WO2005085243A2 - Process for the preparation of cabergoline - Google Patents
Process for the preparation of cabergoline Download PDFInfo
- Publication number
- WO2005085243A2 WO2005085243A2 PCT/HU2005/000022 HU2005000022W WO2005085243A2 WO 2005085243 A2 WO2005085243 A2 WO 2005085243A2 HU 2005000022 W HU2005000022 W HU 2005000022W WO 2005085243 A2 WO2005085243 A2 WO 2005085243A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- cabergoline
- compound
- catalyst
- solvent
- Prior art date
Links
- 229960004596 cabergoline Drugs 0.000 title claims abstract description 55
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims description 44
- 238000002360 preparation method Methods 0.000 title claims description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 18
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- -1 hydrocarbon halide Chemical class 0.000 claims description 11
- 150000004808 allyl alcohols Chemical class 0.000 claims description 8
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical group [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 2
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 10
- 150000001408 amides Chemical class 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- XOLPCQSBSDIBGB-YVWKXTFCSA-N (6ar,9r,10ar)-n-[3-(dimethylamino)propyl]-n-(ethylcarbamoyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC([C@@H]2[C@H](NC[C@@H](C2)C(=O)N(CCCN(C)C)C(=O)NCC)C2)=C3C2=CNC3=C1 XOLPCQSBSDIBGB-YVWKXTFCSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000002955 isolation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 5
- 238000007112 amidation reaction Methods 0.000 description 5
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 150000003335 secondary amines Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical group O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 1
- LYJHVEDILOKZCG-UHFFFAOYSA-N Allyl benzoate Chemical compound C=CCOC(=O)C1=CC=CC=C1 LYJHVEDILOKZCG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 229940123796 Prolactin inhibitor Drugs 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- DXGTUUQHTDOFFQ-UHFFFAOYSA-N [N].C1=CC=C2NC=CC2=C1 Chemical group [N].C1=CC=C2NC=CC2=C1 DXGTUUQHTDOFFQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000012443 analytical study Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- POSICDHOUBKJKP-UHFFFAOYSA-N prop-2-enoxybenzene Chemical compound C=CCOC1=CC=CC=C1 POSICDHOUBKJKP-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
Definitions
- This invention relates to a new process for the preparation of cabergoline of formula
- Cabergoline (I) was firstly prepared according to United States Patent 4,526,892 by reaction of 6-allyl-ergoline-8 ⁇ -carboxylic acid (II) with l-[3-(dimethylamino)propyl)-3- ethylcarbodiimide (EDC) (Scheme 1). Scheme 1
- J. Org. Chem. 2002, 67, 7147-7150 describes an ethyl isocyanate- free method for the production of cabergoline (I) that solves the problem of completing acylation of indole nitrogen, too.
- the first step is the protection of indole nitrogen of amide (IN) preferably as tert-butyl carbamate (Nil).
- Extension of the amide side chain is done by deprotonation of compound (Nil) with sodium hexamethyldisilazide ( ⁇ aHMDS) followed by trapping the anion with phenyl chloroformate (PhOCOCl) to yield the phenyl carbamate (VIII).
- Reaction of compound (VIII) with ethylamine hydrochloride (Et ⁇ H 2 xHCl) gives
- Al Patent Application cabergoline (I) may be prepared by silylating amide (TV) with a silylating agent (e.g. trimethylsilyl trifluoromethane sulfonate - TMSOTf), reacting the obtained product (XI) with ethyl isocyanate (EtNCO) followed by desilylation of intermediate (XII) (Scheme 4).
- a silylating agent e.g. trimethylsilyl trifluoromethane sulfonate - TMSOTf
- WO 01/70740 Al Patent Application describes a new process for the preparation of crystalline form I from the new crystalline form V.
- the form V - which is toluene solvate - is prepared from the mixture of the purified cabergoline (I) with toluene and diethyl ether by a long-lasting complicated process, at low reaction temperature, and the yield is only 45%.
- the crystalline form I is prepared by drying the form V in vacuum.
- WO 01/72746 Al Patent Application describes the preparation of crystalline form VII from the crystalline form I.
- the suspension of form I in n-heptane or 1,4-dioxane is stirred for 48 hours, and then the suspension was filtered to obtain the crystalline form VII.
- the yield is 45.2%.
- WO 01/72747 Al Patent Application describes the crystalline form II and a process for its preparation with approx. 70% yield by stirring the cabergoline (I) for several days in an organic solvent (eg. diethyl ether) at low temperature.
- organic solvent eg. diethyl ether
- cabergoline (I) with a method via new intermediates proposed by the present invention is commercially more advantageous than with the previously disclosed known methods due to the high yield (approx.78%), the milder reaction conditions and the shorter reaction time.
- Another advantage of the use of these intermediates is that they have high hydrophobicity - in comparison to known intermediates bearing two basic function - so their purification by normal phase chromatography (if necessary) is highly effective due to the expanded difference in retention between them and the by-products.
- the present invention relates to a process for preparing cabergoline (I) from ergoline- 8 ⁇ -carboxylic acid C ⁇ alkyl esters via new intermediates and the polymorphic amorphous form of cabergoline (I).
- the process comprises protecting the secondary amine and the indole nitrogen functions of ergoline-8 ⁇ -carboxylic acid . 4 alkyl esters as carbamate derivatives, amidating the obtained protected compound with 3-(dimethylamino)propylamine, reacting the amide with ethyl isocyanate, cleaving the protecting groups and reacting the obtained deprotected secondary amine with an electrophyl allyl alcohol derivative to obtain cabergoline (I).
- the present invention also relates to the new intermediates used in this process.
- the invention also relates to the new amorphous form of cabergoline (I) and the preparation thereof. DETAILED DESCRIPTION OF THE INVENTION
- the invention relates to a process for preparing cabergoline (I) comprising the following steps: (a) Reacting a compound of formula (XIII) - wherein Ri represents a C 1 - 4 alkyl group - in the presence of a catalyst (i) with a compound of formula (XTV), X-COOR 2 (XTV)
- R 2 represents an optionally substituted straight or branched Ci. 6 alkyl group
- X represents a bromine or chlorine atom, or (ii) with a compound of formula (XV), O(COOR 2 ) 2 (XV) wherein R 2 is a group as defined above for formula (XIN);
- Step (a) of the process refers to reacting an ergoline-8 ⁇ -carboxylic acid ester of formula (XIII) with a compound of formula (XIN) or (XV).
- the starting materials, ergoline-8 ⁇ -carboxylic acid esters of formula (XIII) can be prepared according to any method known in the state of the art: e.g. US 4,166,182 Patent or Collect. Czech. Chem. Commun. 1983, 48(5), 1483-1489. Methods that serve for protection of both secondary amines and indole nitrogen are well known from the art. Thus, these functionalities can be protected e.g. as N-alkyl, N-aryl,
- the reaction may be carried out from -50°C to the reflux temperature of the reaction mixture in a suitable aprotic solvent in the presence of an organic or inorganic base as catalyst.
- the reaction step (a) is carried out at a temperature of from 0°C to 50°C in the presence of 4-dimethylaminopyridine catalyst in a hydrocarbon halide solvent.
- ⁇ is methyl and R 2 is tert-butyl.
- Step (b) of the process refers to reacting the carbamate derivative of formula (XVI) obtained in the step (a) with 3-(dimemylamino)propylamine.
- the amidation of ergoline-8 ⁇ -carboxylic acid methyl ester derivatives containing a basic nitrogen in position 6 of the ergoline skeleton with 3-(dimethylamino)propylamine can be accomplished by know methods.
- the reactions can be carried out with a large excess of the amine (i) refluxing the reaction mixture for 10-12 hours without solvent (approx. at 135°C) in the presence of acetic acid catalyst; (ii) heating the reactants for 18 hours at 100°C in ethylene glycol as a solvent with catalytic amount of 2-hydroxypyridine.
- catalysts can be used provided they do not hurt the tert-butoxycarbonyl protecting groups.
- examples of catalysts are organic and inorganic bases such as alkali metal or earth metal hydroxides or carbonates, alkali metal or earth metal alcoholates, pyridine or its derivatives, tertiary amines, etc.; salts such as ammonium chloride, copper(II) acetate, magnesium chloride; and other catalysts such as boron tribromide, dimethylaluminium amides, mixed tin(II) amides or mixtures thereof.
- the amidation can be carried out without solvent or in the presence of a suitable solvent.
- the step (b) is carried out at a temperature of from 50°C to 70°C in an Ci. 6 alkyl alcohol solvent in the presence of 2-hydroxypyridine catalyst.
- the resultant amide of formula (XVII) may be used in the following step after isolation from the reaction mass following conventional procedures, or may be subjected to the subsequent step without isolation.
- Step (c) of the process refers to reacting the ergoline-8 ⁇ -carboxamide derivative of formula (XVII) obtained in the step (b) with ethyl isocyanate (EtNCO).
- the ethyl isocyanate may be used in a 1 to 4 fold molar amount, preferably 2 to 3 molar amount relative to the amount of the amide (XVII).
- the reaction of amide (XVII) with ethyl isocyanate may be accelerated by metal catalysis in the presence of coordination compound(s).
- Suitable metal catalysts include lb and lib metal group salts, preferably copper(I) and copper(II) salts.
- Most preferred salts are copper(I) chloride, co ⁇ per(II) chloride, co ⁇ per(I) bromide and copper(I) iodide.
- the ligands in the coordination compound(s) with lb and lib metals preferably contain phophorous, nitrogen and/or oxygen atoms.
- Examples of the ligands include triarylphophines, tertiary amines, nitriles, amides and ether-type compounds.
- Preferred ligands are triarylphophines, most preferred ligands are triphenylphosphine and tri-p-tolylphophine.
- the reaction is carried out in the presence of a suitable aprotic organic solvent from 0°C to the reflux temperature of the reaction mixture.
- a suitable aprotic organic solvent from 0°C to the reflux temperature of the reaction mixture.
- the step (c) is carried out in hydrocarbon halide solvent, in the presence of cop ⁇ er(I) chloride and/or copper(II) chloride and/or copper(I) bromide and/or copper(l) iodide catalysts and triphenylphosphine or ligand at a temperature of from 30°C to 50°C.
- the reaction product may be isolated and purified following conventional procedures.
- the obtained protected N-acylurea derivatives of formula (XVIII) have high hydrophobicity (in comparison to known intermediates bearing two basic function), their purification by normal phase chromatography (if necessary) is highly effective due to the expanded difference in retention between it and the by-products.
- Step (d) of the process refers to reacting the protected N-acylurea derivative of formula (XVIII) obtained in the step (c), with a strong aqueous inorganic acid to form N-[3- (dimethylamino)propyl]-N-[(ethylamino)carbonyl)-ergoline-8 ⁇ -carboxamide (XIX).
- Methods cleaving the carbamate-type protecting groups from basic nitrogen and indole nitrogen are well known from the art, but not each is suitable for both purposes. Otherwise, with some commonly used methods (e.g. with formic acid or trichloroacetic acid) no significant conversion was observed, while other methods (e.g.
- the strong acid means an acid which has a pK value less than 2 in water.
- Examples for strong inorganic acid are hydrochloric acid, hydrobromic acid, sulfuric acid, hydrochloric acid. The deprotection may be carried out from 0 °C to the reflux temperature of the reaction mixture.
- step (d) is carried out at a temperature of from 40°C to 80°C in aqueous hydrochloric acid.
- the resultant compound of formula (XIX) may be used in the following step after isolation from the reaction mass following conventional procedures, or may be subjected to the subsequent step without isolation.
- Step (e) of the process refers to reacting the obtained 6-deallyl-cabergoline of formula
- XIX 6-deallyl-cabergoline
- electrophyl allyl alcohol derivative in an organic solvent in the presence of palladium or nickel catalyst and ligand(s) yields Cabergoline (I) in high purity.
- electrophyl allyl alcohol derivative are allylic carboxylates such as allyl acetate or allyl benzoate and allyl phenyl ether.
- the catalytic system may be homogeneous or heterogeneous, preferably the catalytic system is homogeneous.
- heterogeneous catalyst examples include palladium on activated carbon or polystyrene in the presence of phosphorous containing ligands, palladium ligated by phosphinated polystyrene or phosphinated silica.
- homogeneous catalyst examples include tetrakis(triphenylphos ⁇ hine)palladium(0), tetraMs(triphenylphosphine)nickel, bis(cycloocta-l,5-diene)nickel, [l,4-bis(diphenyl- phosphino)butane]nickel, allyl palladium chloride dimer and cis,cis,cis- 1,2,3, 4-tetrakis- (diphenylphosphinometyl)cyclopentane.
- the reaction may be carried out in a suitable aprotic organic solvent from 0 °C to the reflux temperature of the reaction mixture.
- the electrophyl allyl alcohol derivative is allyl acetate
- the catalyst is tetrakis(triphenylphosphine)palladium(0)
- the reaction is carried out in an aromatic hydrocarbon solvents at a temperature of from 20°C to 50°C.
- the reaction product may be isolated and purified following conventional procedures.
- the cabergoline (I) can be converted into pharmaceutically acceptable salts.
- the cabergoline (I) or pharmaceutically acceptable salts thereof, can be subsequently formulated with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical composition.
- the used solvent is acetone, methyl acetate or dichloromethane.
- the polymorphic amorphous form of Cabergoline (I) is very stable, the dissolution rate and absorption properties of the amorphous form of Cabergoline (I) are favourable. So the use of the amorphous form of
- Cabergoline (I) in pharmaceutical compositions is advantageous in comparison to known crystalline forms.
- N(6)-COOC(CH 3 ) 3 1.66 (s, 9 ⁇ , N(l)-COOC(CH 3 ) 3 ); 1.78-1.96 (m, 2 ⁇ ,
- the reaction mixture was cooled to ambient temperature, 200 ml of dichloromethane was added and the pH was adjusted to 11 with concentrated aqueous ammonia solution.
- the organic layer was separated and the aqueous layer was extracted with 2x60 ml of dichloromethane.
- the combined organic layer was dried over anhydrous sodium sulphate. The dried solution was either subjected to the subsequent step without isolation of the product or it was concentrated in vacuum to give 8.1 g (94.8%) of the title compound.
- Example 6a The same as in Example 6a, but employing methyl acetate as solvent, 9.85 g (98.5%) of the title compound was obtained.
- XRD XRD
- DSC IR analytical studies the crystalline form of the product is amorphous.
- Figure 1 shows the XRD Spectra of amorphous form of Cabergoline (I).
- Figure 2 shows the DSC Spectra of amorphous form of Cabergoline (I).
- Figure 3 shows the IR Spectra of amorphous form of Cabergoline (I).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/591,202 US7858791B2 (en) | 2004-03-04 | 2005-03-02 | Process for the preparation of cabergoline |
DE602005021461T DE602005021461D1 (en) | 2004-03-04 | 2005-03-02 | PROCESS FOR PREPARING CABERGOLIN |
AT05718154T ATE469149T1 (en) | 2004-03-04 | 2005-03-02 | METHOD FOR PRODUCING CABERGOLINE |
EP05718154A EP1720869B1 (en) | 2004-03-04 | 2005-03-02 | Process for the preparation of cabergoline |
EA200601628A EA010689B1 (en) | 2004-03-04 | 2005-03-02 | Process for the preparation of cabergoline |
Applications Claiming Priority (2)
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HU0400517A HUP0400517A3 (en) | 2004-03-04 | 2004-03-04 | Process for producing cabergoline |
HUP0400517 | 2004-03-04 |
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WO2005085243A2 true WO2005085243A2 (en) | 2005-09-15 |
WO2005085243A3 WO2005085243A3 (en) | 2006-04-06 |
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PCT/HU2005/000022 WO2005085243A2 (en) | 2004-03-04 | 2005-03-02 | Process for the preparation of cabergoline |
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US (1) | US7858791B2 (en) |
EP (1) | EP1720869B1 (en) |
AT (1) | ATE469149T1 (en) |
DE (1) | DE602005021461D1 (en) |
EA (1) | EA010689B1 (en) |
HU (1) | HUP0400517A3 (en) |
WO (1) | WO2005085243A2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1620101A2 (en) * | 2003-05-08 | 2006-02-01 | IVAX Pharmaceuticals s.r.o. | Polymorphs of cabergoline |
WO2008104956A2 (en) * | 2007-02-28 | 2008-09-04 | Ranbaxy Laboratories Limited | Process for the preparation of amorphous cabergoline |
EP2067780A1 (en) * | 2007-12-07 | 2009-06-10 | Axxonis Pharma AG | Ergoline derivatives as selective radical scavengers for neurons |
JP2010507623A (en) * | 2006-10-26 | 2010-03-11 | レツク・フアーマシユーテイカルズ・デー・デー | A method for preparing crystalline forms of cabergoline via a novel stable solvate of cabergoline |
JP2015107980A (en) * | 2010-06-11 | 2015-06-11 | ローズ テクノロジーズ | Transition metal-catalyzed process for preparation of n-allyl compound and use thereof |
JP2015525239A (en) * | 2012-06-22 | 2015-09-03 | マップ・ファーマシューティカルズ・インコーポレイテッド | New cabergoline derivatives |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5382669A (en) * | 1992-03-12 | 1995-01-17 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of ergoline derivatives |
WO2002085902A1 (en) * | 2001-04-16 | 2002-10-31 | Finetech Laboratories Ltd. | Process and intermediates for production of cabergoline and related compounds |
US20020177709A1 (en) * | 2001-04-16 | 2002-11-28 | Gutman Arie L. | Novel process and intermediates for production of cabergoline and related compounds |
-
2004
- 2004-03-04 HU HU0400517A patent/HUP0400517A3/en unknown
-
2005
- 2005-03-02 EP EP05718154A patent/EP1720869B1/en active Active
- 2005-03-02 US US10/591,202 patent/US7858791B2/en not_active Expired - Fee Related
- 2005-03-02 DE DE602005021461T patent/DE602005021461D1/en active Active
- 2005-03-02 EA EA200601628A patent/EA010689B1/en not_active IP Right Cessation
- 2005-03-02 WO PCT/HU2005/000022 patent/WO2005085243A2/en active Application Filing
- 2005-03-02 AT AT05718154T patent/ATE469149T1/en not_active IP Right Cessation
Patent Citations (3)
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US5382669A (en) * | 1992-03-12 | 1995-01-17 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of ergoline derivatives |
WO2002085902A1 (en) * | 2001-04-16 | 2002-10-31 | Finetech Laboratories Ltd. | Process and intermediates for production of cabergoline and related compounds |
US20020177709A1 (en) * | 2001-04-16 | 2002-11-28 | Gutman Arie L. | Novel process and intermediates for production of cabergoline and related compounds |
Non-Patent Citations (1)
Title |
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BATTAGLIA R ET AL: "DISPOSITION AND URINARY METABOLIC PATTERN OF CABERGOLINE, A POTENT DOPAMINERGIC AGONIST, IN RAT, MONKEY AND MAN" XENOBIOTICA, TAYLOR AND FRANCIS, LONDON,, GB, vol. 23, no. 12, 1993, pages 1377-1389, XP009040296 ISSN: 0049-8254 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1620101A2 (en) * | 2003-05-08 | 2006-02-01 | IVAX Pharmaceuticals s.r.o. | Polymorphs of cabergoline |
EP1620101A4 (en) * | 2003-05-08 | 2008-07-09 | Ivax Pharmaceuticals Sro | Polymorphs of cabergoline |
US7531551B2 (en) | 2003-05-08 | 2009-05-12 | Ivax Pharmaceuticals S.R.O. | Polymorphs of cabergoline |
JP2010507623A (en) * | 2006-10-26 | 2010-03-11 | レツク・フアーマシユーテイカルズ・デー・デー | A method for preparing crystalline forms of cabergoline via a novel stable solvate of cabergoline |
WO2008104956A3 (en) * | 2007-02-28 | 2009-08-13 | Ranbaxy Lab Ltd | Process for the preparation of amorphous cabergoline |
WO2008104956A2 (en) * | 2007-02-28 | 2008-09-04 | Ranbaxy Laboratories Limited | Process for the preparation of amorphous cabergoline |
WO2009071607A2 (en) * | 2007-12-07 | 2009-06-11 | Axxonis Pharma Ag | Ergoline derivatives as selective radical scavengers for neurons |
EP2067780A1 (en) * | 2007-12-07 | 2009-06-10 | Axxonis Pharma AG | Ergoline derivatives as selective radical scavengers for neurons |
WO2009071607A3 (en) * | 2007-12-07 | 2009-09-24 | Axxonis Pharma Ag | Ergoline derivatives as selective radical scavengers for neurons |
JP2015107980A (en) * | 2010-06-11 | 2015-06-11 | ローズ テクノロジーズ | Transition metal-catalyzed process for preparation of n-allyl compound and use thereof |
JP2017137317A (en) * | 2010-06-11 | 2017-08-10 | ローズ テクノロジーズ | Transition metal-catalyzed processes for preparation of n-allyl compounds and use thereof |
JP2015525239A (en) * | 2012-06-22 | 2015-09-03 | マップ・ファーマシューティカルズ・インコーポレイテッド | New cabergoline derivatives |
EP2863747A4 (en) * | 2012-06-22 | 2015-12-23 | Map Pharmaceuticals Inc | Novel cabergoline derivatives |
Also Published As
Publication number | Publication date |
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EA200601628A1 (en) | 2007-02-27 |
HUP0400517A3 (en) | 2006-05-29 |
HUP0400517A2 (en) | 2005-11-28 |
US20070293677A1 (en) | 2007-12-20 |
ATE469149T1 (en) | 2010-06-15 |
DE602005021461D1 (en) | 2010-07-08 |
EP1720869A2 (en) | 2006-11-15 |
WO2005085243A3 (en) | 2006-04-06 |
EA010689B1 (en) | 2008-10-30 |
EP1720869B1 (en) | 2010-05-26 |
HU0400517D0 (en) | 2004-05-28 |
US7858791B2 (en) | 2010-12-28 |
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