4 i Red-Al kako bi se dobio spoj formule (I).
8. Postupak sinteze u skladu s patentnim zahtjevom 7, naznačen time, da se spoj formule (I) naknadno ili spaja sa spojem formule (X):
[image]
pri čemu X predstavlja atom halogena,
ili, u nazočnosti redukcijskog sredstva, se izlaže reakciji redukcijske aminacije sa spojem formule (XI):
[image]
gdje R2 predstavlja skupinu odabranu od CHO i CHR3R4,
pri čemu R3 i R4 svaki predstavlja ravnu ili razgrananu (C1-C6)alkoksi skupinu ili
tvore, zajedno s atomom ugljika koji ih nosi, 1,3-dioksan, 1,3-dioksolan ili 1,3-dioksepanski prsten, pri čemu se dobiva ivabradin, koji se potom pretvara u adicijsku sol s farmaceutski prihvatljivom kiselinom, u anhidriranom ili hidratnom obliku.
9. Postupak sinteze u skladu s patentnim zahtjevom 8, naznačen time, da je X atom joda.
10. Postupak sinteze u skladu s patentnim zahtjevom 8, naznačen time, da je spoj formule (I) korišten u obliku hidroklorda u reakciji redukcijske aminacije, pri čemu se dobiva ivabradin u obliku hidroklorida.
11. Postupak sinteze u skladu s patentnim zahtjevom 8 ili patentnim zahtjevom 10, naznačen time, da se reakcija redukcijske aminacije sa spojem formule (XI) izvodi u nazočnosti dihidrogena kataliziranog putem paladija na ugljiku.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1256913A FR2993561B1 (fr) | 2012-07-17 | 2012-07-17 | Procede de synthese enzymatique de la (7s)-1-(3,4-dimethoxy bicyclo[4.2.0]octa-1,3,5-triene 7-yl) n-methyl methanamine, et application a la synthese de l'ivabradine et de ses sels |
| EP13176588.5A EP2687506B1 (fr) | 2012-07-17 | 2013-07-16 | Procédé de synthèse enzymatique de la (7S)-1-(3,4-diméthoxy bicyclo[4.2.0]octa-1,3,5-triène 7-yl) N-méthyl méthanamine, et application à la synthèse de l'Ivabradine et de ses sels |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20150906T1 true HRP20150906T1 (hr) | 2015-09-25 |
Family
ID=46826832
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20150906TT HRP20150906T1 (hr) | 2012-07-17 | 2015-08-27 | Postupak za enzimsku sintezu (7s)-1-(3,4-dimetoksibiciklo [4.2.0]okta-1,3,5-trien-7-il) n-metil metilamina, i uporaba za sintezu ivabradina i njihovih soli |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US9045788B2 (hr) |
| EP (1) | EP2687506B1 (hr) |
| JP (1) | JP5822880B2 (hr) |
| KR (1) | KR101495614B1 (hr) |
| CN (1) | CN103540625B (hr) |
| AR (1) | AR091765A1 (hr) |
| AU (1) | AU2013206562B2 (hr) |
| BR (1) | BR102013017550A2 (hr) |
| CA (1) | CA2820192C (hr) |
| CY (1) | CY1116500T1 (hr) |
| DK (1) | DK2687506T3 (hr) |
| EA (1) | EA024637B1 (hr) |
| ES (1) | ES2547897T3 (hr) |
| FR (1) | FR2993561B1 (hr) |
| GE (1) | GEP20156422B (hr) |
| HR (1) | HRP20150906T1 (hr) |
| HU (1) | HUE025113T2 (hr) |
| JO (1) | JO3159B1 (hr) |
| MA (1) | MA34880B1 (hr) |
| MD (1) | MD4375C1 (hr) |
| MX (1) | MX341588B (hr) |
| MY (1) | MY177115A (hr) |
| NZ (1) | NZ612592A (hr) |
| PL (1) | PL2687506T3 (hr) |
| PT (1) | PT2687506E (hr) |
| RS (1) | RS54082B1 (hr) |
| SA (1) | SA113340722B1 (hr) |
| SG (1) | SG196717A1 (hr) |
| SI (1) | SI2687506T1 (hr) |
| TW (1) | TWI485250B (hr) |
| UA (1) | UA113052C2 (hr) |
| UY (1) | UY34900A (hr) |
| WO (1) | WO2014013179A1 (hr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6616934B2 (ja) * | 2014-05-22 | 2019-12-04 | 株式会社 資生堂 | レナリドミドの光学分割方法 |
| EP3101010A1 (en) | 2015-06-03 | 2016-12-07 | Urquima S.A. | New method for the preparation of highly pure ivabradine base and salts thereof |
| CN110656134B (zh) * | 2018-06-29 | 2023-03-28 | 广东东阳光药业有限公司 | 一种单酯的制备方法 |
| CN110483312A (zh) * | 2019-08-27 | 2019-11-22 | 北京阳光诺和药物研究有限公司 | 一种高纯度盐酸伊伐布雷定及其中间体的制备方法 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE52768B1 (en) * | 1981-04-06 | 1988-02-17 | Boots Co Ltd | 1-arylcyclobutylalkylamine compounds useful as therapeutic agents |
| FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
| US5981267A (en) * | 1996-01-24 | 1999-11-09 | The Scripps Research Institute | Enantioselection of amines using homocarbonates with hydrolase |
| CN100412062C (zh) * | 2001-09-12 | 2008-08-20 | 阿诺麦德股份有限公司 | 对映体纯的氨基取代稠合双环的合成 |
| KR100510379B1 (ko) * | 2003-07-31 | 2005-08-25 | 동부아남반도체 주식회사 | 트렌치 소자 분리 형성 방법 |
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2868775B1 (fr) * | 2004-04-13 | 2008-04-11 | Servier Lab | Nouveau procede de synthese de derives de la 1,3,4,5- tetrahydro-2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2870537A1 (fr) * | 2004-05-19 | 2005-11-25 | Servier Lab | Nouveau procede de synthese du (1s)-4,5-dimethoxy-1-(methyl aminomethyl-)-benzocyclobutane et de ses sels d'addition, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2935381B1 (fr) * | 2008-08-29 | 2010-12-17 | Servier Lab | Nouveau procede de resolution des enantiomerees du (3,4-dimethoxy-bicyclo°4.2.0!octa-1,3,5-trien-7-yl)nitrile et application a la synthese de l'ivabradine |
| CN102264689B (zh) * | 2008-12-22 | 2014-12-31 | 新梅斯托克尔卡公司 | 制备伊伐布雷定的方法 |
| HUP1000245A2 (en) * | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
| EP2495237A1 (en) * | 2011-03-04 | 2012-09-05 | Alembic Pharmaceuticals Limited | An improved process for the preparation of highly pure ivabradine hydrochloride |
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2012
- 2012-07-17 FR FR1256913A patent/FR2993561B1/fr not_active Expired - Fee Related
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2013
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