ES2230487T3 - Derivados de cromano 2,6 utiles como agonistas del receptor beta-3-adrenergico. - Google Patents

Info

Publication number

ES2230487T3

ES2230487T3 ES02723958T ES02723958T ES2230487T3 ES 2230487 T3 ES2230487 T3 ES 2230487T3 ES 02723958 T ES02723958 T ES 02723958T ES 02723958 T ES02723958 T ES 02723958T ES 2230487 T3 ES2230487 T3 ES 2230487T3

Authority

ES

Spain

Prior art keywords

sqbullet

amino

methyl

chromen

dihydro

Prior art date

2001-04-23

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

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• 239000000556 agonist Substances 0.000 title description 8
• VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 title description 5
• -1 R 1 Chemical group 0.000 claims abstract description 273
• 150000001875 compounds Chemical class 0.000 claims abstract description 219
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 86
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 51
• 125000005843 halogen group Chemical group 0.000 claims abstract description 45
• UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims abstract description 44
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 42
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 38
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 37
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 35
• 125000004122 cyclic group Chemical group 0.000 claims abstract description 14
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
• 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 5
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 4
• 239000002253 acid Substances 0.000 claims description 141
• 239000000203 mixture Substances 0.000 claims description 133
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 49
• 125000000217 alkyl group Chemical group 0.000 claims description 44
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
• 150000002148 esters Chemical class 0.000 claims description 33
• 150000003839 salts Chemical class 0.000 claims description 25
• 125000001424 substituent group Chemical group 0.000 claims description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
• KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 16
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 15
• 206010012601 diabetes mellitus Diseases 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 108060003345 Adrenergic Receptor Proteins 0.000 claims description 10
• 102000017910 Adrenergic receptor Human genes 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
• 230000001404 mediated effect Effects 0.000 claims description 8
• 230000002485 urinary effect Effects 0.000 claims description 8
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 7
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 7
• 208000035475 disorder Diseases 0.000 claims description 7
• 150000003536 tetrazoles Chemical class 0.000 claims description 7
• QYSINFPZMCNIDU-UHSQPCAPSA-N 4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]-2-(4-methylphenyl)benzoic acid Chemical compound C1=CC(C)=CC=C1C1=CC(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)=CC=C1C(O)=O QYSINFPZMCNIDU-UHSQPCAPSA-N 0.000 claims description 6
• 208000035150 Hypercholesterolemia Diseases 0.000 claims description 6
• 208000008589 Obesity Diseases 0.000 claims description 6
• 239000008103 glucose Substances 0.000 claims description 6
• 208000006575 hypertriglyceridemia Diseases 0.000 claims description 6
• 125000001624 naphthyl group Chemical group 0.000 claims description 6
• 235000020824 obesity Nutrition 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 102000015779 HDL Lipoproteins Human genes 0.000 claims description 5
• 108010010234 HDL Lipoproteins Proteins 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 5
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
• OWTKRFQGTFKXNQ-PKTZIBPZSA-N 4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]-2,6-dimethylbenzoic acid Chemical compound CC1=C(C(O)=O)C(C)=CC(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)=C1 OWTKRFQGTFKXNQ-PKTZIBPZSA-N 0.000 claims description 4
• LRFBGWSTPPWWDW-RPBOFIJWSA-N 4-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]thiophene-2-carboxylic acid Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(C=C1)=CC=C1C1=CSC(C(O)=O)=C1 LRFBGWSTPPWWDW-RPBOFIJWSA-N 0.000 claims description 4
• JSPZGQIBLFFWEM-RPWUZVMVSA-N 5-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]thiophene-2-carboxylic acid Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(C=C1)=CC=C1C1=CC=C(C(O)=O)S1 JSPZGQIBLFFWEM-RPWUZVMVSA-N 0.000 claims description 4
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 4
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 4
• 206010021639 Incontinence Diseases 0.000 claims description 4
• 230000003143 atherosclerotic effect Effects 0.000 claims description 4
• 239000008280 blood Substances 0.000 claims description 4
• 210000004369 blood Anatomy 0.000 claims description 4
• 150000002431 hydrogen Chemical class 0.000 claims description 4
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
• GLHIAFUUFYHCIJ-RTWAWAEBSA-N (1r)-1-(6-aminopyridin-3-yl)-2-[[(2r)-6-[4-(2h-tetrazol-5-yl)phenyl]-3,4-dihydro-2h-chromen-2-yl]methylamino]ethanol Chemical compound C1=NC(N)=CC=C1[C@@H](O)CNC[C@@H]1OC2=CC=C(C=3C=CC(=CC=3)C=3NN=NN=3)C=C2CC1 GLHIAFUUFYHCIJ-RTWAWAEBSA-N 0.000 claims description 3
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
• XSESTUCLKNZCGJ-UHSQPCAPSA-N 1-(4-chloro-2-methylphenyl)-3-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]sulfonylurea Chemical compound CC1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)C=C1 XSESTUCLKNZCGJ-UHSQPCAPSA-N 0.000 claims description 3
• FSUIRDZQAZKAMK-IAPPQJPRSA-N 1-(4-fluorophenyl)-3-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]sulfonylurea Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1=CC=C(F)C=C1 FSUIRDZQAZKAMK-IAPPQJPRSA-N 0.000 claims description 3
• SVDQIHLVRZJJMJ-PXJZQJOASA-N 1-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]sulfonyl-3-(4-methylphenyl)urea Chemical compound C1=CC(C)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)C=C1 SVDQIHLVRZJJMJ-PXJZQJOASA-N 0.000 claims description 3
• LLSWMDSPHVOGKD-IAPPQJPRSA-N 1-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]sulfonyl-3-phenylurea Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1=CC=CC=C1 LLSWMDSPHVOGKD-IAPPQJPRSA-N 0.000 claims description 3
• YWMCHQQXZXIIPB-SJORKVTESA-N 1-[[(2r)-2-[[[(2r)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino]methyl]-3,4-dihydro-2h-chromene-6-carbonyl]amino]cyclopropane-1-carboxylic acid Chemical compound C1=NC(N)=CC=C1[C@@H](O)CNC[C@@H]1OC2=CC=C(C(=O)NC3(CC3)C(O)=O)C=C2CC1 YWMCHQQXZXIIPB-SJORKVTESA-N 0.000 claims description 3
• YEYWVLQJCBVXLW-IAPPQJPRSA-N 1-cyclohexyl-3-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]sulfonylurea Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 YEYWVLQJCBVXLW-IAPPQJPRSA-N 0.000 claims description 3
• GXGREEWZHKZXMH-IZLXSDGUSA-N 3-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]-n-(2-methylphenyl)sulfonylbenzamide Chemical compound CC1=CC=CC=C1S(=O)(=O)NC(=O)C1=CC=CC(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)=C1 GXGREEWZHKZXMH-IZLXSDGUSA-N 0.000 claims description 3
• CANAPWMKNAYZFT-PXJZQJOASA-N 3-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]-n-(4-methoxyphenyl)sulfonylbenzamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC(=O)C1=CC=CC(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)=C1 CANAPWMKNAYZFT-PXJZQJOASA-N 0.000 claims description 3
• XHKPZFLKONEDLG-RPBOFIJWSA-N 3-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]-n-propylsulfonylbenzamide Chemical compound CCCS(=O)(=O)NC(=O)C1=CC=CC(C=2C=C3CC[C@H](CNC[C@H](O)C=4C=NC=CC=4)OC3=CC=2)=C1 XHKPZFLKONEDLG-RPBOFIJWSA-N 0.000 claims description 3
• IJIHLTKJBVDOSG-RPBOFIJWSA-N 5-[4-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]phenyl]thiophene-3-carboxylic acid Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(C=C1)=CC=C1C1=CC(C(O)=O)=CS1 IJIHLTKJBVDOSG-RPBOFIJWSA-N 0.000 claims description 3
• 125000004414 alkyl thio group Chemical group 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 230000001771 impaired effect Effects 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• UEDWDOWDNMRVKB-SQHAQQRYSA-N n-[6-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]pyridin-3-yl]benzenesulfonamide Chemical compound C([C@@H](OC1=CC=2)CNC[C@H](O)C=3C=NC=CC=3)CC1=CC=2C(N=C1)=CC=C1NS(=O)(=O)C1=CC=CC=C1 UEDWDOWDNMRVKB-SQHAQQRYSA-N 0.000 claims description 3
• NGCUTHMQSLSFJS-IRLDBZIGSA-N n-[6-[(2r)-2-[[[(2r)-2-hydroxy-2-pyridin-3-ylethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]pyridin-3-yl]methanesulfonamide Chemical compound N1=CC(NS(=O)(=O)C)=CC=C1C1=CC=C(O[C@@H](CNC[C@H](O)C=2C=NC=CC=2)CC2)C2=C1 NGCUTHMQSLSFJS-IRLDBZIGSA-N 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000003003 spiro group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 2
• QHPKJUUBGFERPJ-QUCCMNQESA-N 2-[(2r)-2-[[[(2r)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino]methyl]-3,4-dihydro-2h-chromen-6-yl]pyridine-4-carboxylic acid Chemical compound C1=NC(N)=CC=C1[C@@H](O)CNC[C@@H]1OC2=CC=C(C=3N=CC=C(C=3)C(O)=O)C=C2CC1 QHPKJUUBGFERPJ-QUCCMNQESA-N 0.000 claims description 2
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
• 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 2
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 125000001072 heteroaryl group Chemical group 0.000 claims description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
• 206010003210 Arteriosclerosis Diseases 0.000 claims 2
• 208000011775 arteriosclerosis disease Diseases 0.000 claims 2
• 230000002526 effect on cardiovascular system Effects 0.000 claims 2
• 230000002496 gastric effect Effects 0.000 claims 2
• HBZVNWNSRNTWPS-UHFFFAOYSA-N 6-amino-4-hydroxynaphthalene-2-sulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C(O)C2=CC(N)=CC=C21 HBZVNWNSRNTWPS-UHFFFAOYSA-N 0.000 claims 1
• 125000004438 haloalkoxy group Chemical group 0.000 claims 1
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
• 238000000034 method Methods 0.000 description 149
• 238000002360 preparation method Methods 0.000 description 149
• 239000000243 solution Substances 0.000 description 148
• 238000006243 chemical reaction Methods 0.000 description 147
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 112
• 239000000047 product Substances 0.000 description 95
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 89
• 235000019439 ethyl acetate Nutrition 0.000 description 88
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 72
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 71
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 65
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
• 238000005481 NMR spectroscopy Methods 0.000 description 61
• 239000007787 solid Substances 0.000 description 58
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
• 239000011541 reaction mixture Substances 0.000 description 47
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 44
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 40
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 40
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 229910052786 argon Inorganic materials 0.000 description 39
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 32
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 31
• 239000002904 solvent Substances 0.000 description 31
• 239000003921 oil Substances 0.000 description 30
• 235000019198 oils Nutrition 0.000 description 30
• 239000012074 organic phase Substances 0.000 description 30
• 230000014759 maintenance of location Effects 0.000 description 28
• 230000002829 reductive effect Effects 0.000 description 28
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
• 239000012071 phase Substances 0.000 description 27
• 239000000741 silica gel Substances 0.000 description 27
• 229910002027 silica gel Inorganic materials 0.000 description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
• 239000012043 crude product Substances 0.000 description 26
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 26
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• 239000000284 extract Substances 0.000 description 24
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
• 238000000746 purification Methods 0.000 description 24
• 238000003756 stirring Methods 0.000 description 23
• 230000008569 process Effects 0.000 description 22
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
• 239000000725 suspension Substances 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
• 238000010992 reflux Methods 0.000 description 19
• 229940095102 methyl benzoate Drugs 0.000 description 18
• 239000000460 chlorine Substances 0.000 description 17
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 16
• 150000001412 amines Chemical class 0.000 description 16
• 239000008346 aqueous phase Substances 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 15
• 238000004128 high performance liquid chromatography Methods 0.000 description 15
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