CN115884762A - 苯乙酮肟类化合物及其应用 - Google Patents
苯乙酮肟类化合物及其应用 Download PDFInfo
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- CN115884762A CN115884762A CN202180051044.5A CN202180051044A CN115884762A CN 115884762 A CN115884762 A CN 115884762A CN 202180051044 A CN202180051044 A CN 202180051044A CN 115884762 A CN115884762 A CN 115884762A
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- ethyl acetate
- reaction mixture
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- -1 Acetophenone oxime compound Chemical class 0.000 title claims description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 433
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000006430 alkyl cyclopropyl group Chemical group 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 2
- JHNRZXQVBKRYKN-VQHVLOKHSA-N (ne)-n-(1-phenylethylidene)hydroxylamine Chemical class O\N=C(/C)C1=CC=CC=C1 JHNRZXQVBKRYKN-VQHVLOKHSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 600
- 239000000243 solution Substances 0.000 description 247
- 239000011541 reaction mixture Substances 0.000 description 200
- 238000006243 chemical reaction Methods 0.000 description 191
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
- 230000015572 biosynthetic process Effects 0.000 description 178
- 238000003786 synthesis reaction Methods 0.000 description 178
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 169
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 160
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 147
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 142
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 139
- 239000000543 intermediate Substances 0.000 description 131
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 113
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 102
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 96
- 239000003208 petroleum Substances 0.000 description 80
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 77
- 238000010898 silica gel chromatography Methods 0.000 description 71
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 71
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 70
- 239000012043 crude product Substances 0.000 description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 239000012074 organic phase Substances 0.000 description 56
- 208000011231 Crohn disease Diseases 0.000 description 50
- 229910052757 nitrogen Inorganic materials 0.000 description 49
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- 239000000203 mixture Substances 0.000 description 44
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 239000012071 phase Substances 0.000 description 35
- 238000000605 extraction Methods 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000001914 filtration Methods 0.000 description 24
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 22
- 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 22
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000002207 metabolite Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 16
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 15
- 235000019253 formic acid Nutrition 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 13
- 239000000556 agonist Substances 0.000 description 12
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical class [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 241000282414 Homo sapiens Species 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000001270 agonistic effect Effects 0.000 description 10
- 206010008118 cerebral infarction Diseases 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
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- 238000001514 detection method Methods 0.000 description 8
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- 238000011534 incubation Methods 0.000 description 7
- 210000001853 liver microsome Anatomy 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- OKBMHIVCLCZGLA-UHFFFAOYSA-N 5-butyl-6-ethoxydec-5-ene;tin Chemical compound [Sn].CCCCC(CCCC)=C(CCCC)OCC OKBMHIVCLCZGLA-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 239000012448 Lithium borohydride Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 150000004675 formic acid derivatives Chemical class 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
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- LIFAQMGORKPVDH-UHFFFAOYSA-N 7-ethoxycoumarin Chemical compound C1=CC(=O)OC2=CC(OCC)=CC=C21 LIFAQMGORKPVDH-UHFFFAOYSA-N 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 4
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
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Abstract
公开了苯乙酮肟类化合物及其制备方法,具体公开了式(II)所示化合物及其药学上可接受的盐。
Description
PCT国内申请,说明书已公开。
Claims (15)
- PCT国内申请,权利要求书已公开。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2020108478642 | 2020-08-20 | ||
CN202010847864 | 2020-08-20 | ||
CN2021101093111 | 2021-01-26 | ||
CN202110109311 | 2021-01-26 | ||
CN2021101233691 | 2021-01-28 | ||
CN202110123369 | 2021-01-28 | ||
PCT/CN2021/112753 WO2022037525A1 (zh) | 2020-08-20 | 2021-08-16 | 苯乙酮肟类化合物及其应用 |
Publications (1)
Publication Number | Publication Date |
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CN115884762A true CN115884762A (zh) | 2023-03-31 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN202180051044.5A Pending CN115884762A (zh) | 2020-08-20 | 2021-08-16 | 苯乙酮肟类化合物及其应用 |
Country Status (3)
Country | Link |
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US (1) | US20230295076A1 (zh) |
CN (1) | CN115884762A (zh) |
WO (1) | WO2022037525A1 (zh) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1761468A (zh) * | 2003-02-11 | 2006-04-19 | Irm责任有限公司 | 新的二环化合物和组合物 |
JP2009040702A (ja) * | 2007-08-07 | 2009-02-26 | Daiichi Sankyo Co Ltd | 新規アミドプロピオン酸誘導体を含有する医薬組成物 |
EP2695615A3 (en) * | 2008-07-23 | 2014-04-30 | Novartis AG | Sphingosine 1 phosphate receptor modulators and their use to treat muscle inflammation |
EP2646114B1 (en) * | 2010-12-03 | 2014-10-22 | Allergan, Inc. | Novel oxime derivatives as sphingosine 1-phosphate (s1p) receptor modulators |
MX2014004813A (es) * | 2011-10-21 | 2014-05-20 | Novartis Ag | Regimen de dosificacion para un modulador o agonista del receptor s1p. |
-
2021
- 2021-08-16 WO PCT/CN2021/112753 patent/WO2022037525A1/zh active Application Filing
- 2021-08-16 US US18/022,194 patent/US20230295076A1/en active Pending
- 2021-08-16 CN CN202180051044.5A patent/CN115884762A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
US20230295076A1 (en) | 2023-09-21 |
WO2022037525A1 (zh) | 2022-02-24 |
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