FI117387B - Pyranoniyhdisteet, jotka ovat käyttökelpoisia retrovirusinfektioiden hoitoon - Google Patents

Info

Publication number

FI117387B

FI117387B FI964441A FI964441A FI117387B FI 117387 B FI117387 B FI 117387B FI 964441 A FI964441 A FI 964441A FI 964441 A FI964441 A FI 964441A FI 117387 B FI117387 B FI 117387B

Authority

FI

Finland

Prior art keywords

formula

propyl

compound

hydroxy

phenyl

Prior art date

1994-05-06

Links

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• Global Dossier
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• ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 title abstract description 11
• 238000011282 treatment Methods 0.000 title description 67
• 206010038997 Retroviral infections Diseases 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 622
• -1 4-imidazolyl Chemical group 0.000 claims description 218
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 175
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 142
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 108
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 61
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 22
• 229940124530 sulfonamide Drugs 0.000 claims description 13
• 150000003839 salts Chemical class 0.000 claims description 12
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
• 125000004802 cyanophenyl group Chemical group 0.000 claims description 3
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• JFZIIRCVFOAXCP-UHFFFAOYSA-N 6-[[3-[1-(4-hydroxy-6-oxo-2,2-dipropyl-3h-pyran-5-yl)propyl]phenyl]sulfamoyl]pyridine-3-carboxamide Chemical compound O=C1OC(CCC)(CCC)CC(O)=C1C(CC)C1=CC=CC(NS(=O)(=O)C=2N=CC(=CC=2)C(N)=O)=C1 JFZIIRCVFOAXCP-UHFFFAOYSA-N 0.000 claims description 2
• 125000004344 phenylpropyl group Chemical group 0.000 claims description 2
• 241000209140 Triticum Species 0.000 claims 1
• 235000021307 Triticum Nutrition 0.000 claims 1
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
• 241001430294 unidentified retrovirus Species 0.000 abstract description 14
• VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical class C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 abstract description 10
• 230000002401 inhibitory effect Effects 0.000 abstract description 5
• QBDAFARLDLCWAT-UHFFFAOYSA-N 2,3-dihydropyran-6-one Chemical class O=C1OCCC=C1 QBDAFARLDLCWAT-UHFFFAOYSA-N 0.000 abstract description 4
• 210000004962 mammalian cell Anatomy 0.000 abstract description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 556
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 423
• 238000002360 preparation method Methods 0.000 description 259
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 246
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 226
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 214
• 239000000243 solution Substances 0.000 description 173
• 235000019439 ethyl acetate Nutrition 0.000 description 150
• 238000000034 method Methods 0.000 description 115
• 239000000203 mixture Substances 0.000 description 110
• 238000005481 NMR spectroscopy Methods 0.000 description 106
• 150000001412 amines Chemical class 0.000 description 103
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 102
• 239000007787 solid Substances 0.000 description 102
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 97
• 238000007792 addition Methods 0.000 description 90
• 238000006243 chemical reaction Methods 0.000 description 90
• 239000000741 silica gel Substances 0.000 description 79
• 229910002027 silica gel Inorganic materials 0.000 description 79
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
• 239000000047 product Substances 0.000 description 60
• 238000003818 flash chromatography Methods 0.000 description 58
• 239000011541 reaction mixture Substances 0.000 description 56
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 50
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 43
• 238000005160 1H NMR spectroscopy Methods 0.000 description 42
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
• 230000006103 sulfonylation Effects 0.000 description 40
• 238000005694 sulfonylation reaction Methods 0.000 description 40
• 239000006260 foam Substances 0.000 description 38
• 239000003921 oil Substances 0.000 description 38
• 235000019198 oils Nutrition 0.000 description 38
• 239000000543 intermediate Substances 0.000 description 37
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
• ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 36
• 238000003756 stirring Methods 0.000 description 36
• 238000010586 diagram Methods 0.000 description 35
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
• 239000012267 brine Substances 0.000 description 32
• 239000000460 chlorine Substances 0.000 description 32
• 239000012044 organic layer Substances 0.000 description 32
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
• 239000002904 solvent Substances 0.000 description 31
• 239000000725 suspension Substances 0.000 description 31
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 28
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 27
• 229910000104 sodium hydride Inorganic materials 0.000 description 27
• HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 26
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 25
• 150000001408 amides Chemical class 0.000 description 25
• 229910052763 palladium Inorganic materials 0.000 description 24
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 23
• 239000002585 base Substances 0.000 description 23
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 23
• 239000012312 sodium hydride Substances 0.000 description 23
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 23
• 241000725303 Human immunodeficiency virus Species 0.000 description 22
• 239000002480 mineral oil Substances 0.000 description 22
• 235000010446 mineral oil Nutrition 0.000 description 22
• 239000010410 layer Substances 0.000 description 21
• 239000011734 sodium Substances 0.000 description 21
• 102000004190 Enzymes Human genes 0.000 description 20
• 108090000790 Enzymes Proteins 0.000 description 20
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• 235000001671 coumarin Nutrition 0.000 description 20
• 229940088598 enzyme Drugs 0.000 description 20
• 241000282414 Homo sapiens Species 0.000 description 19
• 239000003112 inhibitor Substances 0.000 description 19
• 239000000463 material Substances 0.000 description 19
• 230000002829 reductive effect Effects 0.000 description 19
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
• 239000002253 acid Substances 0.000 description 18
• 229910052757 nitrogen Inorganic materials 0.000 description 18
• OKIJSNGRQAOIGZ-UHFFFAOYSA-N Butopyronoxyl Chemical group CCCCOC(=O)C1=CC(=O)CC(C)(C)O1 OKIJSNGRQAOIGZ-UHFFFAOYSA-N 0.000 description 17
• 108091005804 Peptidases Proteins 0.000 description 17
• 102000035195 Peptidases Human genes 0.000 description 17
• 239000003960 organic solvent Substances 0.000 description 17
• CWWWHACKSNBBMU-UHFFFAOYSA-N 1-phenylhexan-3-one Chemical compound CCCC(=O)CCC1=CC=CC=C1 CWWWHACKSNBBMU-UHFFFAOYSA-N 0.000 description 16
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
• QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 16
• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 16
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 16
• 238000003786 synthesis reaction Methods 0.000 description 16
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 15
• 229960000956 coumarin Drugs 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
• 238000004128 high performance liquid chromatography Methods 0.000 description 14
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
• 235000019341 magnesium sulphate Nutrition 0.000 description 14
• 150000002924 oxiranes Chemical class 0.000 description 14
• 239000000137 peptide hydrolase inhibitor Substances 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 14
• 230000001177 retroviral effect Effects 0.000 description 14
• 239000004365 Protease Substances 0.000 description 13
• HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 13
• KXUGUWTUFUWYRS-UHFFFAOYSA-N 1-methylimidazole-4-sulfonyl chloride Chemical compound CN1C=NC(S(Cl)(=O)=O)=C1 KXUGUWTUFUWYRS-UHFFFAOYSA-N 0.000 description 12
• 108010010369 HIV Protease Proteins 0.000 description 12
• 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 description 12
• 238000005516 engineering process Methods 0.000 description 12
• 150000002148 esters Chemical class 0.000 description 12
• 230000005764 inhibitory process Effects 0.000 description 12
• 229940001593 sodium carbonate Drugs 0.000 description 12
• 229910000029 sodium carbonate Inorganic materials 0.000 description 12
• 230000003612 virological effect Effects 0.000 description 12
• 229960002555 zidovudine Drugs 0.000 description 12
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 11
• 150000007530 organic bases Chemical class 0.000 description 11
• 230000009467 reduction Effects 0.000 description 11
• XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 10
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• 229960000583 acetic acid Drugs 0.000 description 10
• XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 10
• 238000003556 assay Methods 0.000 description 10
• 239000012043 crude product Substances 0.000 description 10
• 238000002451 electron ionisation mass spectrometry Methods 0.000 description 10
• 239000003480 eluent Substances 0.000 description 10
• 239000000284 extract Substances 0.000 description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
• 150000003456 sulfonamides Chemical class 0.000 description 10
• 150000003512 tertiary amines Chemical class 0.000 description 10
• PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 10
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 9
• 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
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• 229910021589 Copper(I) bromide Inorganic materials 0.000 description 9
• 102100034343 Integrase Human genes 0.000 description 9
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 241000700605 Viruses Species 0.000 description 9
• 235000019270 ammonium chloride Nutrition 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 229910000027 potassium carbonate Inorganic materials 0.000 description 9
• 235000019419 proteases Nutrition 0.000 description 9
• 230000010076 replication Effects 0.000 description 9
• 238000000926 separation method Methods 0.000 description 9
• 239000000758 substrate Substances 0.000 description 9
• XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 9
• 229960005080 warfarin Drugs 0.000 description 9
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 8
• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 8
• PXNRZJNTMDCHFR-UHFFFAOYSA-N 4-hydroxy-2-methyl-2,3-dihydropyran-6-one Chemical compound CC1CC(O)=CC(=O)O1 PXNRZJNTMDCHFR-UHFFFAOYSA-N 0.000 description 8
• MRIFFPWOMKLYKZ-UHFFFAOYSA-N 5-(trifluoromethyl)pyridine-2-sulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)N=C1 MRIFFPWOMKLYKZ-UHFFFAOYSA-N 0.000 description 8
• XUXSGYYVYLYBFR-UHFFFAOYSA-N 5-cyanopyridine-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=N1 XUXSGYYVYLYBFR-UHFFFAOYSA-N 0.000 description 8
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
• 241000713772 Human immunodeficiency virus 1 Species 0.000 description 8
• 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 8
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
• 229910052786 argon Inorganic materials 0.000 description 8
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 150000004775 coumarins Chemical class 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
• 230000008569 process Effects 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• 238000006467 substitution reaction Methods 0.000 description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
• CFWJJSGESLDGKF-UHFFFAOYSA-N 2-methoxy-2-methyl-1,3-dioxolane Chemical compound COC1(C)OCCO1 CFWJJSGESLDGKF-UHFFFAOYSA-N 0.000 description 7
• 108010017640 Aspartic Acid Proteases Proteins 0.000 description 7
• 102000004580 Aspartic Acid Proteases Human genes 0.000 description 7
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
• 230000002378 acidificating effect Effects 0.000 description 7
• 239000008346 aqueous phase Substances 0.000 description 7
• 239000007864 aqueous solution Substances 0.000 description 7
• 150000002576 ketones Chemical class 0.000 description 7
• VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 7
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 7
• FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 6
• JTZSFNHHVULOGJ-UHFFFAOYSA-N 3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CN=C1 JTZSFNHHVULOGJ-UHFFFAOYSA-N 0.000 description 6
• ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 6
• IIYVNMXPYWIJBL-UHFFFAOYSA-N 4-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=NC=C1 IIYVNMXPYWIJBL-UHFFFAOYSA-N 0.000 description 6
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
• WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 6
• WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 6
• 239000012346 acetyl chloride Substances 0.000 description 6
• 150000001299 aldehydes Chemical class 0.000 description 6
• 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
• 230000007812 deficiency Effects 0.000 description 6
• 238000010511 deprotection reaction Methods 0.000 description 6
• 201000010099 disease Diseases 0.000 description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
• 238000010828 elution Methods 0.000 description 6
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