ME02110B - Postupak za pripremu opioidnih modulatora - Google Patents
Postupak za pripremu opioidnih modulatoraInfo
- Publication number
- ME02110B ME02110B MEP-2015-31A MEP3115A ME02110B ME 02110 B ME02110 B ME 02110B ME P3115 A MEP3115 A ME P3115A ME 02110 B ME02110 B ME 02110B
- Authority
- ME
- Montenegro
- Prior art keywords
- alkyl
- formula
- group
- compound
- aryl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims 12
- 150000001875 compounds Chemical class 0.000 claims 44
- 125000000217 alkyl group Chemical group 0.000 claims 36
- 125000003118 aryl group Chemical group 0.000 claims 31
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 27
- 125000001072 heteroaryl group Chemical group 0.000 claims 27
- 229910052739 hydrogen Inorganic materials 0.000 claims 20
- 239000001257 hydrogen Substances 0.000 claims 20
- -1 quinolizinyl Chemical group 0.000 claims 16
- 125000001424 substituent group Chemical group 0.000 claims 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 13
- 125000000623 heterocyclic group Chemical group 0.000 claims 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 11
- 239000003960 organic solvent Substances 0.000 claims 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 10
- 102220011920 rs386134158 Human genes 0.000 claims 10
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 9
- 125000003545 alkoxy group Chemical group 0.000 claims 9
- 239000003054 catalyst Substances 0.000 claims 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims 8
- 229910052757 nitrogen Inorganic materials 0.000 claims 8
- 229910052799 carbon Inorganic materials 0.000 claims 7
- 125000001153 fluoro group Chemical group F* 0.000 claims 7
- 125000005553 heteroaryloxy group Chemical group 0.000 claims 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 6
- 125000000304 alkynyl group Chemical group 0.000 claims 6
- 125000004104 aryloxy group Chemical group 0.000 claims 6
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims 5
- 125000005241 heteroarylamino group Chemical group 0.000 claims 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 5
- 125000001769 aryl amino group Chemical group 0.000 claims 4
- 229910052801 chlorine Inorganic materials 0.000 claims 4
- 229910052740 iodine Inorganic materials 0.000 claims 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims 3
- 229910052794 bromium Inorganic materials 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims 3
- 125000002541 furyl group Chemical group 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 150000002367 halogens Chemical class 0.000 claims 3
- 125000002883 imidazolyl group Chemical group 0.000 claims 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims 3
- 125000001041 indolyl group Chemical group 0.000 claims 3
- 150000007529 inorganic bases Chemical class 0.000 claims 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 3
- 150000007530 organic bases Chemical class 0.000 claims 3
- 125000002971 oxazolyl group Chemical group 0.000 claims 3
- 229910052763 palladium Inorganic materials 0.000 claims 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims 3
- 125000004076 pyridyl group Chemical group 0.000 claims 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 3
- 239000002904 solvent Substances 0.000 claims 3
- 125000000335 thiazolyl group Chemical group 0.000 claims 3
- 125000001544 thienyl group Chemical group 0.000 claims 3
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 2
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims 2
- 238000005984 hydrogenation reaction Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or 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 to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Optical Modulation, Optical Deflection, Nonlinear Optics, Optical Demodulation, Optical Logic Elements (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (13)
1. Postupak pripreme spoja formule (I) gdje je C6-10aril ili heteroaril izabran iz grupe koja se sastoji od furil, tienil, pirolil, oksazolil, tiazolil, imidazolil, pirazolil, piridinil, pirimidinil, pirazinil, indolil, izoindolil, indolinil, benzofuril, benzotienil, benzimidazolil, benztiazolil, benzoksazolil, kvinolizinil, kvinolinil, izokvinolinil i kvinazolinil; svako R41P je nezavisno izabrano od C1-6alkil, C1-6alkoksi ili fluoro; RJ i RK su oba nezavisno izabrana od vodika ili C1-4alkila: alternativno, RJ i RK su uzeti zajedno sa atomom dušika za koji su vezani čime formiraju petočlani do sedmočlani heterociklil; Pg1 je dušikova zaštitna grupa; koja sadrži reagiranje spoja formule (X), gdje je XP izabrano od CN, -CO2H, -C(O)-Cl ili -C(O)-OC1-4alkil i gdje je YP izabrano od Br, Cl ili I, čime se dobiva odgovarajući spoj formule (XII); reagiranje spoja formule (XII) sa pogodno supstituiranim spojem formule (XVIII); u prisustvu paladijevog katalizatora; u prisustvu organske ili neorganske baze; u organskom otapalu; na temperaturi većoj od približno sobne temperature; čime se dobiva odgovarajući spoj formule (XIX); reagiranje spoja formule (XIX) sa vodikom ili izvorom vodika; u prisustvu katalizatora; u otapalu; na temperaturi većoj od približno sobne temperature; čime se dobiva odgovarajući spoj formule (XX); reagiranje spoja formule (XX) sa vodenom bazom; u organskom otapalu; čime se dobiva odgovarajući spoj formule (I).
2. Postupak prema Patentnom zahtjevu 1, gdje je fenil; fenil je supstituiran sa R41P grupom na drugoj poziciji i sa drugom R41P grupom na četvrtoj poziciji; svako R41P je nezavisno izabrano od C1-2alkil, C1-2alkoksi ili fluoro; RJ i RK su oba nezavisno izabrana od vodik i C1-4alkil; alternativno, RJ i RK su uzeti zajedno sa atomom dušika za koji su vezani čime formiraju 5-7člani heterociklil; i Pg1 je dušikova zaštitna grupa.
3. Postupak prema Patentnom zahtjevu 1, gdje je fenil; fenil je supstituiran sa R41P grupom na drugoj poziciji i sa drugom R41P grupom na četvrtoj poziciji; svako R41P je metil; RJ i RK su oba vodik; i Pg1 je t-butoksikarbonil.
4. Postupak pripreme spoja formule (I) gdje je C6-10aril ili heteroaril izabran iz grupe koja se sastoji od furil, tienil, pirolil, oksazolil, tiazolil, imidazolil, pirazolil, piridinil, pirimidinil, pirazinil, indolil, izoindolil, indolinil, benzofuril, benzotienil, benzimidazolil, benztiazolil, benzoksazolil, kvinolizinil, kvinolinil, izokvinolinil i kvinazolinil; svako R41P je nezavisno izabrano od C1-6alkil, C1-6alkoksi ili fluoro; RJ i RK su svako nezavisno izabrano od vodik ili C1-4alkil; alternativno, RJ i RK su oba uzeti zajedno sa atomom dušika za koji su vezani čime formiraju 5-7člani heterociklil; Pg1 je dušikova zaštitna grupa; sadržavajući reagiranje spoja formule (XIX) sa vodikom ili izvorom vodika; u prisustvu katalizatora; u otapalu; na temperaturi većoj od približno sobne temperature; čime se dobiva odgovarajući spoj formule (XX); reagiranje spoja formule (XX) sa vodenom bazom; u organskom otapalu; čime se dobiva odgovarajućei spoj formule (I).
5. Postupak pripreme spoja formule (Ia) sadržavajući reagiranje spoja formule (Xa), gdje je XP izabrano od CN, -CO2H, -C(O)-Cl ili -C(O)-OC1-4alkil i gdje je YP izabrano od Br, Cl ili I, čime se dobiva odgovarajući spoj formule (XIIa); reagiranje spoja formule (XIIa) sa pogodno supstituiranim spojem formule (XVIIIa); u prisustvu paladijevog katalizatora; u prisustvu organske ili neorganske baze; u organskom otapalu; na temperaturi većoj od približno sobne temperature; čime se dobiva odgovarajući spoj formule (XIXa); reagiranje spoja formule (XIXa) sa plinovitim vodikom, pod pritiskom dovoljnim za hidrogeniziranje; u prisustvu pogodnog kiralnog katalizatora; na temperaturi većoj od približno sobne temperature; u organskom otapalu; čime se dobiva odgovarajući spoj formule (XXa); reagiranje spoja formule (XXa) sa vodenom bazom; u organskom otapalu; čime se dobiva odgovarajući spoj formule (Ia).
6. Postupak prema Patentnom zahtjevu 5, gdje spoj formule (XIIa) reagira sa spojem formule (XVIIIa) u prisustvu Pd2(dba)3 i P(o-toluen)3.
7. Postupak prema Patentnom zahtjevu 5, gdje je kiralni katalizator [Rh(cod)(R,R-DIPAMP)]+BF4-.
8. Postupak pripreme spoja formule (Ia) sadržavajući reagiranje spoja formule (XIXa) sa plinovitim vodikom, pod pritiskom dovoljnim za hidrogeniziranje; u prisustvu pogodnog kiralnog katalizatora; na temperaturi većoj od približno sobne temperature; u organskom otapalu; čime se dobiva odgovarajući spoj formule (XXa); reagiranje spoja formule (XXa) sa vodenom bazom; u organskom otapalu; čime se dobiva odgovarajući spoj formule (Ia).
9. Postupak pripreme spoja formule (II) gdje je C6-10aril ili heteroaril izabran iz grupe koja se sastoji od furil, tienil, pirolil, oksazolil, tiazolil, imidazolil, pirazolil, piridinil, pirimidinil, pirazinil, indolil, izoindolil, indolinil, benzofuril, benzotienil, benzimidazolil, benztiazolil, benzoksazolil, kvinolizinil, kvinolinil, izokvinolinil i kvinazolinil; svako R41P je nezavisno izabrano od C1-6alkil, C1-6alkoksi ili fluoro; RJ i RK su svako nezavisno izabrano od vodik ili C1-4alkil; alternativno, RJ i RK su uzeti zajedno sa atomom dušika za koji su vezani čime formiraju 5-7člani heterociklil; R1 je izabran iz grupe koja se sastoji od vodik, C1-6alkil; cikloalkil, heterociklil, aril(C1-6)alkil, i heteroaril(C1-6)alkil; pri čemu kada R1 je fenil(C1-6)alkil, fenil je opcionalno fuzioniran za heterociklil ili cikloalkil; pri čemu kada R1 je C1-2alkil, spomenuti C1-2alkil je opcionalno supstituiran sa jednim do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkoksi, aril, cikloalkil, heterociklil, hidroksi, cijano, amino, C1-6alkilamino, (C1-6alkil)2amino, trifluorometil, i karboksi; i dalje, kada R1 je C3-6alkil, spomenuti C3-6alkil je opcionalno supstituiran sa jednim do tri supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkoksi, aril, cikloalkil, heterociklil, hidroksi, cijano, amino, C1-6alkilamino, (C1-6alkil)2amino, trifluorometil, i karboksi; pri čemu su cikloalkil i heterociklil od C1-2alkil i C3-6alkil opcionalno supstituirani sa jednim do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkil, hidroksi (C1-6)alkil, C1-6alkoksi, hidroksi, cijano, amino, C1-6alkilamino, (C1-6alkil)2amino, trifluorometil, karboksi, aril(C1-6) alkoksikarbonil, C1-6alkoksikarbonil, aminokarbonil, C1-6alkilaminokarbonil, (C1-6 alkil)2aminokarbonil, i aminosulfonil; nadalje, pri čemu su cikloalkil i heterociklil od R1 opcionalno supstituirani sa jednim do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkil, hidroksi(C1-6)alkil, C1-6alkoksi, hidroksi, cijano, amino, C1-6alkilamino, (C1-6alkil)2amino, trifluorometil, karboksi, aril(C1-6) alkoksikarbonil, C1-6 alkoksikarbonil, aminokarbonil, C1-6alkilaminokarbonil, (C1-6 alkil)2aminokarbonil, i aminosulfonil; nadalje, gdje su aril i heteroaril porcija od R1 supstituenata aril(C1-6)alkil i heteroaril (C1-6)alkil, opcionalno supstituirani sa jednim do tri R11 supstituenata nezavisno izabranih iz grupe koja se sastoji od C1-6alkil; hidroksi(C1-6)alkil; C1-6alkoksi; C6-10aril(C1-6)alkil; C6-10aril(C1-6)alkoksi; C6-10aril; heteroaril opcionalno supstituiran sa jednim do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-4alkil, C1-4alkoksi, i karboksi; cikloalkil; heterociklil; C6-10ariloksi; heteroariloksi; cikloalkiloksi; heterocikliloksi; amino; C1-6alkilamino; (C1-6 alkil)2amino; C3-6 cikloalkilaminokarbonil; hidroksi(C1-6)alkilaminokarbonil; C6-10arilaminokarbonil gdje je C6-10aril opcionalno supstituiran sa karboksi ili C1-4alkoksikarbonil; heterociklilkarbonil; karboksi; C1-6alkilkarboniloksi; C1-6alkoksikarbonil; C1-6alkilkarbonil; C1-6alkilkarbonilamino; aminokarbonil; C1-6alkilaminokarbonil; (C1-6alkil)2aminokarbonil; cijano; halogen; trifluorometil; trifluorometoksi; i hidroksi; pod uvjetom da je ne više od jednog R11 supstituenta izabrano iz grupe koja se sastoji od C6-10 aril(C1-6)alkil; C6-10aril(C1-6)alkoksi; C6-10aril; heteroaril opcionalno supstituiran sa jednim do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-4alkil, C1-4alkoksi, i karboksi; cikloalkil; heterociklil; C6-10ariloksi; heteroariloksi; cikloalkiloksi; C6-10arilaminokarbonil, heterociklilkarbonil; i heterocikliloksi; R2 je vodik, C1-8alkil, hidroksi(C1-8)alkil, C6-10aril(C1-6)alkoksi(C1-6)alkil, iliC6-10aril(C1-8)alkil; pri čemu je C6-10aril grupa u C6-10aril, koji sadrži supstituente od R2, opcionalno supstituirana sa jednim do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkil, C1-6alkoksi, hidroksi, amino, C1-6 alkilamino, (C1-6alkyl)2amino, aminokarbonil, C1-6alkilaminokarbonil, (C1-6 alkil)2aminokarbonil, cijano, fluoro, kloro, bromo, trifluorometil, i trifluorometoksi; i, pri čemu su C1-6alkil i C1-6alkoksi supstituenti arila opcionalno supstituirani sa hidroksi, amino, C1-6alkilamino, (C1-6alkil)2amino, ili aril; A je izabrano iz grupe koja se sastoji od aril, prsten sistema a-1, a-2, a-3, i a-4, opcionalno supstituirano sa R3 i R5; gdje je A-B izabrano iz grupe koja se sastoji od N-C, C-N, N-N i C-C; gdje je D-E izabrano iz grupe koja se sastoji od O-C, S-C, i ON; i gdje je F-G izabrano iz grupe koja se sastoji od N-O i C-O; R3 je jedan do dva supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkil, aril, aril(C1-6)alkil, aril(C2-6)alkenil, aril(C2-6)alkinil, heteroaril, heteroaril(C1-6)alkil, heteroaril(C2-6) alkenil, heteroaril(C2-6) alkinil, amino, C1-6alkilamino, (C1-6alkil)2amino, arilamino, heteroarilamino, ariloksi, heteroariloksi, trifluorometil, i halogen; pri čemu su aril i heteroaril, kao i aril i heteroaril od aril(C1-6)alkil, aril(C2-6)alkenil, aril(C2-6) alkinil, heteroaril(C1-6)alkil, heteroaril(C2-6)alkenil, heteroaril(C2-6)alkinil, arilamino, heteroarilamino, ariloksi, i heteroariloksi, opcionalno supstituirani sa jednim do pet fluoro supstituenata ili jednim do tri supstituenta nezavisno izabrana iz grupe koja se sastoji od C1-6alkil, hidroksi(C1-6)alkil, C1-6alkoksi, C6-10aril(C1-6)alkil, C6-10 aril (C1-6)alkoksi, C6-10aril, C6-10ariloksi, heteroaril(C1-6)alkil, heteroaril(C1-6)alkoksi, heteroaril, heteroariloksi, C6-10arilamino, heteroarilamino, amino, C1-6alkilamino, (C1-6alkil)2amino, karboksi(C1-6)alkilamino, karboksi, C1-6alkilearbonil, C1-6alkoksikarbonil, C1-6alkilkarbonilamino, aminokarbonil, C1-6alkilaminokarbonil, (C1-6alkil)2aminokarbonil, karboksi(C1-6)alkilaminokarbonil, cijano, halogen, trifluorometil, trifluorometoksi, hidroksi, C1-6alkilsulfonil, i C1-6alkilsulfonilamino; pod uvjetom da je ne više od jednog R3 je izabrano iz grupe koja se sastoji od aril, heteroaril, aril(C1-6)alkil, aril(C2-6)alkenil, aril(C2-6)alkinil, heteroaril, heteroaril(C1-6)alkil, heteroaril(C2-6)alkenil, heteroaril(C2-6)alkinil, arilamino, heteroarilamino, ariloksi, i heteroariloksi; i pri čemu su C1-6alkil, i C1-6alkil od aril(C1-6)alkil i heteroaril(C1-6)alkil, opcionalno supstituirani sa supstituentom izabranim iz grupe koja se sastoji od hidroksi, karboksi, C1-4alkoksikarbonil, amino, C1-6alkilamino, (C1-6alkil)2amino, aminokarbonil, (C1-4)alkilaminokarbonil, di(C1-4) alkilaminokarbonil, aril, heteroaril, arilamino, heteroarilamino, ariloksi, heteroariloksi, aril(C1-4) alkoksi, i heteroaril(C1-4)alkoksi; R5 je supstituent atomu dušika prstena A izabran iz grupe koja se sastoji od vodika i C1-4alkil; Ra i Rb su nezavisno izabrani iz grupe koja se sastoji od vodik, C1-6alkil, i C1-6alkoksikarbonil; alternativno kada su Ra i Rb svaki osim vodika, Ra i Rb su opcionalno uzeti zajedno sa atomom dušika za koji su oba vezani čime se formira 5-8člani monociklični prsten; i farmaceutski prihvatljivi enantiomeri, diastereomeri, racemati, i njihove soli; sadrži reagiranje spoja formule (X), gdje je XP izabrano od CN, -CO2H, -C(O)-Cl ili -C(O)-OC1-4alkil i gdje je YP izabrano od Br, Cl ili I, čime se dobiva odgovarajući spoj formule (XII); reagiranje spoje formule (XII) sa pogodno supstituiranim spojem formule (XVIII), gdje Pg1 je dušikova zaštitna grupa; u prisustvu paladijevog katalizatora; u prisustvu organske ili neorganske baze; u organskom otapalu; na temperaturi većoj od približno sobne temperature; čime se dobiva odgovarajuće spoje formule (XIX); reagiranje spoja formule (XIX) sa vodikom ili izvorom vodika; u prisustvu katalizatora; u otapalu; na temperaturi većoj od približno sobne temperature; čime se dobiva odgovarajuće spoje formule (XX); reagiranje spoja formule (XX) sa vodenom bazom; u organskom otapalu; čime se dobiva odgovarajuće spoje formule (I); reagiranje spoja formule (I), čime se dobiva odgovarajući spoj formule (II).
10. Postupak prema Patentnom zahtjevu 9, gdje je fenil; fenil je supstituiran sa R41P grupom na drugoj poziciji i sa drugom R41P grupom na četvrtoj poziciji; svaki R41P je nezavisno izabran od C1-2alkil, C1-2alkoksi ili fluoro; RJ i RK su svaki nezavisno izabran od vodik ili C1-4alkil; alternativno, RJ i RK su uzeti zajedno sa atomom dušika za koji su vezani čime formiraju 5-7člani heterociklil; i Pg1 je dušikova zaštitna grupa.
11. Postupak prema Patentnom zahtjevu 9, gdje je fenil, fenil je supstituiran sa R41P grupom na drugoj poziciji i sa drugom R41P grupom na četvrtoj poziciji; svaki R41P je metil; RJ i RK su oba vodik; i Pg1 je t-butoksikarbonil.
12. Postupak prema bilo kojem od Patentnih zahtjeva 1-3, 5-7 i 9-11, gdje je XP izabrano od CN, -C(O)-Cl ili -C(O)-OC1-4alkil.
13. Postupak prema bilo kojem od Patentnih zahtjeva 1-3, 5-7 i 9-11, gdje je YP izabrano od Cl ili I.
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| US7041681B2 (en) * | 2002-04-29 | 2006-05-09 | Janssen Pharmaceutica N.V. | Compounds as opioid receptor modulators |
| HUE029852T2 (en) * | 2004-03-15 | 2017-04-28 | Janssen Pharmaceutica Nv | Opioid receptor modulators |
| MX2007011409A (es) * | 2005-03-14 | 2008-02-22 | Johnson & Johnson | Procedimiento de preparacion de moduladores opioides. |
| HUE028538T2 (en) | 2007-07-09 | 2016-12-28 | Forest Tosara Ltd | New Crystals and Procedure 5 - ({[2-Amino-3- (4-carbamoyl-2,6-dimethylphenyl) propionyl] - [1- (4-phenyl-1H-imidazol-2-yl) ethyl] ] -amino} -methyl) -2-methoxybenzoic acid |
| TWI468375B (zh) * | 2008-10-27 | 2015-01-11 | Janssen Pharmaceutica Nv | 製備經保護之ｌ－丙胺酸衍生物之方法 |
| IS2977B (is) | 2015-02-23 | 2017-07-15 | Actavis Group Ptc Ehf. | Aðferð til framleiðslu á milliefnum sem eru nytsamleg við nýsmíði á elúxadólíni |
| JPWO2017043626A1 (ja) * | 2015-09-11 | 2018-06-21 | 株式会社カネカ | 光学活性４−カルバモイル−２，６−ジメチルフェニルアラニン誘導体の製造法 |
| CN105777584B (zh) * | 2016-03-28 | 2018-01-02 | 成都伊诺达博医药科技有限公司 | 丙氨酸衍生物的制备方法 |
| CN105693554B (zh) * | 2016-04-06 | 2017-08-08 | 成都伊诺达博医药科技有限公司 | 丙氨酸衍生物的制备方法 |
| WO2017221213A1 (en) * | 2016-06-23 | 2017-12-28 | Sun Pharmaceutical Industries Limited | Processes for the preparation of eluxadoline |
| WO2018047131A1 (en) * | 2016-09-09 | 2018-03-15 | Sun Pharmaceutical Industries Limited | Amorphous eluxadoline |
| US10479769B2 (en) | 2016-09-20 | 2019-11-19 | Sun Pharmaceutical Industries Limited | Processes for the preparation of eluxadoline |
| CN106866463B (zh) * | 2017-01-24 | 2018-08-28 | 富乐马鸿凯（大连）医药有限公司 | 艾沙度林中间体的制备方法 |
| US10738013B2 (en) | 2017-01-27 | 2020-08-11 | Quimica Sintetica, S.A. | Eluxadoline crystalline forms and processes for their preparation |
| WO2018138272A1 (en) | 2017-01-27 | 2018-08-02 | Quimica Sintetica, S. A. | Eluxadoline crystalline form and process for the preparation thereof |
| CN111377832A (zh) * | 2018-12-27 | 2020-07-07 | 江苏联昇化学有限公司 | 一种伊卢多啉中间体制备的新方法 |
| EP4129402A4 (en) | 2020-03-31 | 2024-06-12 | Mitsubishi Tanabe Pharma Corporation | HYDROXYPYRROLIDINE DERIVATIVE AND MEDICAL USE THEREOF |
| CN114163348A (zh) * | 2020-11-27 | 2022-03-11 | 成都泰蓉生物科技有限公司 | 一种氨酰基取代的l-苯丙氨酸的合成方法 |
| CN114507252B (zh) * | 2022-02-21 | 2023-10-27 | 广西大学 | 新型芳基硅烷化合物的合成方法 |
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- 2007-10-12 ZA ZA200708810A patent/ZA200708810B/xx unknown
- 2007-10-12 CR CR9438A patent/CR9438A/es not_active Application Discontinuation
- 2007-10-15 NO NO20075269A patent/NO340604B1/no not_active IP Right Cessation
- 2007-10-15 NO NO20075268A patent/NO20075268L/no not_active Application Discontinuation
-
2009
- 2009-10-16 US US12/580,641 patent/US20100036132A1/en not_active Abandoned
- 2009-11-25 US US12/625,973 patent/US20100152460A1/en not_active Abandoned
-
2010
- 2010-11-18 IL IL209402A patent/IL209402A/en active IP Right Grant
-
2013
- 2013-07-16 JP JP2013147688A patent/JP5802242B2/ja not_active Expired - Fee Related
-
2015
- 2015-02-19 CY CY20151100172T patent/CY1116104T1/el unknown
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