KR20250028525A - Cgrp 수용체 길항제의 제조 방법 - Google Patents
Cgrp 수용체 길항제의 제조 방법 Download PDFInfo
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- KR20250028525A KR20250028525A KR1020257005576A KR20257005576A KR20250028525A KR 20250028525 A KR20250028525 A KR 20250028525A KR 1020257005576 A KR1020257005576 A KR 1020257005576A KR 20257005576 A KR20257005576 A KR 20257005576A KR 20250028525 A KR20250028525 A KR 20250028525A
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- compound
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- chemical formula
- alkyl
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- 238000000034 method Methods 0.000 title claims abstract description 58
- 230000008569 process Effects 0.000 title abstract description 10
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 title abstract description 7
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 6
- 239000002464 receptor antagonist Substances 0.000 title abstract description 6
- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 title abstract 2
- 239000002253 acid Substances 0.000 claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 116
- 238000006243 chemical reaction Methods 0.000 claims description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 73
- 239000000126 substance Substances 0.000 claims description 61
- -1 [1-(trifluoromethyl)cyclopropyl]methyl Chemical group 0.000 claims description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 47
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 239000011734 sodium Substances 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 241000157855 Cinchona Species 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 16
- 235000021513 Cinchona Nutrition 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- 229930013930 alkaloid Natural products 0.000 claims description 15
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 230000006315 carbonylation Effects 0.000 claims description 13
- 238000005810 carbonylation reaction Methods 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 11
- 229910052744 lithium Inorganic materials 0.000 claims description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- 150000007529 inorganic bases Chemical class 0.000 claims description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims description 9
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 239000011777 magnesium Substances 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 229910010082 LiAlH Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 125000005427 anthranyl group Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical group C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- 229910018286 SbF 6 Inorganic materials 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N methyl propyl carbinol Natural products CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims description 2
- QNVRIHYSUZMSGM-UHFFFAOYSA-N n-butyl methyl carbinol Natural products CCCCC(C)O QNVRIHYSUZMSGM-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000026030 halogenation Effects 0.000 claims 1
- 238000005658 halogenation reaction Methods 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 208000019695 Migraine disease Diseases 0.000 abstract description 13
- 206010027599 migraine Diseases 0.000 abstract description 11
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 abstract description 10
- 238000011282 treatment Methods 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 160
- 239000000203 mixture Substances 0.000 description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- 239000012044 organic layer Substances 0.000 description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 28
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- 239000000725 suspension Substances 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 19
- 239000010410 layer Substances 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
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| US201261610746P | 2012-03-14 | 2012-03-14 | |
| US61/610,746 | 2012-03-14 | ||
| US201261644648P | 2012-05-09 | 2012-05-09 | |
| US61/644,648 | 2012-05-09 | ||
| PCT/US2013/030696 WO2013138418A2 (en) | 2012-03-14 | 2013-03-13 | Process for making cgrp receptor antagonists |
| KR1020247001330A KR20240010553A (ko) | 2012-03-14 | 2013-03-13 | Cgrp 수용체 길항제의 제조 방법 |
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| KR1020247001330A Ceased KR20240010553A (ko) | 2012-03-14 | 2013-03-13 | Cgrp 수용체 길항제의 제조 방법 |
| KR1020217005005A Abandoned KR20210022150A (ko) | 2012-03-14 | 2013-03-13 | Cgrp 수용체 길항제의 제조 방법 |
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| KR1020217005005A Abandoned KR20210022150A (ko) | 2012-03-14 | 2013-03-13 | Cgrp 수용체 길항제의 제조 방법 |
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| US9174989B2 (en) * | 2012-05-09 | 2015-11-03 | Merck Sharp & Dohme Corp. | Process for making CGRP receptor antagonists |
| CN105037210A (zh) * | 2015-05-27 | 2015-11-11 | 江苏大学 | 一种α，β-脱氢-α-氨基酸的合成方法 |
| GB201707938D0 (en) | 2017-05-17 | 2017-06-28 | Univ Sheffield | Compounds |
| KR20230005928A (ko) * | 2020-05-04 | 2023-01-10 | 오츠카 세이야쿠 가부시키가이샤 | Iap 길항제 화합물 및 중간체 및 이를 합성하는 방법 |
| WO2024134683A1 (en) * | 2022-12-21 | 2024-06-27 | Msn Laboratories Private Limited, R&D Center | Novel process for the preparation of intermediate compounds used in the treatment of migraine |
| CN119431222B (zh) * | 2024-11-04 | 2025-10-17 | 杭州澳赛诺生物科技有限公司 | 一种不对称合成乌布吉泮手性中间体的方法 |
| CN119350337A (zh) * | 2024-12-24 | 2025-01-24 | 药康众拓(北京)医药科技有限公司 | 一类氘代哌啶酮酸酰胺氮杂茚满类cgrp抑制剂药物及用途 |
| CN120398716A (zh) * | 2025-04-17 | 2025-08-01 | 珠海奥博凯生物医药技术有限公司 | 一种基于连续流反应技术合成5-氰基-2-氟苯基化合物的方法 |
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| SE0102616D0 (sv) * | 2001-07-25 | 2001-07-25 | Astrazeneca Ab | Novel compounds |
| ATE520661T1 (de) * | 2003-06-27 | 2011-09-15 | Univ Maryland | Heterocyclische verbindungen mit quaternärem stickstoff zum nachweis von wässrigen monosacchariden in physiologischen flüssigkeiten |
| EP1765805B1 (en) | 2004-01-29 | 2013-11-20 | Merck Sharp & Dohme Corp. | Cgrp receptor antagonists |
| CA2599925A1 (en) * | 2005-03-14 | 2006-09-21 | Merck & Co., Inc. | Cgrp receptor antagonists |
| GEP20115140B (en) * | 2006-05-09 | 2011-01-10 | Merck Sharp And Dome Corp | Substituted spirocyclic cgrp receptor antagonists |
| CA2673108A1 (en) * | 2006-12-08 | 2008-06-19 | Merck & Co., Inc. | Constrained spirocyclic compounds as cgrp receptor antagonists |
| US8097750B2 (en) * | 2006-12-20 | 2012-01-17 | Brandeis University | Cinchona alkaloid-catalyzed asymmetric mannich reactions |
| WO2008130524A1 (en) | 2007-04-16 | 2008-10-30 | Merck & Co., Inc. | Aryl heterocyclic cgrp receptor antagonists |
| EP2161996B1 (en) * | 2007-06-05 | 2014-07-16 | Merck Sharp & Dohme Corp. | Heterocyclic carboxamide cgrp receptor antagonists |
| JP5233457B2 (ja) * | 2007-07-17 | 2013-07-10 | セントラル硝子株式会社 | 新規な含フッ素ジカルボン酸およびそれを用いた新規な高分子化合物 |
| KR101098335B1 (ko) * | 2008-07-18 | 2011-12-26 | 성균관대학교산학협력단 | 신코나 기재 이작용성 유기 촉매 및 이를 이용한 메소-고리산무수물의 비대칭 고리 열림 반응을 통한 키랄성헤미에스터의 제조방법 |
| EP2326176B1 (en) * | 2008-08-20 | 2013-09-18 | Merck Sharp & Dohme Corp. | Non-amidic linkers with branched termini as cgrp receptor antagonists |
| JP2012500783A (ja) * | 2008-08-22 | 2012-01-12 | エヴォテック・アクチエンゲゼルシャフト | 新しいブラジキニンｂ１拮抗薬 |
| US8362005B2 (en) | 2008-09-08 | 2013-01-29 | Merk. Sharp & Dohme Corp. | Monocyclic amide CGRP receptor antagonists |
| US8765763B2 (en) * | 2009-06-05 | 2014-07-01 | Boehringer Ingelheim International Gmbh | Substituted piperazines as CGRP antagonists |
| WO2011005731A2 (en) * | 2009-07-08 | 2011-01-13 | Merck Sharp & Dohme Corp. | Process for making cgrp receptor antagonist |
| WO2011014383A1 (en) * | 2009-07-27 | 2011-02-03 | Merck Sharp & Dohme Corp. | Radiolabeled cgrp antagonists |
| TWI522355B (zh) * | 2010-11-12 | 2016-02-21 | 默沙東藥廠 | 六氫吡啶酮甲醯胺氮雜茚滿ｃｇｒｐ受體拮抗劑 |
| EP2637656B1 (en) * | 2010-11-12 | 2016-12-14 | Merck Sharp & Dohme Corp. | N-Piperidinone-indane carboxamides as CGRP receptor antagonists |
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| KR20210116717A (ko) | 2021-09-27 |
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| JP2015516946A (ja) | 2015-06-18 |
| KR20140138705A (ko) | 2014-12-04 |
| EP2825044B1 (en) | 2018-08-15 |
| KR20210022150A (ko) | 2021-03-02 |
| CN104168768B (zh) | 2017-03-01 |
| MX346252B (es) | 2017-03-10 |
| JP2019206586A (ja) | 2019-12-05 |
| KR20200011559A (ko) | 2020-02-03 |
| WO2013138418A2 (en) | 2013-09-19 |
| WO2013138418A3 (en) | 2014-05-30 |
| JP6212534B2 (ja) | 2017-10-11 |
| RU2014141158A (ru) | 2016-05-10 |
| JP2018030858A (ja) | 2018-03-01 |
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| CN104168768A (zh) | 2014-11-26 |
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| BR112014022542A2 (enExample) | 2017-06-20 |
| AU2013232196B2 (en) | 2016-12-01 |
| KR20220164616A (ko) | 2022-12-13 |
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