JP2008505920A

JP2008505920A - 抗菌剤

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Publication number: JP2008505920A
Authority: JP; Japan
Prior art keywords: methyl; pyrido; oxo; methyloxy; dihydro
Prior art date: 2004-07-08
Legal status : Pending

Application number

JP2007520525A

Other languages

English (en)

Japanese (ja)

Other versions

JP2008505920A5 (enExample

Inventor

ウィリアム・ヘンリー・ミラー

ミーガン・ビー・ラウズ

マーク・アンドリュー・シーフェルド

Current Assignee

Glaxo Group Ltd

Original Assignee

Glaxo Group Ltd

Priority date

2004-07-08

Filing date

2005-07-08

Publication date

2008-02-28

2005-07-08 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

2008-02-28 Publication of JP2008505920A publication Critical patent/JP2008505920A/ja

2008-09-04 Publication of JP2008505920A5 publication Critical patent/JP2008505920A5/ja

Status Pending legal-status Critical Current

Links

239000003242 anti bacterial agent Substances 0.000 title description 5
208000035143 Bacterial infection Diseases 0.000 claims abstract description 8
241000124008 Mammalia Species 0.000 claims abstract description 8
208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 8
150000001875 compounds Chemical class 0.000 claims description 267
-1 hydroxy, amino, piperidyl Chemical group 0.000 claims description 211
239000001257 hydrogen Substances 0.000 claims description 117
229910052739 hydrogen Inorganic materials 0.000 claims description 117
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 80
125000000217 alkyl group Chemical group 0.000 claims description 76
238000002360 preparation method Methods 0.000 claims description 53
150000003839 salts Chemical class 0.000 claims description 49
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
150000001412 amines Chemical class 0.000 claims description 36
125000003118 aryl group Chemical group 0.000 claims description 35
150000002431 hydrogen Chemical class 0.000 claims description 33
229910052736 halogen Inorganic materials 0.000 claims description 31
150000002367 halogens Chemical class 0.000 claims description 31
125000004093 cyano group Chemical group *C#N 0.000 claims description 28
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 27
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
238000000034 method Methods 0.000 claims description 21
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 20
229910052731 fluorine Inorganic materials 0.000 claims description 20
239000011737 fluorine Substances 0.000 claims description 20
125000000623 heterocyclic group Chemical group 0.000 claims description 18
239000012453 solvate Substances 0.000 claims description 16
125000004414 alkyl thio group Chemical group 0.000 claims description 15
229910052760 oxygen Inorganic materials 0.000 claims description 15
125000006574 non-aromatic ring group Chemical group 0.000 claims description 14
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
125000004429 atom Chemical group 0.000 claims description 10
125000005843 halogen group Chemical group 0.000 claims description 10
125000002252 acyl group Chemical group 0.000 claims description 9
125000004423 acyloxy group Chemical group 0.000 claims description 9
229910052757 nitrogen Inorganic materials 0.000 claims description 9
125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 8
229910052799 carbon Inorganic materials 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
125000003277 amino group Chemical group 0.000 claims description 7
125000003710 aryl alkyl group Chemical group 0.000 claims description 7
229910052717 sulfur Inorganic materials 0.000 claims description 7
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
239000008194 pharmaceutical composition Substances 0.000 claims description 6
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 5
WCOPEZIWYVDOGJ-NNJIEVJOSA-N 6-[[[(2r)-4-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)-2-hydroxyethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@H]3OCCN(C3)CC(O)C3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 WCOPEZIWYVDOGJ-NNJIEVJOSA-N 0.000 claims description 5
WCOPEZIWYVDOGJ-BUSXIPJBSA-N 6-[[[(2s)-4-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)-2-hydroxyethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)CC(O)C3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 WCOPEZIWYVDOGJ-BUSXIPJBSA-N 0.000 claims description 5
125000005035 acylthio group Chemical group 0.000 claims description 5
125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 5
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
125000005137 alkenylsulfonyl group Chemical group 0.000 claims description 4
125000006242 amine protecting group Chemical group 0.000 claims description 4
125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
125000005647 linker group Chemical group 0.000 claims description 4
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
229910052721 tungsten Inorganic materials 0.000 claims description 4
BEJKRDDWNPMACI-UHFFFAOYSA-N 4-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]-n-methyl-n-[(3-oxo-4h-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]morpholine-2-carboxamide Chemical compound S1CC(=O)NC2=NC(CN(C)C(=O)C3OCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 BEJKRDDWNPMACI-UHFFFAOYSA-N 0.000 claims description 3
XRAJCWSBLKBNDM-UHFFFAOYSA-N 6-[[8-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-3-oxo-1,4,6,7,9,9a-hexahydropyrazino[1,2-a]pyrazin-2-yl]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CN3C(=O)CN4CCN(CC4C3)CCC3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 XRAJCWSBLKBNDM-UHFFFAOYSA-N 0.000 claims description 3
HPYOIEYJFIOJFT-UHFFFAOYSA-N 6-[[8-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-4-oxo-1,3,6,7,9,9a-hexahydropyrazino[1,2-a]pyrazin-2-yl]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CN3CC4N(C(C3)=O)CCN(C4)CCC3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 HPYOIEYJFIOJFT-UHFFFAOYSA-N 0.000 claims description 3
DNJYXXMLVYYZID-APWZRJJASA-N 6-[[[(2r)-4-[(2r)-2-hydroxy-2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@H]3OCCN(C3)C[C@H](O)C3=CC=NC4=CC=C(N=C43)OC)=CC=C21 DNJYXXMLVYYZID-APWZRJJASA-N 0.000 claims description 3
DNJYXXMLVYYZID-LPHOPBHVSA-N 6-[[[(2s)-4-[(2r)-2-hydroxy-2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)C[C@H](O)C3=CC=NC4=CC=C(N=C43)OC)=CC=C21 DNJYXXMLVYYZID-LPHOPBHVSA-N 0.000 claims description 3
QGYGRBYHGOAPRP-SFHVURJKSA-N 6-[[[(2s)-4-[2-(3-fluoro-6-methoxyquinolin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)CCC3=C(F)C=NC4=CC=C(C=C43)OC)=CC=C21 QGYGRBYHGOAPRP-SFHVURJKSA-N 0.000 claims description 3
DJIJBENPXOOCBF-UHFFFAOYSA-N 6-[[[1-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]piperidin-3-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNCC3CCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 DJIJBENPXOOCBF-UHFFFAOYSA-N 0.000 claims description 3
UGOBYQRYYQCZRB-UHFFFAOYSA-N 6-[[[4-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]piperazin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNCC3NCCN(C3)CCC3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 UGOBYQRYYQCZRB-UHFFFAOYSA-N 0.000 claims description 3
OAJYFQBGENGKHJ-UHFFFAOYSA-N 6-[[[4-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNCC3OCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 OAJYFQBGENGKHJ-UHFFFAOYSA-N 0.000 claims description 3
CTRVZTOAQIFNGS-SFHVURJKSA-N 6-methoxy-4-[2-[(2s)-2-[[(3-oxo-4h-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino]methyl]morpholin-4-yl]ethyl]-1,5-naphthyridine-3-carbonitrile Chemical compound S1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)CCC3=C(C#N)C=NC4=CC=C(N=C43)OC)=CC=C21 CTRVZTOAQIFNGS-SFHVURJKSA-N 0.000 claims description 3
INCQTOLYCXVNOH-AWEZNQCLSA-N 7-chloro-6-[[[(2s)-4-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]oxazin-3-one Chemical compound N1C(=O)COC(C=C2Cl)=C1N=C2CNC[C@@H](C1)OCCN1CCC1=C(F)C=NC2=CC=C(OC)N=C21 INCQTOLYCXVNOH-AWEZNQCLSA-N 0.000 claims description 3
125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
125000005361 aryl sulfoxide group Chemical group 0.000 claims description 3
125000005110 aryl thio group Chemical group 0.000 claims description 3
125000004104 aryloxy group Chemical group 0.000 claims description 3
125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
125000001072 heteroaryl group Chemical group 0.000 claims description 3
125000005842 heteroatom Chemical group 0.000 claims description 3
125000005844 heterocyclyloxy group Chemical group 0.000 claims description 3
125000004468 heterocyclylthio group Chemical group 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
125000003396 thiol group Chemical class [H]S* 0.000 claims description 3
MDPIIKLBVPRYLK-HNNXBMFYSA-N (2s)-n-(6-methoxy-1,5-naphthyridin-4-yl)-2-[[(3-oxo-4h-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino]methyl]morpholine-4-carboxamide Chemical compound S1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)C(=O)NC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 MDPIIKLBVPRYLK-HNNXBMFYSA-N 0.000 claims description 2
NZJRODSXVMZZDT-UHFFFAOYSA-N 6-[[7-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-3-oxo-5,6,8,8a-tetrahydro-1h-imidazo[1,5-a]pyrazin-2-yl]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CN3CC4N(C3=O)CCN(C4)CCC3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 NZJRODSXVMZZDT-UHFFFAOYSA-N 0.000 claims description 2
OLLLXPOAZSYQDY-INIZCTEOSA-N 6-[[[(2s)-4-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)CCC3=C(F)C=NC4=CC=C(N=C43)OC)=CC=C21 OLLLXPOAZSYQDY-INIZCTEOSA-N 0.000 claims description 2
NXBSBBMUDZDBMP-SFHVURJKSA-N 6-[[[(2s)-4-[2-(3-fluoro-6-methoxyquinolin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]oxazin-3-one Chemical compound O1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)CCC3=C(F)C=NC4=CC=C(C=C43)OC)=CC=C21 NXBSBBMUDZDBMP-SFHVURJKSA-N 0.000 claims description 2
OXEITQIJQHGVNK-SFHVURJKSA-N 6-methoxy-4-[2-[(2s)-2-[[(3-oxo-4h-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]methyl]morpholin-4-yl]ethyl]-1,5-naphthyridine-3-carbonitrile Chemical compound O1CC(=O)NC2=NC(CNC[C@@H]3OCCN(C3)CCC3=C(C#N)C=NC4=CC=C(N=C43)OC)=CC=C21 OXEITQIJQHGVNK-SFHVURJKSA-N 0.000 claims description 2
NITQQTGQNJQKIJ-INIZCTEOSA-N 8-fluoro-6-[[[(2s)-4-[2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-1,4-benzoxazin-3-one Chemical compound O1CC(=O)NC2=CC(CNC[C@@H]3OCCN(C3)CCC3=C(F)C=NC4=CC=C(N=C43)OC)=CC(F)=C21 NITQQTGQNJQKIJ-INIZCTEOSA-N 0.000 claims description 2
241000790917 Dioxys <bee> Species 0.000 claims description 2
125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 2
125000005360 alkyl sulfoxide group Chemical group 0.000 claims description 2
150000001540 azides Chemical class 0.000 claims description 2
125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 2
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
QVXLXJYKKAKILO-UHFFFAOYSA-N n-[[1-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]piperidin-3-yl]methyl]-3-oxo-4h-1,4-benzothiazine-6-sulfonamide Chemical compound S1CC(=O)NC2=CC(S(=O)(=O)NCC3CCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 QVXLXJYKKAKILO-UHFFFAOYSA-N 0.000 claims description 2
RIVPPGHNETZFKI-UHFFFAOYSA-N n-[[4-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methyl]-3-oxo-4h-1,4-benzothiazine-6-sulfonamide Chemical compound S1CC(=O)NC2=CC(S(=O)(=O)NCC3OCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 RIVPPGHNETZFKI-UHFFFAOYSA-N 0.000 claims description 2
JBYPDPRGTXGQGZ-UHFFFAOYSA-N n-[[4-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methyl]-3-oxo-4h-pyrido[3,2-b][1,4]thiazine-6-carboxamide Chemical compound S1CC(=O)NC2=NC(C(=O)NCC3OCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 JBYPDPRGTXGQGZ-UHFFFAOYSA-N 0.000 claims description 2
125000004356 hydroxy functional group Chemical group O* 0.000 claims 12
125000004446 heteroarylalkyl group Chemical group 0.000 claims 2
OAJYFQBGENGKHJ-GOSISDBHSA-N 6-[[[(2r)-4-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]morpholin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNC[C@H]3OCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 OAJYFQBGENGKHJ-GOSISDBHSA-N 0.000 claims 1
NWWLLPDMCNFPOA-UHFFFAOYSA-N 6-[[[4-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]piperazin-2-yl]methylamino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CNCC3NCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 NWWLLPDMCNFPOA-UHFFFAOYSA-N 0.000 claims 1
PSDYQSWHANEKRV-UHFFFAOYSA-N [S]N Chemical group [S]N PSDYQSWHANEKRV-UHFFFAOYSA-N 0.000 claims 1
LMJJOAJSFFEASA-UHFFFAOYSA-N n-[[1-[2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]piperidin-3-yl]methyl]-3-oxo-4h-pyrido[3,2-b][1,4]thiazine-6-carboxamide Chemical compound S1CC(=O)NC2=NC(C(=O)NCC3CCCN(C3)CCC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 LMJJOAJSFFEASA-UHFFFAOYSA-N 0.000 claims 1
238000011282 treatment Methods 0.000 abstract description 11
UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract 2
XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 2
150000005054 naphthyridines Chemical class 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 297
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 197
239000000243 solution Substances 0.000 description 188
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 106
239000007787 solid Substances 0.000 description 101
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 89
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
239000000203 mixture Substances 0.000 description 73
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 59
238000006243 chemical reaction Methods 0.000 description 52
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 39
238000005481 NMR spectroscopy Methods 0.000 description 39
239000000377 silicon dioxide Substances 0.000 description 39
230000002829 reductive effect Effects 0.000 description 36
239000000463 material Substances 0.000 description 35
235000019439 ethyl acetate Nutrition 0.000 description 34
150000002500 ions Chemical class 0.000 description 34
239000011734 sodium Substances 0.000 description 33
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
238000004440 column chromatography Methods 0.000 description 26
239000000047 product Substances 0.000 description 26
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
125000002887 hydroxy group Chemical group [H]O* 0.000 description 25
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
VEPGNAIYGRUSIA-UHFFFAOYSA-N 3-oxo-4h-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde Chemical compound S1CC(=O)NC2=NC(C=O)=CC=C21 VEPGNAIYGRUSIA-UHFFFAOYSA-N 0.000 description 21
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
239000000741 silica gel Substances 0.000 description 21
229910002027 silica gel Inorganic materials 0.000 description 21
239000002904 solvent Substances 0.000 description 20
GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 18
238000003756 stirring Methods 0.000 description 18
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
238000000746 purification Methods 0.000 description 17
239000000725 suspension Substances 0.000 description 17
239000006260 foam Substances 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
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
239000003921 oil Substances 0.000 description 15
235000019198 oils Nutrition 0.000 description 15
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
125000004432 carbon atom Chemical group C* 0.000 description 13
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