WO2014184501A1 - Procede de synthese du 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable - Google Patents
Procede de synthese du 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable Download PDFInfo
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- WO2014184501A1 WO2014184501A1 PCT/FR2014/051140 FR2014051140W WO2014184501A1 WO 2014184501 A1 WO2014184501 A1 WO 2014184501A1 FR 2014051140 W FR2014051140 W FR 2014051140W WO 2014184501 A1 WO2014184501 A1 WO 2014184501A1
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 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 abstract description 12
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 12
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title abstract description 10
- 239000002253 acid Substances 0.000 title abstract description 7
- HJTHVTHXHHFXMJ-UHFFFAOYSA-N 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile Chemical compound C1=C(OC)C(OC)=CC2=C1C(C#N)C2 HJTHVTHXHHFXMJ-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 150000004677 hydrates Chemical class 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- VTGIVYVOVVQLRL-UHFFFAOYSA-N 1,1-diethoxyethene Chemical compound CCOC(=C)OCC VTGIVYVOVVQLRL-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002524 organometallic group Chemical group 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims 2
- 150000001768 cations Chemical class 0.000 claims 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZYCLQXMMFJREPJ-UHFFFAOYSA-N 1,2-dibromo-4,5-dimethoxybenzene Chemical compound COC1=CC(Br)=C(Br)C=C1OC ZYCLQXMMFJREPJ-UHFFFAOYSA-N 0.000 description 2
- ZDZHWEZKMRRZHH-UHFFFAOYSA-N 3,4-dimethoxy-n-methylbicyclo[4.2.0]octa-1,3,5-trien-7-amine Chemical compound COC1=C(OC)C=C2C(NC)CC2=C1 ZDZHWEZKMRRZHH-UHFFFAOYSA-N 0.000 description 2
- NIBYIBGWKVIFIP-UHFFFAOYSA-N 7,7-diethoxy-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene Chemical compound CCOC1(Cc2cc(OC)c(OC)cc12)OCC NIBYIBGWKVIFIP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 2
- ZDZHWEZKMRRZHH-VIFPVBQESA-N (7s)-3,4-dimethoxy-n-methylbicyclo[4.2.0]octa-1,3,5-trien-7-amine Chemical compound COC1=C(OC)C=C2[C@@H](NC)CC2=C1 ZDZHWEZKMRRZHH-VIFPVBQESA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KADJIKPEXJZLBB-UHFFFAOYSA-N 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-amine;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC2=C1C(N)C2 KADJIKPEXJZLBB-UHFFFAOYSA-N 0.000 description 1
- JDGAPWRQUUOGSO-UHFFFAOYSA-N 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one Chemical compound C1=C(OC)C(OC)=CC2=C1C(=O)C2 JDGAPWRQUUOGSO-UHFFFAOYSA-N 0.000 description 1
- PKRKQYZQPMFUJG-UHFFFAOYSA-N 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile Chemical compound COC1=CC(Br)=C(CCC#N)C=C1OC PKRKQYZQPMFUJG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- -1 3-iodopropyl Chemical group 0.000 description 1
- CPNZASIAJKSBBH-UHFFFAOYSA-N 7,8-dimethoxy-1,3-dihydro-3-benzazepin-2-one Chemical compound C1C(=O)NC=CC2=C1C=C(OC)C(OC)=C2 CPNZASIAJKSBBH-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- JQQMSOPNEBQROS-UHFFFAOYSA-N ethyl n-(3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl)carbamate Chemical compound COC1=C(OC)C=C2C(NC(=O)OCC)CC2=C1 JQQMSOPNEBQROS-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- UJOQFFTUKVPZOJ-UHFFFAOYSA-N hexan-1-ol;potassium Chemical compound [K].CCCCCCO UJOQFFTUKVPZOJ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/06—One of the condensed rings being a six-membered aromatic ring the other ring being four-membered
Definitions
- the present invention relates to a process for the synthesis of 3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-triene-7-carbonitrile of formula (I):
- Ivabradine, as well as its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride possess very interesting pharmacological and therapeutic properties, in particular bradycardia properties, which render these compounds are useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in the various pathologies including rhythm disorders, in particular supraventricular, and in heart failure.
- the preparation and therapeutic use of ivabradine and its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride have been described in European Patent EP 0 534 859.
- the application WO 2011/138 625 describes the preparation of the compound of formula (I) by intramolecular cyclization of 3- (2-bromo-4,5-dimethoxyphenyl) propanenitrile in the presence of lithium diethylamide or lithium diisopropylamide.
- the present invention relates to a process for the synthesis of the compound of formula (I):
- the amount of 1- (isocyanomethylsulfonyl) -4-methylbenzene preferentially used to carry out the conversion of the compound of formula (VII) into a compound of formula (I) is between 2 and 5 equivalents.
- organic bases of alkoxide type such as potassium tert-butanolate, Fe / Y sodium butanolate, potassium efhanolate, sodium ethanolate, potassium methanolate or sodium methanolate.
- the base preferably used for carrying out the conversion of the compound of formula (VII) into a compound of formula (I) is potassium tert-butanolate.
- organic solvents that can be used to carry out the conversion of the compound of formula (VII) into a compound of formula (I)
- the organic solvent used to carry out the conversion of the compound of formula (VII) into a compound of formula (I) may also consist of a mixture of two solvents among the organic solvents mentioned above.
- the solvent preferentially used to carry out the conversion of the compound of formula (VII) into a compound of formula (I) is a mixture of tetrahydrofuran and methanol.
- the conversion of the compound of formula (VII) into a compound of formula (I) is carried out at a temperature preferably of between -20 ° C. and 50 ° C.
- the present invention also relates to a process for synthesizing the compound of formula (I) from the compound of formula (VII), characterized in that said compound of formula (VII) is prepared from the compound of formula (VIII):
- the 1,1-dialkoxyethene preferentially used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX) is 1,1-diethoxyethene.
- the amount of 1,1-diethoxyethene preferentially used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX) is between 0.8 and 5 equivalents.
- organometallic derivatives that can be used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX)
- the organometallic derivative preferentially used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX) is "-butyllithium.
- the amount of -butyllithium preferentially used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX) is between 1 and 3 equivalents.
- organic solvents that can be used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX)
- the solvent preferentially used to carry out the conversion of the compound of formula (VIII) into a compound of formula (IX) is toluene.
- the conversion of the compound of formula (VIII) into a compound of formula (IX) is carried out at a temperature preferably between -20 ° C. and 30 ° C.
- the hydrolysis reaction of the compound of formula (IX) with a compound of formula (VII) may be carried out in an acidic organic acid medium composed of a mixture:
- an organic solvent such as tetrahydrofuran, ethyl acetate, toluene or dichloromethane, and
- an aqueous acid such as hydrochloric acid (IN 12N) in excess.
- the NMR spectra are recorded on a Briiker device at 400 MHz for proton spectra and at 100 MHz for carbon spectra.
- the assembly is as follows: a 50 mL flask equipped with a distillation set (column ⁇ 20 cm, refrigerant -20 cm, distillation thermometer). 20 g of 2-bromo-1,1-difhoxyethane (101.25 mmol) are rapidly added (1 minute) to potassium hexanol / butanolate (102 mmol, 11.4 g) cooled in an ice bath. . It forms a dense white smoke. When the reaction is complete (5-10 minutes), the reaction medium is heated to 120-130 ° C (hotplate reading), and tert-butanol generated during the reaction is distilled at atmospheric pressure.
- NMR 13 C (CDCl 3): 185.8; 155.9; 151.4; 146.2; 138.7; 105.6; 102.3; 56.4; 56.1; 51.0.
- RM 13 C (CDClQ: 151.4, 150.4, 134.2, 129.7, 19.9, 106.9, 106.1, 56.2, 35.5, 22.6.
- Example 4 The amine obtained in Example 4 is reacted with an equimolar amount of (d) camphorsulfonic acid in ethanol. After evaporation of the solvent under vacuum, the salt is recrystallized a first time in ethyl acetate and then in acetonitrile until the target enantiomer is obtained with an optical purity greater than 99% (evaluation by HPLC on Chiralcel ® OD column).
- Example 6 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-dihydro-2H-3-benzazepin-2-one
- the decanted aqueous phase is brought to basic pH with sodium hydroxide and then extracted with ethyl acetate. After neutral washing and drying over MgSO 4 , evaporated in vacuo to give 4.5 g of an oil which is purified on a silica column using a dichloromethane / methanol mixture (90/10) as eluent.
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| FR1354504A FR3005658B1 (fr) | 2013-05-17 | 2013-05-17 | "procede de synthese du 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable" |
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| US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534859A1 (fr) | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | 3-Benzazépin-zones substituées par un groupe benzocyclobutyl- ou indanyl-alkyl-amino-alkyle, utiles dans le traitement des affections cardiovasculaires |
| WO2011138625A1 (en) | 2010-05-07 | 2011-11-10 | Richter Gedeon Nyrt. | Industrial process for the synthesis of ivabradine salts |
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| 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 |
| FR2933975B1 (fr) * | 2008-07-17 | 2011-02-18 | Servier Lab | Nouveau procede de preparation de benzocyclobutenes fonctionnalises,et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable. |
| JP5435127B2 (ja) | 2010-05-06 | 2014-03-05 | 株式会社島津製作所 | 材料試験機 |
| FR3005658B1 (fr) * | 2013-05-17 | 2015-04-24 | Servier Lab | "procede de synthese du 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable" |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534859A1 (fr) | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | 3-Benzazépin-zones substituées par un groupe benzocyclobutyl- ou indanyl-alkyl-amino-alkyle, utiles dans le traitement des affections cardiovasculaires |
| WO2011138625A1 (en) | 2010-05-07 | 2011-11-10 | Richter Gedeon Nyrt. | Industrial process for the synthesis of ivabradine salts |
Non-Patent Citations (3)
| Title |
|---|
| HAROLD HART ET AL: "Synthesis of Benzocyclobutenes from Trichloromethylbenzenes 1a", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 31, no. 7, 1 July 1966 (1966-07-01), pages 2244 - 2250, XP055096673, ISSN: 0022-3263, DOI: 10.1021/jo01345a038 * |
| TETSUJI KAMETANI ET AL: "Regioselectivity in the thermal 1,2-cycloaddition of benzocyclobutenes to 3,4-dihydroisoquinolines", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1 January 1974 (1974-01-01), pages 1712 - 1714, XP055097443, ISSN: 0300-922X, DOI: 10.1039/p19740001712 * |
| VAN LEUSEN D. ET AL.: "Synthetic uses of tosylmethyl isocyanide (TosMIC)", ORGANIC REACTIONS, vol. 57, 15 April 2004 (2004-04-15), XP002719004, DOI: 10.1002/0471264180.or057.03 * |
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| US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
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