ES2396962T3 - Derivados de piperazina utilizados como moduladores de los canales de calcio Cav2.2 - Google Patents

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Publication number

ES2396962T3

ES2396962T3 ES09780587T ES09780587T ES2396962T3 ES 2396962 T3 ES2396962 T3 ES 2396962T3 ES 09780587 T ES09780587 T ES 09780587T ES 09780587 T ES09780587 T ES 09780587T ES 2396962 T3 ES2396962 T3 ES 2396962T3

Authority

ES

Spain

Prior art keywords

sulfonyl

methyl

mmol

piperazine

carbonyl

Prior art date

2008-07-17

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.)

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• 101000935123 Homo sapiens Voltage-dependent N-type calcium channel subunit alpha-1B Proteins 0.000 title description 14
• 102100025342 Voltage-dependent N-type calcium channel subunit alpha-1B Human genes 0.000 title description 14
• 150000004885 piperazines Chemical class 0.000 title description 7
• 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 255
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 70
• 239000001257 hydrogen Substances 0.000 claims abstract description 70
• 150000003839 salts Chemical class 0.000 claims abstract description 45
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 43
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 36
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 33
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 25
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 24
• 150000002367 halogens Chemical class 0.000 claims abstract description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 24
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims abstract description 20
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 10
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 10
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 9
• 150000002431 hydrogen Chemical group 0.000 claims abstract 12
• -1 5-bromo-3-pyridinyl Chemical group 0.000 claims description 54
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 208000002193 Pain Diseases 0.000 claims description 29
• 230000036407 pain Effects 0.000 claims description 26
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
• 238000011282 treatment Methods 0.000 claims description 18
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• BLFJGFDZMABYMY-ZDUSSCGKSA-N (2-methylpyridin-3-yl)-[(2s)-2-methyl-4-[4-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C([C@@H]1C)N(S(=O)(=O)C=2C=CC(=CC=2)C(F)(F)F)CCN1C(=O)C1=CC=CN=C1C BLFJGFDZMABYMY-ZDUSSCGKSA-N 0.000 claims description 6
• GDRUGSHHHSFQCA-UHFFFAOYSA-N (6-chloropyridin-3-yl)-[4-[4-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=NC(Cl)=CC=2)CC1 GDRUGSHHHSFQCA-UHFFFAOYSA-N 0.000 claims description 5
• 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 5
• QXELIOSTVHFZBE-UHFFFAOYSA-N (6-methylpyridin-3-yl)-[4-[4-(trifluoromethoxy)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=NC(C)=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)CC1 QXELIOSTVHFZBE-UHFFFAOYSA-N 0.000 claims description 4
• RMVJAZGUBREIED-UHFFFAOYSA-N [4-(3-chlorophenyl)sulfonylpiperazin-1-yl]-(2-pyrrolidin-1-ylpyridin-3-yl)methanone Chemical compound ClC1=CC=CC(S(=O)(=O)N2CCN(CC2)C(=O)C=2C(=NC=CC=2)N2CCCC2)=C1 RMVJAZGUBREIED-UHFFFAOYSA-N 0.000 claims description 4
• YXHYXKPGADQXIG-UHFFFAOYSA-N (2-ethoxypyridin-3-yl)-[4-(3-fluorophenyl)sulfonylpiperazin-1-yl]methanone Chemical compound CCOC1=NC=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=C(F)C=CC=2)CC1 YXHYXKPGADQXIG-UHFFFAOYSA-N 0.000 claims description 3
• ZRGQEUOVAUFVOM-UHFFFAOYSA-N (2-ethoxypyridin-3-yl)-[4-[4-(trifluoromethoxy)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound CCOC1=NC=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)CC1 ZRGQEUOVAUFVOM-UHFFFAOYSA-N 0.000 claims description 3
• OCEFLWBSOZETIG-UHFFFAOYSA-N (2-ethoxypyridin-3-yl)-[4-[4-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound CCOC1=NC=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC(=CC=2)C(F)(F)F)CC1 OCEFLWBSOZETIG-UHFFFAOYSA-N 0.000 claims description 3
• CEUYIGKOJMRSOK-UHFFFAOYSA-N (5-bromopyridin-3-yl)-[4-(4-chlorophenyl)sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=C(Br)C=NC=2)CC1 CEUYIGKOJMRSOK-UHFFFAOYSA-N 0.000 claims description 3
• YZCBLPYALCPNMC-UHFFFAOYSA-N (6-methoxypyridin-3-yl)-[4-[4-(trifluoromethoxy)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=NC(OC)=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC(OC(F)(F)F)=CC=2)CC1 YZCBLPYALCPNMC-UHFFFAOYSA-N 0.000 claims description 3
• IEKQQRITYSBTQS-UHFFFAOYSA-N 4-[4-(6-methylpyridine-3-carbonyl)piperazin-1-yl]sulfonylbenzonitrile Chemical compound C1=NC(C)=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC(=CC=2)C#N)CC1 IEKQQRITYSBTQS-UHFFFAOYSA-N 0.000 claims description 3
• YQBIDUAWYATDDC-UHFFFAOYSA-N [4-(4-chlorophenyl)sulfonylpiperazin-1-yl]-(6-methylpyridin-3-yl)methanone Chemical compound C1=NC(C)=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=CC(Cl)=CC=2)CC1 YQBIDUAWYATDDC-UHFFFAOYSA-N 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• QODJQPHYLKRIPZ-UHFFFAOYSA-N pyridin-3-yl-[4-[4-(trifluoromethoxy)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=NC=CC=2)CC1 QODJQPHYLKRIPZ-UHFFFAOYSA-N 0.000 claims description 3
• BOMAGPDKTBNMDH-UHFFFAOYSA-N pyridin-3-yl-[4-[4-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=NC=CC=2)CC1 BOMAGPDKTBNMDH-UHFFFAOYSA-N 0.000 claims description 3
• RMCLYNCLAVSCEN-UHFFFAOYSA-N (5,6-dichloropyridin-3-yl)-[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=C(Cl)C(Cl)=NC=2)CC1 RMCLYNCLAVSCEN-UHFFFAOYSA-N 0.000 claims description 2
• UYVYPZDMHLNSHA-UHFFFAOYSA-N (5,6-dichloropyridin-3-yl)-[4-[4-(trifluoromethoxy)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=C(Cl)C(Cl)=NC=2)CC1 UYVYPZDMHLNSHA-UHFFFAOYSA-N 0.000 claims description 2
• ASHMCRLWPKSLCD-UHFFFAOYSA-N (5,6-dichloropyridin-3-yl)-[4-[4-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=C(Cl)C(Cl)=NC=2)CC1 ASHMCRLWPKSLCD-UHFFFAOYSA-N 0.000 claims description 2
• ZKLYSQKKVHPPQF-UHFFFAOYSA-N (5-bromopyridin-3-yl)-[4-[4-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=CC(C(F)(F)F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=C(Br)C=NC=2)CC1 ZKLYSQKKVHPPQF-UHFFFAOYSA-N 0.000 claims description 2
• HRSUCJINLXPUSK-UHFFFAOYSA-N (6-chloropyridin-3-yl)-[4-[4-chloro-3-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound C1=C(Cl)C(C(F)(F)F)=CC(S(=O)(=O)N2CCN(CC2)C(=O)C=2C=NC(Cl)=CC=2)=C1 HRSUCJINLXPUSK-UHFFFAOYSA-N 0.000 claims description 2
• TYVMBFSOALHONW-UHFFFAOYSA-N 4-[4-(2-pyrrolidin-1-ylpyridine-3-carbonyl)piperazin-1-yl]sulfonylbenzonitrile Chemical compound C=1C=CN=C(N2CCCC2)C=1C(=O)N(CC1)CCN1S(=O)(=O)C1=CC=C(C#N)C=C1 TYVMBFSOALHONW-UHFFFAOYSA-N 0.000 claims description 2
• OZJMFUNPTRUCGR-UHFFFAOYSA-N [4-(3-chlorophenyl)sulfonylpiperazin-1-yl]-pyridin-3-ylmethanone Chemical compound ClC1=CC=CC(S(=O)(=O)N2CCN(CC2)C(=O)C=2C=NC=CC=2)=C1 OZJMFUNPTRUCGR-UHFFFAOYSA-N 0.000 claims description 2
• KWXKWJWNJWZUNO-UHFFFAOYSA-N [4-(3-fluorophenyl)sulfonylpiperazin-1-yl]-(2-pyrrolidin-1-ylpyridin-3-yl)methanone Chemical compound FC1=CC=CC(S(=O)(=O)N2CCN(CC2)C(=O)C=2C(=NC=CC=2)N2CCCC2)=C1 KWXKWJWNJWZUNO-UHFFFAOYSA-N 0.000 claims description 2
• DQKMEZZNTFIFIW-UHFFFAOYSA-N [4-(4-fluorophenyl)sulfonylpiperazin-1-yl]-(2-pyrrolidin-1-ylpyridin-3-yl)methanone Chemical compound C1=CC(F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C(=NC=CC=2)N2CCCC2)CC1 DQKMEZZNTFIFIW-UHFFFAOYSA-N 0.000 claims description 2
• GIRAPEKQSIUKNN-UHFFFAOYSA-N [4-[4-chloro-3-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]-(2-ethoxypyridin-3-yl)methanone Chemical compound CCOC1=NC=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=C(C(Cl)=CC=2)C(F)(F)F)CC1 GIRAPEKQSIUKNN-UHFFFAOYSA-N 0.000 claims description 2
• LYSBNIXXVWBJNX-UHFFFAOYSA-N [4-[4-chloro-3-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]-(6-methylpyridin-3-yl)methanone Chemical compound C1=NC(C)=CC=C1C(=O)N1CCN(S(=O)(=O)C=2C=C(C(Cl)=CC=2)C(F)(F)F)CC1 LYSBNIXXVWBJNX-UHFFFAOYSA-N 0.000 claims description 2
• WYADWHAIIFJWJE-UHFFFAOYSA-N [4-[4-chloro-3-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]-pyridin-3-ylmethanone Chemical compound C1=C(Cl)C(C(F)(F)F)=CC(S(=O)(=O)N2CCN(CC2)C(=O)C=2C=NC=CC=2)=C1 WYADWHAIIFJWJE-UHFFFAOYSA-N 0.000 claims description 2
• VFIWKNPSRQCFGU-UHFFFAOYSA-N pyridin-3-yl-[4-[3-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methanone Chemical compound FC(F)(F)C1=CC=CC(S(=O)(=O)N2CCN(CC2)C(=O)C=2C=NC=CC=2)=C1 VFIWKNPSRQCFGU-UHFFFAOYSA-N 0.000 claims description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 198
• 239000000243 solution Substances 0.000 description 139
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
• XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 109
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 103
• 239000000203 mixture Substances 0.000 description 96
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 88
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
• 239000011541 reaction mixture Substances 0.000 description 79
• 238000005160 1H NMR spectroscopy Methods 0.000 description 73
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 71
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 70
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 60
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 58
• 238000006243 chemical reaction Methods 0.000 description 58
• 239000007787 solid Substances 0.000 description 55
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 51
• UXRDAJMOOGEIAQ-CKOZHMEPSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-10,13-dimethyl-16-methylidene-3-oxo-1,2,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@](OC(=O)C)(C(C)=O)[C@@]1(C)CC2 UXRDAJMOOGEIAQ-CKOZHMEPSA-N 0.000 description 51
• 235000019439 ethyl acetate Nutrition 0.000 description 48
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 46
• 239000012044 organic layer Substances 0.000 description 46
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 43
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 39
• 239000000047 product Substances 0.000 description 38
• 239000002904 solvent Substances 0.000 description 37
• 238000003756 stirring Methods 0.000 description 35
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 30
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 29
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 28
• 239000003921 oil Substances 0.000 description 27
• 235000019198 oils Nutrition 0.000 description 27
• 235000017557 sodium bicarbonate Nutrition 0.000 description 27
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 27
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
• 239000010410 layer Substances 0.000 description 26
• 238000000034 method Methods 0.000 description 26
• 239000000463 material Substances 0.000 description 25
• 239000000377 silicon dioxide Substances 0.000 description 25
• 239000013058 crude material Substances 0.000 description 24
• 230000002829 reductive effect Effects 0.000 description 24
• 239000012458 free base Substances 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 210000004027 cell Anatomy 0.000 description 20
• GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 18
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 17
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
• 230000002209 hydrophobic effect Effects 0.000 description 16
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
• 235000019341 magnesium sulphate Nutrition 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 208000035475 disorder Diseases 0.000 description 15
• 239000003814 drug Substances 0.000 description 15
• 239000003643 water by type Substances 0.000 description 15
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 14
• 238000005191 phase separation Methods 0.000 description 14
• YXRANDHKVRJEIY-VIFPVBQESA-N (3s)-3-methyl-1-[4-(trifluoromethyl)phenyl]sulfonylpiperazine Chemical compound C1CN[C@@H](C)CN1S(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 YXRANDHKVRJEIY-VIFPVBQESA-N 0.000 description 13
• 239000007821 HATU Substances 0.000 description 13
• 238000003818 flash chromatography Methods 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 12
• 229960005141 piperazine Drugs 0.000 description 12
• 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 11
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 11
• 241000400611 Eucalyptus deanei Species 0.000 description 10
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
• 239000003446 ligand Substances 0.000 description 10
• 238000011321 prophylaxis Methods 0.000 description 10
• RZOKQIPOABEQAM-UHFFFAOYSA-N 6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=N1 RZOKQIPOABEQAM-UHFFFAOYSA-N 0.000 description 9
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
• 230000008569 process Effects 0.000 description 9
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
• 229910052794 bromium Inorganic materials 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 239000000460 chlorine Substances 0.000 description 8
• 238000004587 chromatography analysis Methods 0.000 description 8
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• 238000002360 preparation method Methods 0.000 description 8
• 239000007858 starting material Substances 0.000 description 8
• 238000012799 strong cation exchange Methods 0.000 description 8
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