OA12101A - Antipicornaviral compounds and compositions, theirpharmaceutical uses, and materials for their synt hesis. - Google Patents

Info

Publication number

OA12101A

OA12101A OA1200200160A OA1200200160A OA12101A OA 12101 A OA12101 A OA 12101A OA 1200200160 A OA1200200160 A OA 1200200160A OA 1200200160 A OA1200200160 A OA 1200200160A OA 12101 A OA12101 A OA 12101A

Authority

OA

OAPI

Prior art keywords

group

pharmaceutically acceptable

compound

substituted

heterocycloalkyl

Prior art date

1999-12-03

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 264
• 239000000203 mixture Substances 0.000 title claims description 100
• 238000003786 synthesis reaction Methods 0.000 title description 9
• 230000015572 biosynthetic process Effects 0.000 title description 8
• 239000000463 material Substances 0.000 title description 7
• 108091005804 Peptidases Proteins 0.000 claims abstract description 21
• 239000004365 Protease Substances 0.000 claims abstract description 21
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• 241001144416 Picornavirales Species 0.000 claims abstract 8
• -1 each Rk is H Chemical group 0.000 claims description 175
• 125000000217 alkyl group Chemical group 0.000 claims description 166
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 134
• 238000000034 method Methods 0.000 claims description 133
• 229910052739 hydrogen Inorganic materials 0.000 claims description 106
• 125000003118 aryl group Chemical group 0.000 claims description 102
• 229910052757 nitrogen Inorganic materials 0.000 claims description 97
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 92
• 125000001072 heteroaryl group Chemical group 0.000 claims description 75
• 125000001424 substituent group Chemical group 0.000 claims description 73
• 239000000651 prodrug Substances 0.000 claims description 72
• 229940002612 prodrug Drugs 0.000 claims description 72
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 62
• 125000006239 protecting group Chemical group 0.000 claims description 44
• 125000004429 atom Chemical group 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 41
• 229910052736 halogen Inorganic materials 0.000 claims description 40
• 125000003545 alkoxy group Chemical group 0.000 claims description 37
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 25
• 125000002252 acyl group Chemical group 0.000 claims description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 22
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
• 125000004104 aryloxy group Chemical group 0.000 claims description 21
• 229930194542 Keto Natural products 0.000 claims description 20
• 125000000468 ketone group Chemical group 0.000 claims description 20
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 19
• 230000000694 effects Effects 0.000 claims description 19
• 229910052731 fluorine Inorganic materials 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
• 125000001188 haloalkyl group Chemical group 0.000 claims description 18
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 17
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 17
• 229910052717 sulfur Inorganic materials 0.000 claims description 17
• 125000003441 thioacyl group Chemical group 0.000 claims description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 16
• 125000003282 alkyl amino group Chemical group 0.000 claims description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 15
• 150000002430 hydrocarbons Chemical class 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 15
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 14
• 238000003556 assay Methods 0.000 claims description 13
• 125000005110 aryl thio group Chemical group 0.000 claims description 11
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 10
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 230000002401 inhibitory effect Effects 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 125000005323 thioketone group Chemical group 0.000 claims description 10
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 10
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 9
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000001769 aryl amino group Chemical group 0.000 claims description 8
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 8
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 8
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 8
• 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 8
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 7
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 7
• 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 7
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 7
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 7
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 7
• 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 7
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 7
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 7
• 238000004113 cell culture Methods 0.000 claims description 7
• 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 7
• 125000005201 cycloalkylcarbonyloxy group Chemical group 0.000 claims description 7
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 7
• 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 7
• 125000005204 heteroarylcarbonyloxy group Chemical group 0.000 claims description 7
• 125000005368 heteroarylthio group Chemical group 0.000 claims description 7
• 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 claims description 6
• 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 6
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 6
• 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 6
• 125000004671 dialkylaminothiocarbonyl group Chemical group 0.000 claims description 6
• 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 6
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 239000003981 vehicle Substances 0.000 claims description 4
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 3
• 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
• 230000001404 mediated effect Effects 0.000 claims description 3
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 2
• 239000004215 Carbon black (E152) Substances 0.000 claims description 2
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
• 229930195733 hydrocarbon Natural products 0.000 claims description 2
• 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 2
• SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 6
• 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
• 229910052698 phosphorus Inorganic materials 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 323
• 108010091324 3C proteases Proteins 0.000 abstract description 13
• 238000010189 synthetic method Methods 0.000 abstract description 2
• 230000004071 biological effect Effects 0.000 abstract 2
• 241000709664 Picornaviridae Species 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
• 238000005481 NMR spectroscopy Methods 0.000 description 91
• 229910052799 carbon Inorganic materials 0.000 description 77
• 238000006243 chemical reaction Methods 0.000 description 75
• 241000710122 Rhinovirus B14 Species 0.000 description 70
• YIYBQIKDCADOSF-UHFFFAOYSA-N alpha-Butylen-alpha-carbonsaeure Natural products CCC=CC(O)=O YIYBQIKDCADOSF-UHFFFAOYSA-N 0.000 description 66
• 239000000047 product Substances 0.000 description 65
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 61
• 235000019439 ethyl acetate Nutrition 0.000 description 57
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
• 239000012267 brine Substances 0.000 description 55
• 239000000243 solution Substances 0.000 description 55
• 101150041968 CDC13 gene Proteins 0.000 description 53
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
• 230000008569 process Effects 0.000 description 48
• 239000011541 reaction mixture Substances 0.000 description 41
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
• 150000001412 amines Chemical class 0.000 description 39
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
• 238000003818 flash chromatography Methods 0.000 description 32
• 238000007429 general method Methods 0.000 description 32
• 239000002253 acid Substances 0.000 description 31
• 238000000746 purification Methods 0.000 description 31
• BNMPIJWVMVNSRD-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NO1 BNMPIJWVMVNSRD-UHFFFAOYSA-N 0.000 description 29
• 239000007787 solid Substances 0.000 description 28
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 26
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• 150000003254 radicals Chemical class 0.000 description 25
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 24
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 24
• 241000710130 Human rhinovirus 1A Species 0.000 description 23
• 241000710124 Human rhinovirus A2 Species 0.000 description 23
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 23
• 230000002829 reductive effect Effects 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
• 241000700605 Viruses Species 0.000 description 20
• 150000002148 esters Chemical class 0.000 description 20
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 235000019198 oils Nutrition 0.000 description 18
• 238000010992 reflux Methods 0.000 description 18
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 17
• 238000003756 stirring Methods 0.000 description 17
• 231100001274 therapeutic index Toxicity 0.000 description 17
• 239000003039 volatile agent Substances 0.000 description 17
• 239000012074 organic phase Substances 0.000 description 16
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
• 101150046236 CNR1 gene Proteins 0.000 description 15
• 239000000460 chlorine Substances 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
• 238000010511 deprotection reaction Methods 0.000 description 14
• 125000004494 ethyl ester group Chemical group 0.000 description 14
• CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 13
• 229910000343 potassium bisulfate Inorganic materials 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• 241000430519 Human rhinovirus sp. Species 0.000 description 12
• 239000007832 Na2SO4 Substances 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 239000006260 foam Substances 0.000 description 12
• 229910052938 sodium sulfate Inorganic materials 0.000 description 12
• 235000011152 sodium sulphate Nutrition 0.000 description 12
• 238000005160 1H NMR spectroscopy Methods 0.000 description 11
• 241001635223 Coxsackievirus B2 Species 0.000 description 11
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 150000001408 amides Chemical class 0.000 description 11
• 241000710128 Human rhinovirus A23 Species 0.000 description 10
• NIONDZDPPYHYKY-UHFFFAOYSA-N Z-hexenoic acid Natural products CCCC=CC(O)=O NIONDZDPPYHYKY-UHFFFAOYSA-N 0.000 description 10
• 229910052786 argon Inorganic materials 0.000 description 10
• 238000010828 elution Methods 0.000 description 10
• 229930195734 saturated hydrocarbon Natural products 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• 241000709711 Coxsackievirus B5 Species 0.000 description 9
• 230000002378 acidificating effect Effects 0.000 description 9
• 125000003277 amino group Chemical group 0.000 description 9
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
• BOAFCICMVMFLIT-UHFFFAOYSA-N 3-nitro-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1[N+]([O-])=O BOAFCICMVMFLIT-UHFFFAOYSA-N 0.000 description 8
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
• 229960000583 acetic acid Drugs 0.000 description 8
• 125000002619 bicyclic group Chemical group 0.000 description 8
• 229940093499 ethyl acetate Drugs 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• GXHMMDRXHUIUMN-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O GXHMMDRXHUIUMN-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
• 238000010898 silica gel chromatography Methods 0.000 description 8
• 229910052708 sodium Inorganic materials 0.000 description 8
• 239000011734 sodium Substances 0.000 description 8
• 239000002904 solvent Substances 0.000 description 8
• 238000011282 treatment Methods 0.000 description 8
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
• 235000011054 acetic acid Nutrition 0.000 description 7
• 230000008878 coupling Effects 0.000 description 7
• 238000010168 coupling process Methods 0.000 description 7
• 238000005859 coupling reaction Methods 0.000 description 7
• 239000006185 dispersion Substances 0.000 description 7
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
• 239000012312 sodium hydride Substances 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• 239000000126 substance Substances 0.000 description 7
• 238000012360 testing method Methods 0.000 description 7
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• UQONAEXHTGDOIH-AWEZNQCLSA-N O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 Chemical compound O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 UQONAEXHTGDOIH-AWEZNQCLSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 235000001014 amino acid Nutrition 0.000 description 6
• 229940024606 amino acid Drugs 0.000 description 6
• 150000001413 amino acids Chemical class 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 6
• 150000004702 methyl esters Chemical class 0.000 description 6
• VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 6
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
• 238000010926 purge Methods 0.000 description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
• WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 6
• IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 6
• BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 6
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