TW202116781A - 新穎雜環化合物 - Google Patents

Info

Publication number

TW202116781A

TW202116781A TW109123050A TW109123050A TW202116781A TW 202116781 A TW202116781 A TW 202116781A TW 109123050 A TW109123050 A TW 109123050A TW 109123050 A TW109123050 A TW 109123050A TW 202116781 A TW202116781 A TW 202116781A

Authority

TW

Taiwan

Prior art keywords

chloro

compound

formula

group

phenyl

Prior art date

2019-07-09

Links

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• Global Dossier
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• 150000002391 heterocyclic compounds Chemical class 0.000 title abstract 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 279
• 238000000034 method Methods 0.000 claims abstract description 170
• -1 cyano, hydroxyl Chemical group 0.000 claims description 206
• 150000003839 salts Chemical class 0.000 claims description 109
• 229910052739 hydrogen Inorganic materials 0.000 claims description 96
• 239000001257 hydrogen Substances 0.000 claims description 96
• 229910052736 halogen Inorganic materials 0.000 claims description 84
• 125000001072 heteroaryl group Chemical group 0.000 claims description 83
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 81
• 150000002367 halogens Chemical class 0.000 claims description 80
• 238000006243 chemical reaction Methods 0.000 claims description 61
• 150000002431 hydrogen Chemical class 0.000 claims description 56
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 50
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 48
• 241000124008 Mammalia Species 0.000 claims description 46
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
• 125000003118 aryl group Chemical group 0.000 claims description 42
• 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 40
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
• 208000002193 Pain Diseases 0.000 claims description 39
• 125000001424 substituent group Chemical group 0.000 claims description 37
• 238000002360 preparation method Methods 0.000 claims description 32
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
• 230000002265 prevention Effects 0.000 claims description 29
• 230000036407 pain Effects 0.000 claims description 26
• 239000002585 base Substances 0.000 claims description 25
• 125000000623 heterocyclic group Chemical group 0.000 claims description 25
• 230000004770 neurodegeneration Effects 0.000 claims description 24
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 24
• 101150003085 Pdcl gene Proteins 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 22
• 201000006417 multiple sclerosis Diseases 0.000 claims description 21
• PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 21
• 125000005843 halogen group Chemical group 0.000 claims description 20
• 125000001153 fluoro group Chemical group F* 0.000 claims description 19
• 208000024827 Alzheimer disease Diseases 0.000 claims description 17
• 239000007821 HATU Substances 0.000 claims description 17
• 206010028980 Neoplasm Diseases 0.000 claims description 17
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 16
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 16
• 208000018737 Parkinson disease Diseases 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 15
• 239000003153 chemical reaction reagent Substances 0.000 claims description 15
• 208000020016 psychiatric disease Diseases 0.000 claims description 15
• 208000030886 Traumatic Brain injury Diseases 0.000 claims description 14
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 13
• 125000000217 alkyl group Chemical group 0.000 claims description 13
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
• 230000009529 traumatic brain injury Effects 0.000 claims description 13
• 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 claims description 12
• 206010029240 Neuritis Diseases 0.000 claims description 12
• 206010029350 Neurotoxicity Diseases 0.000 claims description 12
• 206010044221 Toxic encephalopathy Diseases 0.000 claims description 12
• 230000007135 neurotoxicity Effects 0.000 claims description 12
• 231100000228 neurotoxicity Toxicity 0.000 claims description 12
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 12
• OZMLUMPWPFZWTP-UHFFFAOYSA-N 2-(tributyl-$l^{5}-phosphanylidene)acetonitrile Chemical compound CCCCP(CCCC)(CCCC)=CC#N OZMLUMPWPFZWTP-UHFFFAOYSA-N 0.000 claims description 11
• 150000002009 diols Chemical class 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 125000004076 pyridyl group Chemical group 0.000 claims description 11
• 208000019901 Anxiety disease Diseases 0.000 claims description 10
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
• 230000036506 anxiety Effects 0.000 claims description 10
• 239000003054 catalyst Substances 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
• 208000019695 Migraine disease Diseases 0.000 claims description 9
• 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 9
• 208000006011 Stroke Diseases 0.000 claims description 9
• 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 claims description 9
• 238000002512 chemotherapy Methods 0.000 claims description 9
• 201000010099 disease Diseases 0.000 claims description 9
• 206010015037 epilepsy Diseases 0.000 claims description 9
• 206010027599 migraine Diseases 0.000 claims description 9
• 208000004296 neuralgia Diseases 0.000 claims description 9
• 230000003959 neuroinflammation Effects 0.000 claims description 9
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
• 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
• 125000002883 imidazolyl group Chemical group 0.000 claims description 8
• 201000001119 neuropathy Diseases 0.000 claims description 8
• 230000007823 neuropathy Effects 0.000 claims description 8
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 8
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 208000000094 Chronic Pain Diseases 0.000 claims description 7
• KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 7
• 206010033128 Ovarian cancer Diseases 0.000 claims description 7
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 7
• 150000001412 amines Chemical class 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 7
• 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 7
• 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 7
• 206010009944 Colon cancer Diseases 0.000 claims description 6
• 208000007101 Muscle Cramp Diseases 0.000 claims description 6
• 208000005298 acute pain Diseases 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 6
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 6
• 208000029742 colonic neoplasm Diseases 0.000 claims description 6
• 238000006880 cross-coupling reaction Methods 0.000 claims description 6
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
• 150000007529 inorganic bases Chemical class 0.000 claims description 6
• 150000007530 organic bases Chemical class 0.000 claims description 6
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
• 238000006467 substitution reaction Methods 0.000 claims description 6
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
• LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 5
• 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 101100226004 Rattus norvegicus Erc2 gene Proteins 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• 239000012025 fluorinating agent Substances 0.000 claims description 4
• 230000000269 nucleophilic effect Effects 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 239000011593 sulfur Substances 0.000 claims description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 238000003477 Sonogashira cross-coupling reaction Methods 0.000 claims description 3
• 239000013543 active substance Substances 0.000 claims description 3
• 230000008878 coupling Effects 0.000 claims description 3
• 238000010168 coupling process Methods 0.000 claims description 3
• 238000005859 coupling reaction Methods 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• 201000010901 lateral sclerosis Diseases 0.000 claims description 3
• 208000005264 motor neuron disease Diseases 0.000 claims description 3
• 239000007800 oxidant agent Substances 0.000 claims description 3
• 229910052723 transition metal Inorganic materials 0.000 claims description 3
• 150000003624 transition metals Chemical class 0.000 claims description 3
• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 2
• UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 2
• 102000005398 Monoacylglycerol Lipase Human genes 0.000 claims description 2
• 108020002334 Monoacylglycerol lipase Proteins 0.000 claims description 2
• 125000003277 amino group Chemical group 0.000 claims description 2
• 229940125797 compound 12 Drugs 0.000 claims description 2
• 230000018044 dehydration Effects 0.000 claims description 2
• 238000006297 dehydration reaction Methods 0.000 claims description 2
• 229940043279 diisopropylamine Drugs 0.000 claims description 2
• 230000001590 oxidative effect Effects 0.000 claims description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
• 210000003205 muscle Anatomy 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 104
• 230000008569 process Effects 0.000 abstract description 21
• 238000004519 manufacturing process Methods 0.000 abstract description 5
• 239000000543 intermediate Substances 0.000 description 326
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 276
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 181
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 174
• 239000000047 product Substances 0.000 description 138
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 137
• 235000019439 ethyl acetate Nutrition 0.000 description 134
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 114
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 98
• 239000007787 solid Substances 0.000 description 88
• 239000000243 solution Substances 0.000 description 83
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
• 239000000377 silicon dioxide Substances 0.000 description 75
• 239000007858 starting material Substances 0.000 description 74
• 238000004440 column chromatography Methods 0.000 description 70
• 238000004128 high performance liquid chromatography Methods 0.000 description 61
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
• WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 56
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 50
• 229910052786 argon Inorganic materials 0.000 description 49
• 238000003818 flash chromatography Methods 0.000 description 46
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
• 239000003921 oil Substances 0.000 description 45
• 235000019198 oils Nutrition 0.000 description 45
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
• 239000011541 reaction mixture Substances 0.000 description 43
• 239000011734 sodium Substances 0.000 description 43
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
• 239000012267 brine Substances 0.000 description 39
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 36
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 34
• 229910052938 sodium sulfate Inorganic materials 0.000 description 34
• 235000011152 sodium sulphate Nutrition 0.000 description 34
• 239000012043 crude product Substances 0.000 description 33
• 238000000746 purification Methods 0.000 description 33
• 239000002904 solvent Substances 0.000 description 33
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
• 229910004298 SiO 2 Inorganic materials 0.000 description 30
• YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 29
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 26
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
• 238000004808 supercritical fluid chromatography Methods 0.000 description 24
• 239000012074 organic phase Substances 0.000 description 23
• 229920006395 saturated elastomer Polymers 0.000 description 23
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• 238000002953 preparative HPLC Methods 0.000 description 22
• 150000003335 secondary amines Chemical class 0.000 description 22
• 229940050390 benzoate Drugs 0.000 description 21
• 239000012044 organic layer Substances 0.000 description 20
• 125000006239 protecting group Chemical group 0.000 description 20
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
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• 239000000741 silica gel Substances 0.000 description 18
• 229910002027 silica gel Inorganic materials 0.000 description 18
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
• 125000004432 carbon atom Chemical group C* 0.000 description 17
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 16
• 239000000460 chlorine Substances 0.000 description 16
• 239000012230 colorless oil Substances 0.000 description 16
• 235000021342 arachidonic acid Nutrition 0.000 description 15
• 239000013058 crude material Substances 0.000 description 15
• 229940095102 methyl benzoate Drugs 0.000 description 15
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 13
• BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 12
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 11
• OWPJVOSLLKRKQJ-UHFFFAOYSA-N methyl 3-bromo-2-chlorobenzoate Chemical compound COC(=O)C1=CC=CC(Br)=C1Cl OWPJVOSLLKRKQJ-UHFFFAOYSA-N 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
• 235000011181 potassium carbonates Nutrition 0.000 description 11
• 238000007127 saponification reaction Methods 0.000 description 11
• 239000000126 substance Substances 0.000 description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 125000003545 alkoxy group Chemical group 0.000 description 10
• 230000015572 biosynthetic process Effects 0.000 description 10
• 210000004556 brain Anatomy 0.000 description 10
• UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 10
• 230000000670 limiting effect Effects 0.000 description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
• 238000003756 stirring Methods 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
• NSILYQWHARROMG-QMMMGPOBSA-N tert-butyl (3s)-3-(hydroxymethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN[C@H](CO)C1 NSILYQWHARROMG-QMMMGPOBSA-N 0.000 description 10
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
• 239000008346 aqueous phase Substances 0.000 description 9
• 235000019253 formic acid Nutrition 0.000 description 9
• 230000002401 inhibitory effect Effects 0.000 description 9
• 238000012360 testing method Methods 0.000 description 9
• VIUDWLLKFANPLX-UHFFFAOYSA-N 2-chloro-3-methoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1Cl VIUDWLLKFANPLX-UHFFFAOYSA-N 0.000 description 8
• HNDMZOCUYWBPNO-UHFFFAOYSA-N ClC1=C(C(=O)O)C=CC=C1C=1C(=NNC=1)F Chemical compound ClC1=C(C(=O)O)C=CC=C1C=1C(=NNC=1)F HNDMZOCUYWBPNO-UHFFFAOYSA-N 0.000 description 8
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