PT2137196E - Compostos tricíclicos contendo azoto como agentes antibacterianos - Google Patents

Info

Publication number

PT2137196E

PT2137196E PT08749580T PT08749580T PT2137196E PT 2137196 E PT2137196 E PT 2137196E PT 08749580 T PT08749580 T PT 08749580T PT 08749580 T PT08749580 T PT 08749580T PT 2137196 E PT2137196 E PT 2137196E

Authority

PT

Portugal

Prior art keywords

dihydro

methyl

amino

dione

piperidinyl

Prior art date

2007-04-20

Links

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• Global Dossier
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• 239000003242 anti bacterial agent Substances 0.000 title description 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title 1
• -1 thio (C1 -C6) alkyl Chemical group 0.000 claims description 353
• 150000001875 compounds Chemical class 0.000 claims description 262
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 168
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 145
• 239000012458 free base Substances 0.000 claims description 108
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 69
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• 239000001257 hydrogen Substances 0.000 claims description 48
• 150000003839 salts Chemical class 0.000 claims description 31
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
• OPQFKYZLJABARW-UHFFFAOYSA-N 1,4,7-triazatricyclo[6.3.1.04,12]dodeca-2,6,8(12),9-tetraene-5,11-dione Chemical compound N1=CC(=O)N2C=CN3C(=O)C=CC1=C32 OPQFKYZLJABARW-UHFFFAOYSA-N 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
• MMUYWCUHCPWDAH-UHFFFAOYSA-N 1,4-diazatricyclo[6.3.1.04,12]dodeca-2,6,8(12),9-tetraene-5,11-dione Chemical compound C1=CC(=O)N2C=CN3C(=O)C=CC1=C32 MMUYWCUHCPWDAH-UHFFFAOYSA-N 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
• 125000006574 non-aromatic ring group Chemical group 0.000 claims description 16
• 125000003118 aryl group Chemical group 0.000 claims description 15
• 150000001204 N-oxides Chemical class 0.000 claims description 14
• 125000004429 atom Chemical group 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 208000035143 Bacterial infection Diseases 0.000 claims description 8
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 150000002367 halogens Chemical group 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• PJKGAYRITLVRLH-LLVKDONJSA-N (2r)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3h,8h-2a,5,8a-triazaacenaphthylene-3,8-dione Chemical compound C1CC(N)CCN1C[C@H](CN1C(C=C2)=O)N3C1=C2N=CC3=O PJKGAYRITLVRLH-LLVKDONJSA-N 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000000623 heterocyclic group Chemical group 0.000 claims description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 125000003277 amino group Chemical group 0.000 claims description 6
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• 201000008827 tuberculosis Diseases 0.000 claims description 6
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
• BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000005647 linker group Chemical group 0.000 claims description 4
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
• RPTVNNSZTGSBJN-UHFFFAOYSA-N 2-[[4-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethylamino)piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound O1CCOC(C=N2)=C1C=C2CNC(CC1)CCN1CC1CN2C(=O)C=NC3=C2N1C(=O)C=C3 RPTVNNSZTGSBJN-UHFFFAOYSA-N 0.000 claims description 3
• 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 3
• 125000005605 benzo group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
• 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
• 206010062255 Soft tissue infection Diseases 0.000 claims description 2
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
• 125000006413 ring segment Chemical group 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• 229910052721 tungsten Inorganic materials 0.000 claims description 2
• 208000019206 urinary tract infection Diseases 0.000 claims description 2
• MMKKZZRTGQEWMB-UHFFFAOYSA-N 1-({4-[([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-4h,9h-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione Chemical compound C1N(C=23)C(=O)C=CC=2C=CC(=O)N3C1CN(CC1)CCC1NCC(N=C1)=CC2=C1OCS2 MMKKZZRTGQEWMB-UHFFFAOYSA-N 0.000 claims 2
• RHGRMWGOKQLRGE-MSOLQXFVSA-N (2R)-2-[[(2S)-2-[([1,3]oxathiolo[5,4-c]pyridin-6-ylmethylamino)methyl]morpholin-4-yl]methyl]-1,4-diazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C([C@@H]1OCCN(C1)C[C@H]1N2C(=O)C=CC=3C=CC(N(C1)C=32)=O)NCC(N=C1)=CC2=C1OCS2 RHGRMWGOKQLRGE-MSOLQXFVSA-N 0.000 claims 1
• GLTMIYGEUVNRHF-MOPGFXCFSA-N (2R)-2-[[(2S)-2-[[(6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl)methylamino]methyl]morpholin-4-yl]methyl]-1,4-diazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound N12C(=O)C=CC(C=CC3=O)=C1N3C[C@H]2CN(CCO1)C[C@@H]1CNCC1=CC(OCCO2)=C2C=C1F GLTMIYGEUVNRHF-MOPGFXCFSA-N 0.000 claims 1
• CBWKIERCSVTDRI-HXUWFJFHSA-N (2R)-2-[[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethylamino)piperidin-1-yl]methyl]-1,4-diazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound O1CCOC2=CC(CNC3CCN(CC3)C[C@H]3N4C(=O)C=CC=5C=CC(N(C3)C=54)=O)=CC=C21 CBWKIERCSVTDRI-HXUWFJFHSA-N 0.000 claims 1
• PEVLAFPJSPRSFM-JOCHJYFZSA-N (2R)-2-[[4-(3,4-dihydro-2H-chromen-7-ylmethylamino)piperidin-1-yl]methyl]-1,4-diazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1CCOC2=CC(CNC3CCN(CC3)C[C@H]3N4C(=O)C=CC=5C=CC(N(C3)C=54)=O)=CC=C21 PEVLAFPJSPRSFM-JOCHJYFZSA-N 0.000 claims 1
• UVVRJTUMMNJDBE-QGZVFWFLSA-N (2R)-2-[[4-([1,2,5]thiadiazolo[3,4-b]pyridin-6-ylmethylamino)piperidin-1-yl]methyl]-1,4-diazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound C1=NC2=NSN=C2C=C1CNC(CC1)CCN1C[C@H]1N2C(=O)C=CC(C=CC3=O)=C2N3C1 UVVRJTUMMNJDBE-QGZVFWFLSA-N 0.000 claims 1
• FZNZGXHLNWWFRD-QGZVFWFLSA-N (2R)-2-[[4-[(4-fluoro-1H-benzimidazol-2-yl)methylamino]piperidin-1-yl]methyl]-1,4-diazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound N12C(=O)C=CC(C=CC3=O)=C1N3C[C@H]2CN(CC1)CCC1NCC(N1)=NC2=C1C=CC=C2F FZNZGXHLNWWFRD-QGZVFWFLSA-N 0.000 claims 1
• OUFUZFYHLBRNHA-QGZVFWFLSA-N (3R)-3-[[4-(2,3-dihydro-[1,4]oxathiino[2,3-c]pyridin-7-ylmethylamino)piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound S1CCOC(C=N2)=C1C=C2CNC(CC1)CCN1C[C@H]1N2C(=O)C=NC(C=CC3=O)=C2N3C1 OUFUZFYHLBRNHA-QGZVFWFLSA-N 0.000 claims 1
• BTPHCQKZRYEOES-MRXNPFEDSA-N (3R)-3-[[4-[(3-oxo-4H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound N12C(=O)C=NC(C=CC3=O)=C1N3C[C@H]2CN(CC1)CCC1NCC1=CC=C2SCC(=O)NC2=N1 BTPHCQKZRYEOES-MRXNPFEDSA-N 0.000 claims 1
• XIZMQMZFYXGFKF-QGZVFWFLSA-N (3R)-3-[[4-[(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methylamino]piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.04,12]dodeca-6,8(12),9-triene-5,11-dione Chemical compound O1CCOC2=C1C=CC(CNC1CCN(C[C@H]3N4C=5N(C(C=CC=5N=CC4=O)=O)C3)CC1)=C2F XIZMQMZFYXGFKF-QGZVFWFLSA-N 0.000 claims 1
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
• 241000588697 Enterobacter cloacae Species 0.000 claims 1
• 241000194032 Enterococcus faecalis Species 0.000 claims 1
• 241000194031 Enterococcus faecium Species 0.000 claims 1
• 241000588724 Escherichia coli Species 0.000 claims 1
• 241000606768 Haemophilus influenzae Species 0.000 claims 1
• 241000588915 Klebsiella aerogenes Species 0.000 claims 1
• 241000588747 Klebsiella pneumoniae Species 0.000 claims 1
• 206010024971 Lower respiratory tract infections Diseases 0.000 claims 1
• 241000588655 Moraxella catarrhalis Species 0.000 claims 1
• 101150020251 NR13 gene Proteins 0.000 claims 1
• 241000588770 Proteus mirabilis Species 0.000 claims 1
• 241000589517 Pseudomonas aeruginosa Species 0.000 claims 1
• 206010057190 Respiratory tract infections Diseases 0.000 claims 1
• 101000585507 Solanum tuberosum Cytochrome b-c1 complex subunit 7 Proteins 0.000 claims 1
• 241000191967 Staphylococcus aureus Species 0.000 claims 1
• 241000122973 Stenotrophomonas maltophilia Species 0.000 claims 1
• 241000193998 Streptococcus pneumoniae Species 0.000 claims 1
• 241000193996 Streptococcus pyogenes Species 0.000 claims 1
• 206010046306 Upper respiratory tract infection Diseases 0.000 claims 1
• 125000004220 acenaphthylen-1-yl group Chemical group [H]C1=C(*)C2=C3C1=C([H])C([H])=C([H])C3=C([H])C([H])=C2[H] 0.000 claims 1
• 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims 1
• 229940092559 enterobacter aerogenes Drugs 0.000 claims 1
• 229940032049 enterococcus faecalis Drugs 0.000 claims 1
• 229940047650 haemophilus influenzae Drugs 0.000 claims 1
• 208000020029 respiratory tract infectious disease Diseases 0.000 claims 1
• 206010040872 skin infection Diseases 0.000 claims 1
• 229940031000 streptococcus pneumoniae Drugs 0.000 claims 1
• 238000002560 therapeutic procedure Methods 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 957
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 955
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 212
• 239000011541 reaction mixture Substances 0.000 description 198
• 239000000243 solution Substances 0.000 description 184
• 239000007787 solid Substances 0.000 description 179
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 154
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 153
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 142
• 239000000047 product Substances 0.000 description 137
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 136
• 239000000203 mixture Substances 0.000 description 128
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 115
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 103
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 84
• 229910052786 argon Inorganic materials 0.000 description 77
• 230000002829 reductive effect Effects 0.000 description 76
• 239000000284 extract Substances 0.000 description 74
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 70
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 68
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 68
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 68
• 235000019341 magnesium sulphate Nutrition 0.000 description 68
• 229920006395 saturated elastomer Polymers 0.000 description 66
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 60
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
• 239000012043 crude product Substances 0.000 description 58
• 239000000377 silicon dioxide Substances 0.000 description 56
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 54
• 239000000725 suspension Substances 0.000 description 53
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 50
• 238000003786 synthesis reaction Methods 0.000 description 50
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 49
• 230000015572 biosynthetic process Effects 0.000 description 49
• 238000005481 NMR spectroscopy Methods 0.000 description 48
• 239000002904 solvent Substances 0.000 description 47
• 239000003921 oil Substances 0.000 description 46
• 235000019198 oils Nutrition 0.000 description 46
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
• 239000008346 aqueous phase Substances 0.000 description 42
• 238000006243 chemical reaction Methods 0.000 description 42
• 235000019439 ethyl acetate Nutrition 0.000 description 42
• 239000012074 organic phase Substances 0.000 description 42
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 41
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
• 238000002360 preparation method Methods 0.000 description 39
• HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 38
• 238000004587 chromatography analysis Methods 0.000 description 38
• 235000017557 sodium bicarbonate Nutrition 0.000 description 36
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
• 150000002118 epoxides Chemical class 0.000 description 33
• 238000005160 1H NMR spectroscopy Methods 0.000 description 32
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 31
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 30
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
• 238000003756 stirring Methods 0.000 description 28
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
• 229910000027 potassium carbonate Inorganic materials 0.000 description 24
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
• 238000000034 method Methods 0.000 description 23
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
• 235000019441 ethanol Nutrition 0.000 description 22
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 19
• 150000001412 amines Chemical class 0.000 description 19
• 239000012071 phase Substances 0.000 description 18
• 229910052938 sodium sulfate Inorganic materials 0.000 description 18
• 235000011152 sodium sulphate Nutrition 0.000 description 18
• 239000003208 petroleum Substances 0.000 description 17
• 230000002209 hydrophobic effect Effects 0.000 description 16
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 15
• 239000007858 starting material Substances 0.000 description 15
• FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 14
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 14
• 238000004440 column chromatography Methods 0.000 description 14
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 13
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
• 229910000104 sodium hydride Inorganic materials 0.000 description 13
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
• 229910021529 ammonia Inorganic materials 0.000 description 12
• 239000000706 filtrate Substances 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• 239000006260 foam Substances 0.000 description 12
• 239000003960 organic solvent Substances 0.000 description 12
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
• IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 11
• 238000007363 ring formation reaction Methods 0.000 description 11
• 239000012312 sodium hydride Substances 0.000 description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
• PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 10
• 238000001704 evaporation Methods 0.000 description 10
• 230000008020 evaporation Effects 0.000 description 10
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