WO2002085902A1 - Procede et intermediaires de production de cabergoline et de composes associes - Google Patents
Procede et intermediaires de production de cabergoline et de composes associes Download PDFInfo
- Publication number
- WO2002085902A1 WO2002085902A1 PCT/IL2001/000344 IL0100344W WO02085902A1 WO 2002085902 A1 WO2002085902 A1 WO 2002085902A1 IL 0100344 W IL0100344 W IL 0100344W WO 02085902 A1 WO02085902 A1 WO 02085902A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- trimethylsilyl
- compound
- formula
- carbon atoms
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 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 abstract description 26
- 229960004596 cabergoline Drugs 0.000 title abstract description 18
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 8
- 238000005828 desilylation reaction Methods 0.000 claims abstract description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims abstract description 5
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 5
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical group 0.000 claims abstract description 4
- 229910052751 metal Inorganic materials 0.000 claims abstract description 4
- 239000002184 metal Substances 0.000 claims abstract description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 3
- -1 aralkyl radicals Chemical class 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000006884 silylation reaction Methods 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical group C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- JNOGVQJEBGEKMG-UHFFFAOYSA-N (1-methoxy-2-methylprop-1-enoxy)-trimethylsilane Chemical compound COC(=C(C)C)O[Si](C)(C)C JNOGVQJEBGEKMG-UHFFFAOYSA-N 0.000 claims description 2
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 claims description 2
- LUBVCBITQHEVCJ-UHFFFAOYSA-N 1-trimethylsilylpyrrolidin-2-one Chemical compound C[Si](C)(C)N1CCCC1=O LUBVCBITQHEVCJ-UHFFFAOYSA-N 0.000 claims description 2
- RZYHXKLKJRGJGP-UHFFFAOYSA-N 2,2,2-trifluoro-n,n-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)N([Si](C)(C)C)C(=O)C(F)(F)F RZYHXKLKJRGJGP-UHFFFAOYSA-N 0.000 claims description 2
- HNUKTDKISXPDPA-UHFFFAOYSA-N 2-oxopropyl Chemical group [CH2]C(C)=O HNUKTDKISXPDPA-UHFFFAOYSA-N 0.000 claims description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 2
- MSPCIZMDDUQPGJ-UHFFFAOYSA-N N-methyl-N-(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)N(C)C(=O)C(F)(F)F MSPCIZMDDUQPGJ-UHFFFAOYSA-N 0.000 claims description 2
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- QWQONZVLXJGXHV-UHFFFAOYSA-N [chlorosulfonyloxy(dimethyl)silyl]methane Chemical compound C[Si](C)(C)OS(Cl)(=O)=O QWQONZVLXJGXHV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical group N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- VHOLOZYRMQVHBK-UHFFFAOYSA-N benzotriazol-1-yl(trimethyl)silane Chemical compound C1=CC=C2N([Si](C)(C)C)N=NC2=C1 VHOLOZYRMQVHBK-UHFFFAOYSA-N 0.000 claims description 2
- KRUQDZRWZXUUAD-UHFFFAOYSA-N bis(trimethylsilyl) sulfate Chemical compound C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C KRUQDZRWZXUUAD-UHFFFAOYSA-N 0.000 claims description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229910001507 metal halide Inorganic materials 0.000 claims description 2
- 150000005309 metal halides Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- WPSPBNRWECRRPK-UHFFFAOYSA-N trimethyl(1,2,4-triazol-1-yl)silane Chemical compound C[Si](C)(C)N1C=NC=N1 WPSPBNRWECRRPK-UHFFFAOYSA-N 0.000 claims description 2
- JCUPGHJJFSUZRF-UHFFFAOYSA-N trimethylsilyl benzenesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C1=CC=CC=C1 JCUPGHJJFSUZRF-UHFFFAOYSA-N 0.000 claims description 2
- NTJPIRDYMVYFNP-UHFFFAOYSA-M trimethylsilylmethanesulfonate Chemical compound C[Si](C)(C)CS([O-])(=O)=O NTJPIRDYMVYFNP-UHFFFAOYSA-M 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 5
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 125000004665 trialkylsilyl group Chemical group 0.000 claims 1
- 229940066528 trichloroacetate Drugs 0.000 claims 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims 1
- 239000012948 isocyanate Substances 0.000 abstract description 8
- 150000002513 isocyanates Chemical class 0.000 abstract description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 7
- 235000013877 carbamide Nutrition 0.000 abstract description 6
- 150000003672 ureas Chemical class 0.000 abstract description 5
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- 102000003946 Prolactin Human genes 0.000 abstract description 2
- 108010057464 Prolactin Proteins 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 229940097325 prolactin Drugs 0.000 abstract description 2
- 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 compound 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 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 19
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- JJTHJEHDIBAMMM-YFVAEKQCSA-N (6ar,9r,10ar)-n-[3-(dimethylamino)propyl]-7-prop-2-enyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)NCCCN(C)C)=C3C2=CNC3=C1 JJTHJEHDIBAMMM-YFVAEKQCSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- WBHOPARXKSYXRI-IRUJWGPZSA-N (6ar,9r,10ar)-n-carbamoyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical class C1=CC([C@@H]2[C@H](NC[C@@H](C2)C(=O)NC(=O)N)C2)=C3C2=CNC3=C1 WBHOPARXKSYXRI-IRUJWGPZSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000939 antiparkinson agent Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 150000004673 fluoride salts Chemical class 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- JSHASCFKOSDFHY-UHFFFAOYSA-N 1-butylpyrrolidine Chemical compound CCCCN1CCCC1 JSHASCFKOSDFHY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FGWQRDGADJMULT-UHFFFAOYSA-N 4-(4-methylpiperidin-1-yl)pyridine Chemical compound C1CC(C)CCN1C1=CC=NC=C1 FGWQRDGADJMULT-UHFFFAOYSA-N 0.000 description 1
- 229940123796 Prolactin inhibitor Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910001515 alkali metal fluoride Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 229940125688 antiparkinson agent Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- HAIZQIKYAKUOBN-UHFFFAOYSA-N trimethylsilyl 2,2,2-trichloroacetate Chemical compound C[Si](C)(C)OC(=O)C(Cl)(Cl)Cl HAIZQIKYAKUOBN-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 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 dopamine agonists such as Cabergoline, to some novel intermediates used in this process and to their preparation.
- R represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a phenyl group or a dimethylamino alkyl group -(CH 2 ) n NMe2
- R represents any of the groups which R may represent, or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl residue, R represents a hydrocarbon group having from 1 to 4 carbon atoms, R represents a hydrogen or a halogen atom or a methylthio or phenylthio group and R represents a hydrogen atom or a methyl group; have shown potent dopamine agonist properties and have been useful as anti-Parkinson drugs and as prolactin inhibitors (US 5,382,669 and Eur. J. Med. Chem., 1989, v. 24, 421).
- One of the most potent prolactin inhibitor of this class is l-(6-allylergoline-8 ⁇ -carbonyl)-l-[3-(dimethylamino)propyl]-3-ethylurea (international non-proprietary name Cabergoline) [la] (Eur. J. Med. Chem., 1989, v. 24, 421) which was firstly prepared by reaction of 6-allylergoline-8 ⁇ -carboxylic acid [7] with l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide (US 4,526,892) (Scheme 1):
- the present invention provides a commercially acceptable process for producing N-(ergoline-8 ⁇ -carbonyl)ureas of formula [I]:
- R is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and dimethylamino alkyl group -(CH2) n NMe2 in which n is an integer
- R is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer
- R represents a hydrocarbon group having from 1 to 4 carbon atoms
- R is selected from hydrogen, halogen, methylthio and phenylthio group; which process comprises silylating an ergoline- 8-carboxamide of formula [2],
- the present invention describes a novel process for the preparation of N-(ergoline-8 ⁇ -carbonyl)urea compounds of formula [I]. Particularly, the present invention utilizes the silylation of of ergoline-8 ⁇ -carboxamide [2] in order to selectively activate it's amide group in the subsequent reaction with isocyanate.
- This novel approach has the following advantages:
- Reagents used for silylation and desilylation are not toxic, commercially available and inexpensive.
- silylating agents suitable for silylating amides
- a compound of formula [3] is preferably used for this purpose to give intermediate N-silylamide of the formula [4], tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof; intermediate [4] reacts with isocyanate of formula [5] :
- R , R and R may be the same or different and are selected from the group consisting of alkyl having from 1 to 6 carbon atoms, aryl and arallcyl radicals;
- Y is selected from the group consisting of chloro, bromo, iodo, (haloalkyl)- sulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, (trialkylsilyloxy)sulfonyloxy, imidazolyl, N-acyl-N-alkylamino, N-acyl-N-(trialkylsilyl)amino, (trialkylsilyl)- amino, N,N-dialkylamino, isopropenyloxy, 1 -alkoxy- 1-alkenyloxy and trichloroacetoxy radicals;
- the silylating agent may be used in a 0.5 to 10 fold molar amount, preferably from 0.9 to 5 fold molar amount, relative to the amount of the ergoline-8 ⁇ -carboxamide [2].
- silylating agents are selected from trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate, trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl chloride, bromide or iodide, trimethylsilyl trichloroacetate and trifluoroacetate, 1 -(trimethylsilyl)imidazol, 1 -(trimethylsilyl)- 1 ,2,4-triazole, 1 -(trimethylsilyl)- lH-benzotriazole, 1 -(trimethylsilyl)-2-pyrrolidinone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, methyl trimethylsilyl dimethylketene acetal, bis(trimethylsilyl)sulfate, N,0-bis(trimethylsilyl)acetamide and bis(trimethylsilyl)s
- the silylation reaction may be carried out from -50 °C to the reflux temperature of the reaction mixture.
- the silylation is carried out from 0° to 50 °C.
- Organic or inorganic acids or salts may accelerate the silylation.
- acids include mineral acids such as sulfuric acid or hydrogen halide.
- salts include metal halides, tertiary ammonium halides, ammonium halides, ammonium sulfate, pyridine or it's derivatives hydrohalides.
- organic or inorganic bases accelerate the silylation reaction.
- organic bases are tertiary amines, sterically hindered secondary amines, pyridine or there derivatives, l,5-diazabicyclo[4.3.0]non-5-ene (DB ⁇ ), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof.
- tertiary amines examples include 1-ethylpiperidine, 1-butylpyrrolidine, diisopropylethylamine, triethylamine, N,N,N,N-tetramethylethylenediamine, l,4-diazabicyclo[2.2.2]octane or mixture thereof.
- sterically hindered secondary amines are diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethyl ⁇ iperidine or mixture thereof.
- pyridine derivatives are 4-dimethylaminopyridine (DMAP),
- the solvent for the silylation reaction may be any suitable aprotic organic solvent provided it does not inhibit the reaction.
- suitable aprotic organic solvent examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides such as dichloromethane and chloroform; ether solvents such as ether, isopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, N,N-dimethylformamide (DMF), NN-dimethylacetamide or 1-methylpyrrolidin
- the resultant silylated product may be used in the following step after isolation from the reaction mass, or may be subjected to the subsequent step without isolation.
- the resultant product is reacted with a compound of formula [5], which may be used in a 1 to 10 fold molar amount, preferably 2 to 5 fold molar amount relative to the amount of the ergoline-8 ⁇ -carboxamide [2].
- the reaction may be carried out at temperature from -50 °C to reflux temperature of the reaction mixture.
- the reaction is carried out at 0 - 50 °C without isolating silylated ergoline- 8 ⁇ -carboxamide from the reaction mass.
- the reaction of silylated ergoline-8 ⁇ -carboxamide with isocyanate may be carried out without solvent, but preferably, the reaction is carried out in any organic aprotic solvent which does not inhibit the reaction.
- organic aprotic solvent examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides such as dichloromethane and chloroform; ether solvents such as ether, isopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, N,N
- the reaction of silylated ergoline-8 ⁇ -carboxamide with isocyanate may be accelerated by transition metal(s) salt(s) and/or coordination compound(s) or fluoride-ions.
- transition metals include copper or zinc.
- the said transition metal(s) salt(s) are copper and/or zinc halides.
- the said ligands in the coordination compound(s) with transition metal(s) contain phosphorous, nitrogen and/or oxygen atoms.
- the ligands include triarylphosphines, pyridine or it's derivatives, tertiary amines, nitriles, amides and ether-type compounds.
- the desilylation can be carried out by, for example, using fluoride salts optionally in the presence of phase transfer catalysts.
- fluoride salts include tetraalkylammonium fluoride, benzyltrialkylammonium fluoride and alkali metal fluoride.
- phase transfer catalysts include tetraalkylammonium salts, benzyltrialkylammonium salts and crown ethers.
- Cabergoline [la] may be prepared from amide [2a] according to Scheme 3:
- Example 1 compound [lb] was obtained using phenyl isocyanate instead of ethyl isocyanate.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Cette invention concerne un procédé de préparation de N-(ergoline-8β-carbonyle)urées de la formule [I], de leurs stéréoisomères ainsi que de leurs sels d'addition acide. Ce procédé consiste à effectuer une silylation d'une ergoline -8β-carboxamide de la formule [2], de leurs stéréoisomères ainsi que de leurs sels de métal ou d'ammonium ou de leurs sels d'addition acide, ainsi qu'à faire réagir le produit obtenu avec un isocyanate R1N=C=O [5], R1 étant sélectionné parmi un alkyle comportant entre 1 et 4 atomes de carbone, cyclohexyle, phényle et un groupe diméthylamino alkyle (CH¿2?)nNMe2, n étant un nombre entier, R?2¿ étant sélectionné parmi hydrogène, alkyle comportant entre 1 et 4 atomes de carbone, cyclohexyle, phényle, un groupe diméthylamino alkyle (CH¿2?)nNMe2, n étant un nombre entier, pyridyle, pyrimidyle, pyrazinyle, thiazolyle ou thiadiazolyle, R?3¿ représentant un groupe hydrocarbure comportant entre 1 et 4 atomes de carbone, et R4 étant sélectionné parmi hydrogène, halogène, un groupe méthylthio et phénylthio. Ce procédé consiste ensuite à effectuer une désilylation. Cette nouvelle approche constitue un procédé efficace de préparation de N-(ergoline-8β-carbonyle)urées de la formule [I] pouvant être utilisées comme médicaments luttant contre la maladie de Parkinson, et comme inhibiteurs de la prolactine. L'un des agents anti-prolactiniques les plus efficaces de la classe de composés préparés selon la présente invention est la carbergoline. Les ergolines silylatées, qui sont obtenues comme intermédiaires dans le procédé de la présente invention, constituent de nouveaux composés et représentent un autre aspect de cette invention.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002412861A CA2412861A1 (fr) | 2001-04-16 | 2001-04-16 | Procede et intermediaires de production de cabergoline et de composes associes |
| EP01923942A EP1379526A1 (fr) | 2001-04-16 | 2001-04-16 | Procede et intermediaires de production de cabergoline et de composes associes |
| PCT/IL2001/000344 WO2002085902A1 (fr) | 2001-04-16 | 2001-04-16 | Procede et intermediaires de production de cabergoline et de composes associes |
| HU0303557A HUP0303557A2 (hu) | 2001-04-16 | 2001-04-16 | Eljárás és intermedierek cabergolin és származékai előállítására |
| JP2002583429A JP2004525187A (ja) | 2001-04-16 | 2001-04-16 | カベルゴリンおよび関連化合物の製造のための方法および中間体 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IL2001/000344 WO2002085902A1 (fr) | 2001-04-16 | 2001-04-16 | Procede et intermediaires de production de cabergoline et de composes associes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002085902A1 true WO2002085902A1 (fr) | 2002-10-31 |
Family
ID=11043042
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IL2001/000344 WO2002085902A1 (fr) | 2001-04-16 | 2001-04-16 | Procede et intermediaires de production de cabergoline et de composes associes |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1379526A1 (fr) |
| JP (1) | JP2004525187A (fr) |
| CA (1) | CA2412861A1 (fr) |
| HU (1) | HUP0303557A2 (fr) |
| WO (1) | WO2002085902A1 (fr) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005085243A2 (fr) * | 2004-03-04 | 2005-09-15 | Richter Gedeon Vegyészeti Gyár Rt. | Nouveau procede de production de la cabergoline |
| EP1617856A2 (fr) * | 2003-04-11 | 2006-01-25 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Analogues chimeres de la somatostatine-dopamine |
| FR2877945A1 (fr) * | 2004-11-18 | 2006-05-19 | Archemis Sa | Procede de la preparation de la cabergoline |
| US7217822B2 (en) | 2005-03-17 | 2007-05-15 | Synthon Ip Inc. | Process for making cabergoline |
| WO2007091039A3 (fr) * | 2006-02-08 | 2007-10-18 | Resolution Chemicals Ltd | Production de cabergoline et nouvelle forme polymorphique de ce composé |
| US7939665B2 (en) | 2007-05-04 | 2011-05-10 | Apotex Pharmachem Inc. | Efficient process for the preparation of cabergoline and its intermediates |
| US8952128B2 (en) | 2012-11-01 | 2015-02-10 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9777039B2 (en) | 2012-11-01 | 2017-10-03 | Ipsen Pharma S.A.S. | Somatostatin analogs and dimers thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1925616A1 (fr) * | 2006-10-26 | 2008-05-28 | LEK Pharmaceuticals D.D. | Procédé pour la préparation de formes crystallines de la cabergoline via des solvates stables de la cabergoline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2103603A (en) * | 1981-08-11 | 1983-02-23 | Erba Farmitalia | Ergoline derivatives |
-
2001
- 2001-04-16 EP EP01923942A patent/EP1379526A1/fr not_active Withdrawn
- 2001-04-16 JP JP2002583429A patent/JP2004525187A/ja active Pending
- 2001-04-16 WO PCT/IL2001/000344 patent/WO2002085902A1/fr not_active Application Discontinuation
- 2001-04-16 HU HU0303557A patent/HUP0303557A2/hu unknown
- 2001-04-16 CA CA002412861A patent/CA2412861A1/fr not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2103603A (en) * | 1981-08-11 | 1983-02-23 | Erba Farmitalia | Ergoline derivatives |
Non-Patent Citations (1)
| Title |
|---|
| ZOECKLER, M. T. ET AL: "Homogeneous catalytic formation of carbon-nitrogen bonds. 2. Catalytic activation of the silicon-nitrogen bond", J. ORG. CHEM. (1983), 48(15), 2539-43, XP002184892 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8822442B2 (en) | 2003-04-11 | 2014-09-02 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| EP1617856A2 (fr) * | 2003-04-11 | 2006-01-25 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Analogues chimeres de la somatostatine-dopamine |
| EP1617856A4 (fr) * | 2003-04-11 | 2010-05-26 | Ipsen Pharma | Analogues chimeres de la somatostatine-dopamine |
| WO2005085243A3 (fr) * | 2004-03-04 | 2006-04-06 | Richter Gedeon Vegyeszet | Nouveau procede de production de la cabergoline |
| WO2005085243A2 (fr) * | 2004-03-04 | 2005-09-15 | Richter Gedeon Vegyészeti Gyár Rt. | Nouveau procede de production de la cabergoline |
| EA010689B1 (ru) * | 2004-03-04 | 2008-10-30 | Рихтер Гедеон Ведьесети Дьяр Рт. | Новый способ получения каберголина |
| FR2877945A1 (fr) * | 2004-11-18 | 2006-05-19 | Archemis Sa | Procede de la preparation de la cabergoline |
| WO2006053899A1 (fr) * | 2004-11-18 | 2006-05-26 | Archemis | Procede de preparation de la cabergoline |
| US7217822B2 (en) | 2005-03-17 | 2007-05-15 | Synthon Ip Inc. | Process for making cabergoline |
| WO2007091039A3 (fr) * | 2006-02-08 | 2007-10-18 | Resolution Chemicals Ltd | Production de cabergoline et nouvelle forme polymorphique de ce composé |
| US7939665B2 (en) | 2007-05-04 | 2011-05-10 | Apotex Pharmachem Inc. | Efficient process for the preparation of cabergoline and its intermediates |
| US8952128B2 (en) | 2012-11-01 | 2015-02-10 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9603942B2 (en) | 2012-11-01 | 2017-03-28 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9731027B2 (en) | 2012-11-01 | 2017-08-15 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9777039B2 (en) | 2012-11-01 | 2017-10-03 | Ipsen Pharma S.A.S. | Somatostatin analogs and dimers thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0303557A2 (hu) | 2004-03-01 |
| CA2412861A1 (fr) | 2002-10-31 |
| EP1379526A1 (fr) | 2004-01-14 |
| JP2004525187A (ja) | 2004-08-19 |
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