HRP20160262T1 - Novi postupak za sintezu ivabradina i njegovih farmaceutski prihvatljivih kiselih adicijskih soli - Google Patents
Novi postupak za sintezu ivabradina i njegovih farmaceutski prihvatljivih kiselih adicijskih soli Download PDFInfo
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- HRP20160262T1 HRP20160262T1 HRP20160262TT HRP20160262T HRP20160262T1 HR P20160262 T1 HRP20160262 T1 HR P20160262T1 HR P20160262T T HRP20160262T T HR P20160262TT HR P20160262 T HRP20160262 T HR P20160262T HR P20160262 T1 HRP20160262 T1 HR P20160262T1
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- 238000000034 method Methods 0.000 title claims 16
- 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
- 239000002253 acid Substances 0.000 title claims 2
- 150000003839 salts Chemical class 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims 54
- 230000015572 biosynthetic process Effects 0.000 claims 15
- 238000003786 synthesis reaction Methods 0.000 claims 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 12
- 239000003513 alkali Substances 0.000 claims 11
- 238000005804 alkylation reaction Methods 0.000 claims 10
- 239000003960 organic solvent Substances 0.000 claims 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 9
- 238000010930 lactamization Methods 0.000 claims 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 8
- 238000001308 synthesis method Methods 0.000 claims 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 6
- 230000007062 hydrolysis Effects 0.000 claims 6
- 238000006460 hydrolysis reaction Methods 0.000 claims 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 3
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 230000001476 alcoholic effect Effects 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 239000007822 coupling agent Substances 0.000 claims 3
- 239000002904 solvent Substances 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims 1
- OMMZSDGGKVRGGP-UHFFFAOYSA-N 1-methylsulfonylbenzotriazole Chemical compound C1=CC=C2N(S(=O)(=O)C)N=NC2=C1 OMMZSDGGKVRGGP-UHFFFAOYSA-N 0.000 claims 1
- HUOZQNYBSXLFPF-UHFFFAOYSA-N 2-[2-[2-(3-hydroxypropylamino)ethyl]-4,5-dimethoxyphenyl]acetonitrile Chemical compound COC1=CC(CCNCCCO)=C(CC#N)C=C1OC HUOZQNYBSXLFPF-UHFFFAOYSA-N 0.000 claims 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 1
- -1 Ethyl N-{2-[2-(cyanomethyl)-4,5-dimethoxyphenyl]ethyl}-β-alanine oxalate Chemical compound 0.000 claims 1
- 150000000996 L-ascorbic acids Chemical class 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical class CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 235000010323 ascorbic acid Nutrition 0.000 claims 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims 1
- 229910001863 barium hydroxide Inorganic materials 0.000 claims 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 claims 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 1
- 235000011087 fumaric acid Nutrition 0.000 claims 1
- 150000002238 fumaric acids Chemical class 0.000 claims 1
- 150000002311 glutaric acids Chemical class 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- 150000002689 maleic acids Chemical class 0.000 claims 1
- 150000002691 malonic acids Chemical class 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 235000006408 oxalic acid Nutrition 0.000 claims 1
- 150000002913 oxalic acids Chemical class 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 235000011044 succinic acid Nutrition 0.000 claims 1
- 150000003444 succinic acids Chemical class 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 125000005490 tosylate group Chemical group 0.000 claims 1
Classifications
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
- C07C55/07—Salts thereof
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/22—All rings being cycloaliphatic the ring system containing eight carbon atoms, e.g. pentalene
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (27)
1. Postupak za sintezu ivabradina formule (I):
[image]
naznačen time, da je spoj formule (VI):
[image]
izložen reakciji laktamizacije, u nazočnosti sredstva za spajanje i lužine,
u organskom otapalu,kako bi se dobio ivabradin formule (I), koji se može pretvoriti u adicijske soli istog s farmaceutski prihvatljivom kiselinom odabranom od klorovodične kiseline, bromovodične kiseline, sumporne kiseline, fosforne kiseline, octene kiseline, trifluoroctene kiseline, mliječne kiseline, piruvinske kiseline, malonske kiseline, sukcinske kiseline, glutarne kiseline, fumarne kiseline, vinske kiseline, maleinske kiseline, limunske kiseline, askorbinske kiseline, oksalne kiseline , metansulfonske kiseline, benzensulfonske kiseline i kamforne kiseline te u njihove hidrate.
2. Postupak sinteze u skladu s patentnim zahtjevom 1, naznačen time, da sredstvo za spajanje koje se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) je odabrano od oksalil klorida, tionil klorida, N,N- dicikloheksilkarbodiimida (DCC), 1-etil-3-(3-dimetilaminopropil)karbodiimida (EDCI), N,N-karbonildiimidazola (CDI), 1-propanfosfonske kiseline cikličkog anhidrida (T3P) i 1-(metilsulfonil)-1H-benzotriazola.
3. Postupak sinteze u skladu s patentnim zahtjevom 2, naznačen time, da sredstvo za spajanje koje se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) je tionil klorid.
4. Postupak sinteze u skladu s patentnim zahtjevom 3, naznačen time, da je količina tionil klorida koja se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) između 1 i 5 ekvivalenata, zaključno.
5. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time, da je lužina koja se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) odabrana od trietilamina, diizopropiletilamina i piridina.
6. Postupak sinteze u skladu s patentnim zahtjevom 5, naznačen time, da lužina koja se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) je trietilamin.
7. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 6, naznačen time, da je organsko otapalo koje se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) odabrano od diklorometana, tetrahidrofurana, acetonitrila, acetona i toluena.
8. Postupak sinteze u skladu s patentnim zahtjevom 7, naznačen time, da organsko otapalo koje se koristi za izvođenje reakcije za laktamizaciju spoja formule (VI) je diklorometan.
9. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 8, naznačen time, da je reakcija za laktamizaciju spoja formule (VI) izvedena pri temperaturi između 0°C i 40°C, zaključno.
10. Postupak sinteze u skladu s patentnim zahtjevom 1, naznačen time, da je spoj formule (VI) pripravljen
počevši od spoja formule (VII):
[image]
koji reagira sa spojem formule (VIII):
[image]
pri čemu X predstavlja atom halogena, mezilnu skupinu ili tosilat skupinu, u nazočnosti lužine, u organskom otapalu, kako bi se dobio spoj formule (IX):
[image]
koji je hidroliziran, djelovanjem lužine u smjesi organskog otapala i vode, kako bi se dobio spoj formule (VI):
[image]
11. Postupak sinteze u skladu s patentnim zahtjevom 1, naznačen time, da je spoj formule (VI) pripravljen počevši od spoja formule (X):
[image]
koji reagira s hidrokloridom spoja formule (III):
[image]
u nazočnosti lužine,
u organskom otapalu,
kako bi se dobio spoj formule (IX):
[image]
koji je hidroliziran, djelovanjem lužine u smjesi organskog otapala i vode, kako bi se dobio spoj formule (VI):
[image]
12. Postupak sinteze u skladu ili s patentnim zahtjevom 10 ili s patentnim zahtjevom 11, naznačen time, da je lužina koja se koristi za izvođenje reakcije alkilacije između spoja formule (VII) i spoja formule (VIII) ili reakciji alkilacije između spoja formule (X) i hidroklorida spoja formule (III) odabrana od kalijevog karbonata, natrijevog karbonata, cezijevog karbonata, kalijevog hidrogen karbonata, natrijevog hidrogen karbonata, trietilamina, diizopropiletilamina i piridina.
13. Postupak sinteze u skladu s patentnim zahtjevom 12, naznačen time, da lužina koja se koristi za izvođenje reakcije alkilacije spoja formule (VII) i spoja formule (VIII) ili reakcije alkilacije između spoja formule (X) i hidroklorida spoja formule (III) je trietilamin.
14. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 10 do 13, naznačen time, da organsko otapalo koje se koristi za izvođenje reakcije alkilacije između spoja formule (VII) i spoja formule (VIII) ili reakcije alkilacije između spoja formule (X) i hidroklorida spoja formule (III) je odabrano od acetonitrila, acetona, metil etil ketona (MEK), dimetilformamida (DMF), N-metilpirolidona (NMP) i dimetil sulfoksida (DMSO).
15. Postupak sinteze u skladu s patentnim zahtjevom 14, naznačen time, da organsko otapalo koje se koristi za izvođenje reakcije alkilacije između spoja formule (VII) i spoja formule (VIII) ili reakcije alkilacije između spoja formule (X) i hidroklorida spoja formule (III) je acetonitril.
16. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 10 do 15, naznačen time, da se reakcija alkilacije između spoja formule (VII) i spoja formule (VIII) ili reakcija alkilacije između spoja formule (X) i hidroklorida spoja formule (III) izvodi pri temperaturi između 20°C i 100°C, zaključno.
17. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 10 do 16, naznačen time, da lužina koja se koristi u hidrolizi spoja formule (IX) kako bi se dobio spoj (VI) je odabrana od kalijevog hidroksida, natrijevog hidroksida, litijevog hidroksida i barijevog hidroksida.
18. Postupak sinteze u skladu s patentnim zahtjevom 17, naznačen time, da lužina koja se koristi u hidrolizi spoja formule (IX) kako bi se dobio spoj formule (VI) je natrijev hidroksid.
19. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 10 do 18, naznačen time, da organsko otapalo koje se koristi u izvođenju hidrolize spoja formule (IX) kako bi se dobio spoj formule (VI) je alkoholno otapalo.
20. Postupak sinteze u skladu s patentnim zahtjevom 19, naznačen time, da alkoholno otapalo koje se koristi za izvođenje hidrolize spoja formule (IX) kako bi se dobio spoj formule (VI) je odabrano od metanola, etanola, izopropanola i butanola.
21. Postupak sinteze u skladu s patentnim zahtjevom 20, naznačen time, da alkoholno otapalo koje se koristi za izvođenje hidrolize spoja formule (IX) kako bi se dobio spoj formule (VI) je etanol.
22. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 10 do 21, naznačen time, da se hidroliza spoja formule (IX) kako bi se dobio spoj formule (VI) izvodi pri temperaturi između 0°C i 110°C, zaključno.
23. Spoj, formule (VI):
[image]
24. Spoj formule (IX):
[image]
25. Spoj formule (X):
[image]
26. Etil N-{2-[2-(cijanometil)-4,5-dimetoksifenil]etil}-β-alaninat oksalat.
27. (2-{2-[(3 -hidroksipropil)amino]etil} -4,5-dimetoksifenil)acetonitril.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1252728A FR2988720B1 (fr) | 2012-03-27 | 2012-03-27 | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
EP13161193.1A EP2644597B1 (fr) | 2012-03-27 | 2013-03-26 | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
Publications (1)
Publication Number | Publication Date |
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HRP20160262T1 true HRP20160262T1 (hr) | 2016-04-08 |
Family
ID=47901913
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HRP20160262TT HRP20160262T1 (hr) | 2012-03-27 | 2016-03-14 | Novi postupak za sintezu ivabradina i njegovih farmaceutski prihvatljivih kiselih adicijskih soli |
Country Status (36)
Country | Link |
---|---|
US (1) | US8835627B2 (hr) |
EP (1) | EP2644597B1 (hr) |
JP (1) | JP5580915B2 (hr) |
KR (1) | KR101468398B1 (hr) |
CN (1) | CN103450082B (hr) |
AR (1) | AR090497A1 (hr) |
AU (1) | AU2013201622C1 (hr) |
BR (1) | BR102013007107A2 (hr) |
CA (1) | CA2810060C (hr) |
CL (1) | CL2013000820A1 (hr) |
CY (1) | CY1117356T1 (hr) |
DK (1) | DK2644597T3 (hr) |
EA (1) | EA022774B1 (hr) |
ES (1) | ES2568057T3 (hr) |
FR (1) | FR2988720B1 (hr) |
GE (1) | GEP20156369B (hr) |
HK (1) | HK1189892A1 (hr) |
HR (1) | HRP20160262T1 (hr) |
HU (1) | HUE028715T2 (hr) |
JO (1) | JO3086B1 (hr) |
MA (1) | MA34584B1 (hr) |
MD (1) | MD4468C1 (hr) |
MX (1) | MX2013002990A (hr) |
MY (1) | MY185046A (hr) |
NZ (1) | NZ608253A (hr) |
PE (1) | PE20131318A1 (hr) |
PL (1) | PL2644597T3 (hr) |
PT (1) | PT2644597E (hr) |
RS (1) | RS54652B1 (hr) |
SA (1) | SA113340412B1 (hr) |
SG (1) | SG193735A1 (hr) |
SI (1) | SI2644597T1 (hr) |
TW (1) | TWI457325B (hr) |
UA (1) | UA113396C2 (hr) |
UY (1) | UY34685A (hr) |
WO (1) | WO2013144500A1 (hr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
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US3795683A (en) * | 1970-08-19 | 1974-03-05 | Hoffmann La Roche | 2,3,4,5-tetrahydro-1h-3-benzazepines |
DE2639718A1 (de) * | 1976-09-03 | 1978-03-16 | Thomae Gmbh Dr K | Neue phenylaethylamine |
US4121924A (en) * | 1976-09-16 | 1978-10-24 | The International Nickel Company, Inc. | Alloy for rare earth treatment of molten metals and method |
US4490369A (en) * | 1981-05-19 | 1984-12-25 | Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung | Benzazepine derivatives, their pharmaceutical compositions and method of use |
FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
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 |
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 |
JP5198877B2 (ja) * | 2006-01-31 | 2013-05-15 | 株式会社エーピーアイ コーポレーション | ベンゾアゼピノン類の製造方法 |
ES2381771T3 (es) * | 2006-11-30 | 2012-05-31 | Cadila Healthcare Limited | Procedimiento para la preparación de hidrocloruro de ivabradina |
WO2008132139A2 (en) * | 2007-04-27 | 2008-11-06 | Ucb Pharma S.A. | New heterocyclic derivatives useful for the treatment of cns disorders |
FR2920773B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Derives de 1,2,4,5-tetrahydro-3h-benzazepines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2941695B1 (fr) * | 2009-02-04 | 2011-02-18 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
ME00986B (me) * | 2009-03-31 | 2012-06-20 | Servier Lab | Novi postupak sinteze ivabradina i njegovih adicionih soli sa farmaceutski prihvatljivom kiselinom |
FR2950343B1 (fr) * | 2009-09-18 | 2011-11-18 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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 |
HUP1000245A2 (en) * | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
FR2984320B1 (fr) * | 2011-12-20 | 2013-11-29 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2984319B1 (fr) * | 2011-12-20 | 2013-12-27 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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 |
-
2012
- 2012-03-27 FR FR1252728A patent/FR2988720B1/fr not_active Expired - Fee Related
-
2013
- 2013-03-14 CA CA2810060A patent/CA2810060C/fr not_active Expired - Fee Related
- 2013-03-14 PE PE2013000508A patent/PE20131318A1/es not_active Application Discontinuation
- 2013-03-14 MA MA35740A patent/MA34584B1/fr unknown
- 2013-03-14 NZ NZ608253A patent/NZ608253A/en not_active IP Right Cessation
- 2013-03-15 MX MX2013002990A patent/MX2013002990A/es active IP Right Grant
- 2013-03-18 UY UY0001034685A patent/UY34685A/es not_active Application Discontinuation
- 2013-03-18 AU AU2013201622A patent/AU2013201622C1/en not_active Ceased
- 2013-03-18 SG SG2013019583A patent/SG193735A1/en unknown
- 2013-03-19 MY MYPI2013700443A patent/MY185046A/en unknown
- 2013-03-19 JO JOP/2013/0077A patent/JO3086B1/ar active
- 2013-03-21 TW TW102110111A patent/TWI457325B/zh not_active IP Right Cessation
- 2013-03-24 SA SA113340412A patent/SA113340412B1/ar unknown
- 2013-03-25 US US13/849,798 patent/US8835627B2/en not_active Expired - Fee Related
- 2013-03-25 GE GEAP201313040A patent/GEP20156369B/en unknown
- 2013-03-25 CL CL2013000820A patent/CL2013000820A1/es unknown
- 2013-03-26 KR KR1020130032073A patent/KR101468398B1/ko active IP Right Grant
- 2013-03-26 EA EA201300281A patent/EA022774B1/ru not_active IP Right Cessation
- 2013-03-26 ES ES13161193.1T patent/ES2568057T3/es active Active
- 2013-03-26 RS RS20160188A patent/RS54652B1/en unknown
- 2013-03-26 UA UAA201303751A patent/UA113396C2/uk unknown
- 2013-03-26 SI SI201330161A patent/SI2644597T1/sl unknown
- 2013-03-26 PL PL13161193T patent/PL2644597T3/pl unknown
- 2013-03-26 JP JP2013063204A patent/JP5580915B2/ja active Active
- 2013-03-26 WO PCT/FR2013/050654 patent/WO2013144500A1/fr active Application Filing
- 2013-03-26 HU HUE13161193A patent/HUE028715T2/en unknown
- 2013-03-26 AR ARP130100973A patent/AR090497A1/es unknown
- 2013-03-26 BR BRBR102013007107-2A patent/BR102013007107A2/pt not_active Application Discontinuation
- 2013-03-26 EP EP13161193.1A patent/EP2644597B1/fr active Active
- 2013-03-26 PT PT131611931T patent/PT2644597E/pt unknown
- 2013-03-26 DK DK13161193.1T patent/DK2644597T3/en active
- 2013-03-27 CN CN201310101027.5A patent/CN103450082B/zh not_active Expired - Fee Related
- 2013-03-27 MD MDA20130016A patent/MD4468C1/ro not_active IP Right Cessation
-
2014
- 2014-04-01 HK HK14103115.8A patent/HK1189892A1/zh not_active IP Right Cessation
-
2016
- 2016-03-14 HR HRP20160262TT patent/HRP20160262T1/hr unknown
- 2016-03-22 CY CY20161100243T patent/CY1117356T1/el unknown
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