WO2004092126A2 - Process and intermediates for the preparation of pyrrolidine carboxylic acids - Google Patents
Process and intermediates for the preparation of pyrrolidine carboxylic acids Download PDFInfo
- Publication number
- WO2004092126A2 WO2004092126A2 PCT/US2004/011253 US2004011253W WO2004092126A2 WO 2004092126 A2 WO2004092126 A2 WO 2004092126A2 US 2004011253 W US2004011253 W US 2004011253W WO 2004092126 A2 WO2004092126 A2 WO 2004092126A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- phenyl
- heteroaryl
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000000543 intermediate Substances 0.000 title abstract description 19
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical class OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 93
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 84
- -1 (1) pyridinyl Chemical group 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000001624 naphthyl group Chemical group 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 150000001414 amino alcohols Chemical class 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 230000003213 activating effect Effects 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- VMKAFJQFKBASMU-KRWDZBQOSA-N (3as)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole Chemical compound C([C@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-KRWDZBQOSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 9
- 229930045534 Me ester-Cyclohexaneundecanoic acid Natural products 0.000 claims description 9
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 9
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 6
- 150000001649 bromium compounds Chemical group 0.000 claims description 6
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 claims description 4
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 4
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 4
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical group CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 206010057671 Female sexual dysfunction Diseases 0.000 abstract description 3
- 206010057672 Male sexual dysfunction Diseases 0.000 abstract description 3
- 208000008589 Obesity Diseases 0.000 abstract description 3
- 208000035475 disorder Diseases 0.000 abstract description 3
- 235000020824 obesity Nutrition 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 2
- 102000001796 Melanocortin 4 receptors Human genes 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 65
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 14
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VREKTDQOMSTPDN-NWDGAFQWSA-N (3s,4r)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-1-ium-3-carboxylate Chemical compound C1N(C(C)(C)C)C[C@@H](C(O)=O)[C@@H]1C1=CC=C(F)C=C1F VREKTDQOMSTPDN-NWDGAFQWSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000002222 fluorine compounds Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 3
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PSEHHVRCDVOTID-YYNWCRCSSA-N chloro-bis[(1r,3s,4r,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@@H]([C@H]1C)B(Cl)[C@H]2C[C@@H]3C[C@@H](C3(C)C)[C@@H]2C)[C@H]2C(C)(C)[C@@H]1C2 PSEHHVRCDVOTID-YYNWCRCSSA-N 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 3
- 238000004896 high resolution mass spectrometry Methods 0.000 description 3
- QJRYYOWARFCJQZ-UHFFFAOYSA-N pyrrolidine-1-carbonitrile Chemical compound N#CN1CCCC1 QJRYYOWARFCJQZ-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 0 *[C@@](CN(*)C1)[C@@]1C(O)=O Chemical compound *[C@@](CN(*)C1)[C@@]1C(O)=O 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 102000008316 Type 4 Melanocortin Receptor Human genes 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000005219 aminonitrile group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000001805 chlorine compounds Chemical group 0.000 description 2
- PSEHHVRCDVOTID-VMAIWCPRSA-N chloro-bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@H]([C@@H]1C)B(Cl)[C@H]2[C@H](C)[C@]3(C[C@@](C2)(C3(C)C)[H])[H])[C@@]2([H])C(C)(C)[C@]1([H])C2 PSEHHVRCDVOTID-VMAIWCPRSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 150000003235 pyrrolidines Chemical class 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 1
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- RUEXQFPLRRIFTI-UHFFFAOYSA-N 1-$l^{1}-oxidanyl-2,2,5,5-tetramethylpyrrole-3-carboxamide Chemical compound CC1(C)C=C(C(N)=O)C(C)(C)N1[O] RUEXQFPLRRIFTI-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 1
- BZKNJKWNSIUCCI-UHFFFAOYSA-N 4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid Chemical compound OC(=O)C1CNCC1C1=CC=C(F)C=C1F BZKNJKWNSIUCCI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005964 Acibenzolar-S-methyl Substances 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- TZANTSKRYJQTMM-CQSZACIVSA-N CC(C)(C)N(CCC#N)C[C@H](c(c(F)c1)ccc1F)O Chemical compound CC(C)(C)N(CCC#N)C[C@H](c(c(F)c1)ccc1F)O TZANTSKRYJQTMM-CQSZACIVSA-N 0.000 description 1
- HWKDKMWNIGHDAE-LLVKDONJSA-N CC(C)(C)NC[C@H](c(c(F)c1)ccc1F)O Chemical compound CC(C)(C)NC[C@H](c(c(F)c1)ccc1F)O HWKDKMWNIGHDAE-LLVKDONJSA-N 0.000 description 1
- CSDVBGPWNYKOCE-UHFFFAOYSA-N Cc1ccc(C(CCl)=O)c(F)c1 Chemical compound Cc1ccc(C(CCl)=O)c(F)c1 CSDVBGPWNYKOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010219 Compulsions Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004378 Melanocortin Receptors Human genes 0.000 description 1
- 108090000950 Melanocortin Receptors Proteins 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- LUDHEANGPFVUIE-MRVPVSSYSA-N O[C@H](CCl)c(c(F)c1)ccc1F Chemical compound O[C@H](CCl)c(c(F)c1)ccc1F LUDHEANGPFVUIE-MRVPVSSYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 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
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 150000003945 chlorohydrins Chemical class 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 230000037410 cognitive enhancement Effects 0.000 description 1
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NRUQNUIWEUZVLI-UHFFFAOYSA-O diethanolammonium nitrate Chemical compound [O-][N+]([O-])=O.OCC[NH2+]CCO NRUQNUIWEUZVLI-UHFFFAOYSA-O 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000008102 immune modulation Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000336 melanocortin receptor agonist Substances 0.000 description 1
- 230000006993 memory improvement Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 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
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical class ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 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 class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention provides a process for the preparation of pyrrolidine carboxylic acids of general formula (I).
- the present invention also provides intermediates useful in the disclosed process.
- the compounds of formula (I) are intermediates useful for the preparation of the pyrrolidine compounds of the general formula (II), wherein R2 is phenyl, unsubstituted or substituted with one to three R3 groups, r is 1 and s is 1.
- the compounds of formula (II), along with their use as melanocortin receptor agonists were disclosed in WO 02/068387 (published on September 6, 2002), and WO 02/068388 (published on September 6, 2002).
- the compounds of formula (II) are also useful as agents for the treatment, control or prevention of diseases, disorders or conditions responsive to the activation of one or more of the melanocortin receptors including, but are not limited to, MC-1, MC-2, MC-3, MC-4, or MC-5.
- Such diseases, disorders or conditions include, but are not limited to, obesity, diabetes mellitus, hypertension, hyperlipidemia, osteoarthiitis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, male and female sexual dysfunction, fever, inflammation, immune modulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer' s disease.
- Some compounds encompassed by formula (II) show highly selective affinity for the melanocortin-4 receptor (MC-4R) relative to MC-IR, MC-2R, MC-3R, and MC-5R, which makes them especially useful in the prevention and treatment of obesity, as well as male and/or female sexual dysfunction, including erectile dysfunction.
- MC-4R melanocortin-4 receptor
- MC-5R MC-IR, MC-2R, MC-3R, and MC-5R
- the present invention is directed to an efficient chiral synthesis that produces a pyrrolidine acid of structural formula (I) in a higher yield and utilizes less expensive chemical reagents.
- the synthetic sequence comprises 5 steps with an overall yield of about 71% and a chiral purity of >99.9 % ee of the pyrrolidine acid without the use of chromatography.
- This invention is concerned with a process for preparing compounds of structural formula (I) and certain useful intermediates obtained during that process.
- the process involves the chiral reduction of the halogenated ketone (IV) to form a halogenated alcohol (V).
- the halogenated alcohol (V) is then converted to the amino alcohol (VII), via the epoxide intermediate (VI), by treatment with a base and subsequent treatment with a primary amine.
- the alcohol of compound (VIII) is then converted to a leaving group (shown as -OZ in intermediate LX) by treatment with an alcohol activating reagent, such as C1P0(0R6)2, C1P0(N(R6)2)2, MSCI, Ms2 ⁇ , TsCl or Ts2 ⁇ .
- an alcohol activating reagent such as C1P0(0R6)2, C1P0(N(R6)2)2, MSCI, Ms2 ⁇ , TsCl or Ts2 ⁇ .
- the present invention provides a process for the preparation of compounds of structural formula (I): (D
- Rl is selected from the group consisting of (1) hydrogen,
- R2 is selected from the group consisting of
- heteroaryl is selected from the group consisting of (1) pyridinyl, (2) furyl,
- each R3 is independently selected from the group consisting of
- OCH2CF3 in which heteroaryl is as defined above; alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C ⁇ _4 alkyl, trifluoromethyl, and C ⁇ _4 alkoxy; and wherein any methylene (CH2) carbon atom in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Cl .4 alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
- each R is independently selected from the group consisting of
- alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, Ci-4 alkyl, hydroxy, and C1-4 alkoxy; or two R4 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC ⁇ .4 alkyl; and n is 0, 1, 2, 3 or 4;
- Rl and R2 are as defined above, by treating an alcohol of structural formula (V), wherein X is chloride or bromide and R2 is as defined above,
- R2 is phenyl or thienyl optionally substituted with one to three groups independently selected from R3.
- R2 is phenyl optionally substituted with one to three groups independently selected fromR3.
- Li a subclass of this class, R2 is selected from the group of phenyl; ortho, p ra-difluorophenyl; and /r ⁇ r ⁇ -methoxyphenyl. In a subclass of this subclass, R is ortho, pora-difluorophenyl.
- R3 is selected from the group consisting of halogen, -CF 3 , and OR4.
- R3 is selected from the group consisting of fluoride, bromide, chloride, -CF , and -OC ⁇ _6 alkyl.
- R3 is selected from fluoride, bromide, -CF , and -OCH3.
- n is 0, 1 or 2. In a class of this embodiment n is 0 or 1. In a subclass of this embodiment, n is 0. In another embodiment of the present invention, the reducing agent used to treat the compound of formula (IV) of step (a) is (+)-DIP chloride.
- the compound of formula (IV) of step (a) is treated with a reducing agent in the presence of a catalyst.
- the reducing agent is selected from the group consisting of borane-N,N-diethyl aniline, borane-THF, and borane-dimethylsulfide.
- the reducing agent is borane-N,N-diethyl aniline.
- the catalyst is selected from the group consisting of (S)-CBS and (S)-2-methyl CBS oxazaborolidine.
- the catalyst is (S)-2-methyl CBS oxazaborolidine.
- alcohol of formula (V) is treated with an amine of general formula R NH2, wherein Rl is selected from the group consisting of hydrogen,
- Rl is tert-butyl or -CH2-phenyl. In a subclass of this class, Rl is tert-butyl.
- the alcohol of formula (V) is treated with a base selected from the group consisting of NaOH, LiOH, KOH.
- the base is NaOH.
- the alcohol of formula (V) is treated in a solvent selected from methanol or ethanol.
- the solvent is methanol.
- the solvent is refmxing methanol.
- the amino alcohol of structural formula (VII) is isolated by recrystallization from heptane or hexane.
- the solvent is heptane.
- the compound of formula (XI) is the compound wherein Y is CN. In another embodiment of the present invention, the compound of formula (XI) is the compound wherein Y is -C ⁇ 2R ⁇ , wherein 5 is C1.4 alkyl. In a class of this embodiment Y is -CO2CH3, -C ⁇ 2CH2CH 3 , or
- Y is -CO2CH2CH3, or -C ⁇ 2CH2CH2CH2CH 3 .
- the compound of formula (VIE) is formed by heating the mixture to reflux.
- the compound of formula (VHl) is formed by adding ethanol, formamide or a mixture thereof.
- the compound of formula (VIU) is formed by adding a 1: 1 mixture of ethanol: formamide.
- the compound of formula (VD3) is isolated by recrystallizing from heptane or hexane.
- the compound of formula (VIE) is treated with an alcohol activating reagent selected from the group consisting of C1P0(0R6)2, C1P0(N(R6)2)2, MsCl, Ms2 ⁇ , TsCl, and Ts2 ⁇ , wherein R6 is C1.4 alkyl or phenyl.
- the alcohol activating reagent is chlorodiethyl phosphate.
- the compound of formula (VHl) is treated with a base selected from the group consisting of lithium hexamethyldisilazide, sodium hexamethyl disilazide, and potassium hexamethyldisilazide.
- the base is lithium hexamethyl disilazide.
- the compound of formula (VIU) is treated at a temperature of about -30 to about + 10 C. In a class of this embodiment, the temperature is about -15 C.
- the pyrrolidine compound of formula (X) is hydrolyzed with a base selected from the group consisting of NaOH, LiOH and KOH.
- a base selected from the group consisting of NaOH, LiOH and KOH.
- the base is NaOH.
- the base is aqueous NaOH.
- the pyrrolidine compound of formula (X) is hydrolyzed in a solvent selected from the group consisting of methanol, ethanol, and isopropanol. h a class of this embodiment, the solvent is ethanol.
- the product of step (f) is isolated by forming a zwitterion of the trans pyrrolidine acid of structural formula (I)
- the zwitterion of the pyrrolidine acid of formula (I) is formed at the isoelectric pH using an acid or a base, h one subclass of this class, the acid is selected from sulfuric acid or hydrochloric acid. In a subclass ofthis subclass, the acid is sulfuric acid. In another subclass ofthis class, the isoelectric pH is about 6 and a stoichiometric amount of acid is added.
- the zwitterion of the pyrrolidine acid of formula (I) is recrystallized from a solvent selected from the group consisting of ethanol, isopropyl alcohol, methyl tert-butyl ether or a mixture thereof.
- the solvent is a mixture of isopropyl alcohol and methyl tert-butyl ether.
- the solvent is 1:3 isopropyl alcohoLmethyl tert-butyl ether.
- the present invention also provides a process for the preparation of compounds of structural formula (I):
- Rl is selected from the group consisting of
- R is selected from the group consisting of (1) Ci-4 alkyl, (2) -(CH2)n-cycloalkyl,
- heteroaryl is selected from the group consisting of
- each R3 is independently selected from the group consisting of
- OCH 2 CF 3 in which heteroaryl is as defined above; alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, Ci-4 alkyl, trifluoromethyl, and Ci-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C ⁇ _4 alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
- each R4 is independently selected from the group consisting of
- alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, Ci-4 alkyl, hydroxy, and Ci-4 alkoxy; or two R4 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NCi-4 alkyl; and n is 0, 1, 2, 3 or 4;
- the pyrrolidine compound of formula (X) is hydrolyzed with a base selected from the group consisting of NaOH, LiOH and KOH.
- the base is NaOH.
- the base is aqueous NaOH.
- the pyrrolidine compound of formula (X) is hydrolyzed in a solvent selected from the group consisting of methanol, ethanol, and isopropanol. In a class of this embodiment, the solvent is ethanol.
- the present invention also provides a process for the preparation of compounds of structural formula (XLX):
- Rl is selected from the group consisting of (1) hydrogen, (2) amidino,
- each R3 is independently selected from the group consisting of
- OCH 2 CF 3 in which heteroaryl is as defined above; alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C ⁇ _4 alkyl, trifluoromethyl, and Ci-4 alkoxy; and wherein any methylene (CH2) carbon atom in R is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C ⁇ _4 alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
- heteroaryl is as defined above; alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected
- each R4 is independently selected from the group consisting of
- alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, Ci-4 alkyl, hydroxy, and Ci-4 alkoxy; or two R 4 groups together with the atom to which they are attached form a 4 - to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NCi .4 alkyl; and n is 0, 1, 2, 3, or 4;
- X is bromide or chloride, and R is as defined above, with a reducing agent, and isolating the resulting product;
- X is chloride or bromide and R3 are as defined above, with an amine of general formula RINH2, wherein R is as defined above, and a base in a solvent, and isolating the resulting product;
- Ci -4 alkyl, and R and R3 are as defined above,
- Y is -CN or -C ⁇ 2R ⁇
- R5 is Ci_4 alkyl, and isolating the resulting product
- 3 is selected from the group consisting of halogen, -CF 3 , and OR4.
- R3 is selected from the group consisting of fluoride, bromide, chloride, -CF3, and -OC ⁇ -6 alkyl. In a subclass ofthis class, R3 is selected from fluoride, bromide, CF3, and -OCH3.
- the reducing agent used to treat the compound of formula (XII) of step (a) is (+)-DIP chloride. In another embodiment of the present invention, the compound of formula (XII) of step (a) is treated with a reducing agent in the presence of a catalyst.
- the reducing agent is selected from the group consisting of borane-N,N-diethyl aniline, borane-THF, and borane-dimethylsulfide.
- the reducing agent is borane-N,N-diethyl aniline.
- the catalyst is selected from the group consisting of (S)-CBS and (S)-2-methyl CBS oxazaborolidine.
- the catalyst is (S)-2-methyl CBS oxazaborolidine.
- alcohol of formula (Xlfl) is treated with an amine of general formula R H2, wherein Rl is selected from the group consisting of hydrogen, -(CH2)nPhenyl, or Ci- ⁇ alkyl.
- Rl is tert-butyl or -CH2-phenyl.
- Rl is tert-butyl.
- the alcohol of formula (Xfll) is treated with a base selected from the group consisting of NaOH, LiOH, KOH.
- the base is NaOH.
- the alcohol of formula (XIII) is treated in a solvent selected from methanol or ethanol.
- the solvent is methanol.
- the solvent is refluxing methanol.
- the amino alcohol of structural formula (XV) is isolated by recrystallization from heptane or hexane.
- the solvent is heptane.
- the compound of formula (XI) is the compound wherein Y is CN.
- the compound of formula (XI) is the compound wherein Y is -C ⁇ 2R ⁇ , wherein R ⁇ is Ci-4 alkyl.
- Y is -CO2CH3, -C ⁇ 2CH2CH 3 , or -C ⁇ 2CH2CH2CH2CH 3 .
- Y is -C ⁇ 2CH2CH 3 , or -C ⁇ 2CH2CH2CH2CH2CH.
- the compound of structural formula (XVI) is formed by heating the mixture to reflux.
- the compound of structural formula (XVI) is formed by adding ethanol, formamide or a mixture thereof.
- the compound of structural formula (XVI) is formed by adding a 1:1 mixture of ethanol:formamide.
- the compound of structural formula (XVI) is isolated by recrystallizing from heptane or hexane.
- the compound of structural formula (XVI) is treated with an alcohol activating reagent selected from the group consisting of C1P0(0R6)2, ClPO(N(R6)2)2, MsCl, Ms2 ⁇ , TsCl, and Ts2 ⁇ , wherein R 6 is C1-4 alkyl or phenyl.
- the alcohol activating reagent is chlorodiethyl phosphate.
- the compound of structural formula (XVI) is treated with a base selected from the group consisting of lithium hexamethyldisilazide, sodium hexamethyl disilazide, and potassium hexamethyldisilazide. In a class of this embodiment, the base is lithium hexamethyl disilazide.
- the compound of structural formula (XVT) is treated at a temperature of about -30 to about +10 C. In a class of this embodiment, the temperature is about -15 C.
- the pyrrolidine compound of formula (XVi ⁇ ) is hydrolyzed with a base selected from the group consisting of NaOH, LiOH and KOH. In one class ofthis embodiment, the base is NaOH. hi a subclass ofthis class, the base is aqueous NaOH.
- the pyrrolidine compound of formula (XVT) is treated at a temperature of about -30 to about +10 C. In a class of this embodiment, the temperature is about -15 C.
- the pyrrolidine compound of formula (XVi ⁇ ) is hydrolyzed with a base selected from the group consisting of NaOH, LiOH and KOH. In one class ofthis embodiment, the base is NaOH. hi a subclass ofthis class, the base is aqueous NaOH.
- XVIH is hydrolyzed in a solvent selected from the group consisting of methanol, ethanol, and isopropanol. h a class of this embodiment, the solvent is ethanol.
- step (f) is isolated by forming a zwitterion of the trans pyrrolidine acid of structural formula (XLX)
- the zwitterion of the pyrrolidine acid of formula (XIX) is formed at the isoelectric pH using an acid, hi one subclass of this class, the acid is selected from sulfuric acid or hydrochloric acid. In a subclass of this subclass, the acid is sulfuric acid. In another subclass of this class, the isoelectric pH is about 6 and a stoichiometric amount of acid is added.
- the zwitterion of the pyrrolidine acid of formula (XLX) is recrystallized from a solvent selected from the group consisting of ethanol, isopropyl alcohol, methyl tert-butyl ether or a mixture thereof, h a subclass ofthis class, the solvent is a mixture of isopropyl alcohol and methyl tert-butyl ether. In a subclass ofthis subclass, the solvent is 1:3 isopropyl alcoho methyl tert-butyl ether.
- the present invention also provides a process for the preparation of compounds of structural formula (XLX):
- Rl is selected from the group consisting of
- each R3 is independently selected from the group consisting of
- OCH2CF3 in which heteroaryl is as defined above; alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C ⁇ -4 alkyl, trifluoromethyl, and Ci-4 alkoxy; and wherein any methylene (CH2) carbon atom in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Cl-4 alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
- each R is independently selected from the group consisting of (1) hydrogen
- alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, Cl-4 alkyl, hydroxy, and Ci-4 alkoxy; or two R4 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC ⁇ _4 alkyl; and n is 0, 1, 2, 3 or 4;
- XVfll is hydrolyzed with a base selected from the group consisting of NaOH, LiOH and KOH.
- the base is NaOH.
- the base is aqueous NaOH.
- the pyrrolidine compound of formula (XVITf) is hydrolyzed in a solvent selected from the group consisting of methanol, ethanol, and isopropanol.
- the solvent is ethanol.
- the compound of formula I is compound 1-9
- the zwitterion is formed by the addition of sulfuric acid or hydrochloric acid
- the zwitterion is formed by the addition of sulfuric acid.
- the compound of formula I is compound 2
- the zwitterion is formed by the addition of sulfuric acid or hydrochloric acid. In another class ofthis embodiment, the zwitterion is formed by the addition of sulfuric acid.
- the compound of formula I is compound 3
- the zwitterion is formed by the addition of sulfuric acid or hydrochloric acid. In another class of this embodiment, the zwitterion is formed by the addition of sulfuric acid.
- alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration.
- exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
- halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
- aryl includes phenyl and naphthyl.
- heteroaryl includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
- "5- or 6-Membered heteroaryl” represents a monocyclic heteroaromatic ring.
- heteroaryls useful in this invention include wherein heteroaryl is selected from the group consisting of pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl, and the like.
- Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine and thienopyridine.
- heteroaryl is selected from the group consisting of pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, triazinyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxathiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl.
- cycloalkyl is intended to include non-aromatic rings containing only carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- heterocycloalkyl is intended to include non-aromatic heterocycles containing one to four heteroatoms selected from nitrogen, oxygen and sulfur.
- examples of a 5 or 6-membered heterocycloalkyl include piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like. Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example, NR 4 R 4 may represent NH2, NHCH3, N(CH 3 )CH2CH 3 , and the like.
- the R-enantiomer of alcohol 1-2 may be prepared by treating 14. with (-) DIP chloride, or by treating 14 with a borane reducing agent and a catalyst, such as (R)-CBS or (R)-2-methyl CBS oxazaborolidine under similar reaction conditions.
- the 3R, 4S diastereomer of 14 may be made in a similar fashion.
- the reduction of acetophenone 1 may also be affected by treatment with sodium borohydride and trimethylsilyl chloride catalyzed by (S)- , ⁇ -diphenyl pyrrolidine methanol, or by treatment of acetophenone 14 via asymmetric transfer hydrogenation using chiral rhodium complex catalysis.
- amino nitrile 1 ⁇ 5 Treatment of amino alcohol L4 with acrylonitrile and heating to reflux, followed by the addition of ethanol, formamide, or a mixture thereof, in the later stages of the reaction, affords the amino nitrile 1 ⁇ 5.
- the amino nitrile X5 may be further purified by recrystallizing from heptane or hexane.
- the pyrrolidine nitrile 1 7 was formed by the conversion of the alcohol of nitrile L5 into a leaving group by treatment with an alcohol activating reagent, such as CTPO(OEf)2, to form intermediate
- intermediate L6 in situ.
- a base such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide
- R6 is Ci-4alkyl or phenyl.
- Acid J 9 is formed from nitrile 1 7 via the amide intermediate J 8.
- the pH at the isoelectric point is about pH 6.
- the zwitterion of 1 ⁇ 9 may be recrystallized from ethanol to give the trans pyrrolidine acid zwitterion of 1-9.
- the zwitterion of 1 ⁇ 9 may also be recrystallized as an HCl salt from acetonitrile.
- (S)-Me CBS and (S)-2-methyl-CBS-OAB are (S)-2-methyl CBS oxazaborolidine;
- BOC is tert-butyl carbamate;
- DEAN diethyl aniline;
- DMF is NN-dimethyl formamide;
- EtOAc is ethyl acetate;
- EtOH is ethanol;
- g grams; h or hr is hours;
- H2 is hydrogen;
- HCl hydrochloric acid
- HPLC high pressure liquid chromatography;
- mmHg millimeters of mercury;
- IPA is isopropyl alcohol;
- kg is kilograms;
- L is liters;
- LiHMDS is lithium hexamethyl disilazide;
- M is molar;
- mL is milliliters;
- MeOH is methanol, min is minutes, mol is moles;
- Ms is methanesulfonyl;
- Example 1 is provided to illustrate the invention and is not to be construed as limiting the scope of the invention in any manner.
- a representative experimental procedure utilizing the novel process is detailed below.
- the following Example is directed to the preparation of compound 1-9, but doing so is not intended to limit the present invention to a process for making that specific compound.
- Step B Preparation of Compound 1-4
- NaOH can be added. After 12-20 hours of refluxing, the mixture was concentrated in vacuo to 1/3 volume, then water (5 L) and MTBE (20 L) were added. The resulting layers were separated, and the aqueous phase was re-extracted with MTBE (2 x 2 L). The combined extracts were washed with saturated aqueous NaCI (1 L), then concentrated in vacuo. Heptane (40 L) was added and the concentration was continued to bring the volume to 20 L. The resulting mixture was then heated to -90 °C to dissolve all solids, and allowed to cool to 22 °C to crystallize over 4 hours. The mixture was then cooled to 0 °C, stirred 12-15 hr, and filtered.
- a mixture of aminoethanol X4 from Step B (5.205 kg, 22.68 mol) and acrylonitrile (26.9 L, 408 mol) was heated at reflux (-77 °C) under a nitrogen atmosphere. After heating for 20 hours (with -90% conversion), one equivalent each of ethanol (1.32 L, 22.68 mol) and formamide (0.9 L, 22.68 mol) was added, and heating was continued for 12 hours. After cooling to 22 °C, the solution was concentrated by distillation (80-90 torr at 20-22 °C pot temperature) to 12 L volume. The resulting residue was diluted with isopropyl acetate (22 L) and re-concentrated (55-75 torr and 22-27 °C pot temperature).
- the reaction mixture was quenched with water (50.6 L) at ⁇ 15 °C and extracted with n-heptane (40.5 L) at 20 °C.
- the organic layer was washed with 10% aqueous NaCI solution (52 L).
- the organic layer was carefully extracted with 3 N HCl solution (40.6 L, 121.8 mol) with cooling to keep the temperature ⁇ 35 °C.
- the aqueous layer (58 L) was adjusted to pH 11-12 with 50% aq NaOH (6.13 L, 116.1 mol) and extracted with n-heptane (54 L). The layers were separated.
- Cis- Pyrrolidine Nitrile-HCl Salt lH-NMR (d4-CH 3 OH, 400.25 MHz) ⁇ 7.57 (m, IH), 7.16-7.03 (om, 2H), 4.82 (s, OH), 4.20-4.08 (m, 2H),
- the resulting slurry was heated to reflux (-80 °C) for 2 hours (which only partly dissolves product). The mixture was then allowed to cool. After cooling to 16 °C, MTBE (30.4 L, 3 volumes relative to IPA) was added to the mixture over 5 hours to give a 1:3 ratio of IPA:MTBE. After stirring at 16-17 °C for 3 days, the slurry was filtered, and the solids were washed with 12 L 1:3 IPA:MTBE. The solids were dried in vacuo (150 torr) at 50 °C, with a nitrogen sweep through the batch, for 3 days. Zwitterion IS was isolated as a white crystalline solid.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002521487A CA2521487A1 (en) | 2003-04-14 | 2004-04-09 | Process and intermediates for the preparation of pyrrolidine carboxylic acids |
EP04750027A EP1615882A2 (en) | 2003-04-14 | 2004-04-09 | Process and intermediates for the preparation of pyrrolidine carboxylic acids |
US10/550,640 US20060199958A1 (en) | 2003-04-14 | 2004-04-09 | Process and intermediates for the preparation of pyrrolidine carboxylic acids |
JP2006509940A JP2006523700A (en) | 2003-04-14 | 2004-04-09 | Methods and intermediates for the preparation of pyrrolidinecarboxylic acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46279503P | 2003-04-14 | 2003-04-14 | |
US60/462,795 | 2003-04-14 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2004092126A2 true WO2004092126A2 (en) | 2004-10-28 |
WO2004092126A3 WO2004092126A3 (en) | 2005-01-20 |
WO2004092126B1 WO2004092126B1 (en) | 2005-03-31 |
Family
ID=33299992
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/011253 WO2004092126A2 (en) | 2003-04-14 | 2004-04-09 | Process and intermediates for the preparation of pyrrolidine carboxylic acids |
Country Status (8)
Country | Link |
---|---|
US (1) | US20060199958A1 (en) |
EP (1) | EP1615882A2 (en) |
JP (1) | JP2006523700A (en) |
CN (1) | CN1774419A (en) |
AR (1) | AR044510A1 (en) |
CA (1) | CA2521487A1 (en) |
TW (1) | TW200504011A (en) |
WO (1) | WO2004092126A2 (en) |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006123762A1 (en) * | 2005-05-16 | 2006-11-23 | Sumitomo Chemical Company, Limited | Process for production of pyrrolidine compounds |
WO2009037306A2 (en) * | 2007-09-21 | 2009-03-26 | Basf Se | Accelerated amide and ester reductions with amine boranes and additives |
US7649002B2 (en) | 2004-02-04 | 2010-01-19 | Pfizer Inc | (3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists |
WO2010119848A1 (en) | 2009-04-14 | 2010-10-21 | アステラス製薬株式会社 | Novel method for producing optically active pyrrolidine compound |
CN104695023A (en) * | 2015-02-14 | 2015-06-10 | 河北科技大学 | Tetrahydro pyrrole monohydrate-2-carboxylic acid monocrystal and preparation method thereof |
US9879018B2 (en) | 2015-10-16 | 2018-01-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl and solid state forms thereof |
US10550126B2 (en) | 2015-10-16 | 2020-02-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
WO2021091283A1 (en) | 2019-11-07 | 2021-05-14 | Lg Chem, Ltd. | Melanocortin-4 receptor agonists |
WO2022092908A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Amorphous melanocortin-4 receptor agonist |
WO2022092909A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystalline form i of melanocortin receptor agonist compound, and method for preparing same |
WO2022092914A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystal form iv of melanocortin receptor agonist compound, and preparation method therefor |
WO2022092913A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystalline form iii of melanocortin receptor agonist compound and method for preparing same |
WO2022092910A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystal type ii of malanocortin receptor agonist compound and method for preparing same |
US11365198B2 (en) | 2015-10-16 | 2022-06-21 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
WO2022139444A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Crystal type ii of melanocortin receptor agonist compound and method for preparing same |
WO2022139443A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Crystalline form i of melanocortin receptor agonist compound and method for preparing same |
WO2022139441A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Amorphous melanocortin receptor agonist and method for preparing same |
WO2022139446A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Crystalline form iii of melanocortin receptor agonist compound and preparation method therefor |
WO2022182194A1 (en) | 2021-02-26 | 2022-09-01 | 주식회사 엘지화학 | Melanocortin-4 receptor agonist |
WO2022235107A1 (en) | 2021-05-07 | 2022-11-10 | 주식회사 엘지화학 | Co-crystal of melanocortin receptor agonist compound and vanillin and method for preparing same |
WO2022235104A1 (en) | 2021-05-06 | 2022-11-10 | 주식회사 엘지화학 | Crystalline form v of melanocortin receptor agonist compound, and method for preparing same |
WO2022235105A1 (en) | 2021-05-06 | 2022-11-10 | 주식회사 엘지화학 | Crystal form vii of melanocortin receptor agonist compound and method for preparing same |
WO2022235106A1 (en) | 2021-05-07 | 2022-11-10 | 주식회사 엘지화학 | Crystal form iv of organic acid salts of melanocortin receptor agonist compound, and preparation method thereof |
WO2022235103A1 (en) | 2021-05-07 | 2022-11-10 | 주식회사 엘지화학 | Sulfate crystals of melanocortin receptor agonist compound and method of producing same |
US11512092B2 (en) | 2015-10-16 | 2022-11-29 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11524964B2 (en) | 2015-10-16 | 2022-12-13 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11773106B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3886854A4 (en) | 2018-11-30 | 2022-07-06 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998057933A1 (en) * | 1997-06-17 | 1998-12-23 | Abbott Laboratories | Pyrrolidine carboxylic acid derivatives as endothelin antagonists |
WO2002068387A2 (en) * | 2001-02-28 | 2002-09-06 | Merck & Co., Inc. | Acylated piperidine derivatives as melanocortin-4 receptor agonists |
WO2002068388A2 (en) * | 2001-02-28 | 2002-09-06 | Merck & Co., Inc. | Acylated piperidine derivatives as melanocortin-4 receptor agonists |
-
2004
- 2004-04-06 AR ARP040101164A patent/AR044510A1/en unknown
- 2004-04-09 WO PCT/US2004/011253 patent/WO2004092126A2/en not_active Application Discontinuation
- 2004-04-09 CA CA002521487A patent/CA2521487A1/en not_active Abandoned
- 2004-04-09 EP EP04750027A patent/EP1615882A2/en not_active Withdrawn
- 2004-04-09 US US10/550,640 patent/US20060199958A1/en not_active Abandoned
- 2004-04-09 CN CNA2004800098822A patent/CN1774419A/en active Pending
- 2004-04-09 JP JP2006509940A patent/JP2006523700A/en not_active Withdrawn
- 2004-04-13 TW TW093110274A patent/TW200504011A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998057933A1 (en) * | 1997-06-17 | 1998-12-23 | Abbott Laboratories | Pyrrolidine carboxylic acid derivatives as endothelin antagonists |
WO2002068387A2 (en) * | 2001-02-28 | 2002-09-06 | Merck & Co., Inc. | Acylated piperidine derivatives as melanocortin-4 receptor agonists |
WO2002068388A2 (en) * | 2001-02-28 | 2002-09-06 | Merck & Co., Inc. | Acylated piperidine derivatives as melanocortin-4 receptor agonists |
Cited By (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7649002B2 (en) | 2004-02-04 | 2010-01-19 | Pfizer Inc | (3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists |
WO2006123762A1 (en) * | 2005-05-16 | 2006-11-23 | Sumitomo Chemical Company, Limited | Process for production of pyrrolidine compounds |
WO2009037306A2 (en) * | 2007-09-21 | 2009-03-26 | Basf Se | Accelerated amide and ester reductions with amine boranes and additives |
WO2009037306A3 (en) * | 2007-09-21 | 2009-11-12 | Basf Se | Accelerated amide and ester reductions with amine boranes and additives |
CN101801897A (en) * | 2007-09-21 | 2010-08-11 | 巴斯夫欧洲公司 | Promote acid amides and ester reduction with amine borine and additive |
US8013189B2 (en) | 2007-09-21 | 2011-09-06 | Basf Se | Accelerated amide and ester reductions with amine boranes and additives |
WO2010119848A1 (en) | 2009-04-14 | 2010-10-21 | アステラス製薬株式会社 | Novel method for producing optically active pyrrolidine compound |
EP2420487A1 (en) * | 2009-04-14 | 2012-02-22 | Astellas Pharma Inc. | Novel method for producing optically active pyrrolidine compound |
EP2420487A4 (en) * | 2009-04-14 | 2012-10-17 | Astellas Pharma Inc | Novel method for producing optically active pyrrolidine compound |
CN104695023A (en) * | 2015-02-14 | 2015-06-10 | 河北科技大学 | Tetrahydro pyrrole monohydrate-2-carboxylic acid monocrystal and preparation method thereof |
CN104695023B (en) * | 2015-02-14 | 2017-02-01 | 河北科技大学 | Tetrahydro pyrrole monohydrate-2-carboxylic acid monocrystal and preparation method thereof |
US11535625B2 (en) | 2015-10-16 | 2022-12-27 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11680069B2 (en) | 2015-10-16 | 2023-06-20 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9951080B2 (en) | 2015-10-16 | 2018-04-24 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-alpha]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9963459B1 (en) | 2015-10-16 | 2018-05-08 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-alpla]pyrrolo[2,3-e]-pyrazin-8-YL)-N-(2,2,2-Trifluoroethyl)pyrrol and solid state forms thereof |
US10017517B2 (en) | 2015-10-16 | 2018-07-10 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluorethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10202393B2 (en) | 2015-10-16 | 2019-02-12 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10202394B2 (en) | 2015-10-16 | 2019-02-12 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10344036B2 (en) | 2015-10-16 | 2019-07-09 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-#a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-#carboxamide and solid state forms thereof |
US10519164B2 (en) | 2015-10-16 | 2019-12-31 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3,ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10550126B2 (en) | 2015-10-16 | 2020-02-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10597400B2 (en) | 2015-10-16 | 2020-03-24 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carb oxamide and solid state forms thereof |
US10730883B2 (en) | 2015-10-16 | 2020-08-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10981924B2 (en) | 2015-10-16 | 2021-04-20 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10981923B2 (en) | 2015-10-16 | 2021-04-20 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10995095B2 (en) | 2015-10-16 | 2021-05-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carb oxamide and solid state forms thereof |
US12091415B2 (en) | 2015-10-16 | 2024-09-17 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11186584B2 (en) | 2015-10-16 | 2021-11-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11198697B1 (en) | 2015-10-16 | 2021-12-14 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US12077545B2 (en) | 2015-10-16 | 2024-09-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11993605B2 (en) | 2015-10-16 | 2024-05-28 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11993606B2 (en) | 2015-10-16 | 2024-05-28 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11976077B2 (en) | 2015-10-16 | 2024-05-07 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms therof |
US11795175B2 (en) | 2015-10-16 | 2023-10-24 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11365198B2 (en) | 2015-10-16 | 2022-06-21 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11787815B1 (en) | 2015-10-16 | 2023-10-17 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11780848B2 (en) | 2015-10-16 | 2023-10-10 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide and solid state forms thereof |
US11780847B1 (en) | 2015-10-16 | 2023-10-10 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide and solid state forms thereof |
US11773106B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11773105B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]- pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11767326B2 (en) | 2015-10-16 | 2023-09-26 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11718627B2 (en) | 2015-10-16 | 2023-08-08 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9879019B2 (en) | 2015-10-16 | 2018-01-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11661425B2 (en) | 2015-10-16 | 2023-05-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11535626B2 (en) | 2015-10-16 | 2022-12-27 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1 carboxamide and solid state forms thereof |
US11512092B2 (en) | 2015-10-16 | 2022-11-29 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11524964B2 (en) | 2015-10-16 | 2022-12-13 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11535624B2 (en) | 2015-10-16 | 2022-12-27 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9879018B2 (en) | 2015-10-16 | 2018-01-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl and solid state forms thereof |
WO2021091283A1 (en) | 2019-11-07 | 2021-05-14 | Lg Chem, Ltd. | Melanocortin-4 receptor agonists |
WO2022092910A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystal type ii of malanocortin receptor agonist compound and method for preparing same |
WO2022092908A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Amorphous melanocortin-4 receptor agonist |
WO2022092909A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystalline form i of melanocortin receptor agonist compound, and method for preparing same |
WO2022092914A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystal form iv of melanocortin receptor agonist compound, and preparation method therefor |
WO2022092913A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사 엘지화학 | Crystalline form iii of melanocortin receptor agonist compound and method for preparing same |
WO2022139443A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Crystalline form i of melanocortin receptor agonist compound and method for preparing same |
WO2022139441A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Amorphous melanocortin receptor agonist and method for preparing same |
WO2022139444A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Crystal type ii of melanocortin receptor agonist compound and method for preparing same |
WO2022139446A1 (en) | 2020-12-22 | 2022-06-30 | 주식회사 엘지화학 | Crystalline form iii of melanocortin receptor agonist compound and preparation method therefor |
WO2022182194A1 (en) | 2021-02-26 | 2022-09-01 | 주식회사 엘지화학 | Melanocortin-4 receptor agonist |
WO2022235104A1 (en) | 2021-05-06 | 2022-11-10 | 주식회사 엘지화학 | Crystalline form v of melanocortin receptor agonist compound, and method for preparing same |
WO2022235105A1 (en) | 2021-05-06 | 2022-11-10 | 주식회사 엘지화학 | Crystal form vii of melanocortin receptor agonist compound and method for preparing same |
WO2022235103A1 (en) | 2021-05-07 | 2022-11-10 | 주식회사 엘지화학 | Sulfate crystals of melanocortin receptor agonist compound and method of producing same |
WO2022235107A1 (en) | 2021-05-07 | 2022-11-10 | 주식회사 엘지화학 | Co-crystal of melanocortin receptor agonist compound and vanillin and method for preparing same |
WO2022235106A1 (en) | 2021-05-07 | 2022-11-10 | 주식회사 엘지화학 | Crystal form iv of organic acid salts of melanocortin receptor agonist compound, and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CN1774419A (en) | 2006-05-17 |
WO2004092126A3 (en) | 2005-01-20 |
JP2006523700A (en) | 2006-10-19 |
AR044510A1 (en) | 2005-09-14 |
WO2004092126B1 (en) | 2005-03-31 |
US20060199958A1 (en) | 2006-09-07 |
CA2521487A1 (en) | 2004-10-28 |
TW200504011A (en) | 2005-02-01 |
EP1615882A2 (en) | 2006-01-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1615882A2 (en) | Process and intermediates for the preparation of pyrrolidine carboxylic acids | |
JP7051970B2 (en) | Method for producing a compound having PDE4 inhibitory activity | |
KR102630456B1 (en) | Method of manufacturing brivaracetam | |
KR100284216B1 (en) | Asymmetric Preparation of Florfenicol, Thiamphenicol, Chloramphenicol and Oxazoline Intermediates | |
JP2008534657A (en) | Intermediate compound for the preparation of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3: 6,7] -oxepino [4,5-c] pyrrole | |
TWI438188B (en) | Production method of intermediate compound for synthesizing medicament | |
US20110087030A1 (en) | Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole | |
WO2020094434A1 (en) | Process for preparation of optically enriched isoxazolines | |
CA2930870C (en) | Processes for the preparation of pyrimidinylcyclopentane compounds | |
JP2010532356A (en) | Methods and intermediates for the synthesis of 1,2-substituted 3,4-dioxo-1-cyclobutene compounds | |
US7223867B2 (en) | Preparation of benzosuberonylpiperidine compounds | |
JP2015003908A (en) | Hydroxyproline derivative | |
EP1340743A1 (en) | Optically active amine derivative and method of synthesis | |
JP2004526797A (en) | Method for producing 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl] chroman | |
WO2006062890A1 (en) | Method of making imidazole-2-thiones | |
KR101686087B1 (en) | Process for Production of Optically Active Indoline Derivatives or Salts Thereof | |
KR0136706B1 (en) | Process for 3-amino pyrrolidine derivatives | |
US5710283A (en) | Preparation of chiral pyrrolidinone derivatives | |
EP0659178A1 (en) | Chiral quinolone intermediates | |
KR100850558B1 (en) | Process for preparing useful in synthesis of atorvastatin | |
CN101506146B (en) | Process for preparing 3-amino-5-fluoro-4-dialkoxypentanoi c acid ester | |
JPS63503384A (en) | Effective stereoconservative synthesis of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines and their intermediates | |
JP2024502364A (en) | Method for producing pyrrolopyridine derivatives | |
KR100424393B1 (en) | Process for the preparation of oxiracetam | |
KR20230158354A (en) | New Method for preparing Edoxaban intermediate, and the method for preparing Edoxaban using thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
B | Later publication of amended claims |
Effective date: 20041119 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10550640 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2521487 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 4613/DELNP/2005 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006509940 Country of ref document: JP Ref document number: 20048098822 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004750027 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004750027 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2004750027 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 10550640 Country of ref document: US |