DE69626915T2 - 8-Arylalkyl- und 8-Arylheteroalkyl-5, 11-dihydro-6H-dipyrido-(3,2-b:2', 3'-e)(1,4)diazepine und ihre Verwendung zur Vorbeugung oder Behandlung von HIV-Infektion - Google Patents

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Publication number

DE69626915T2

DE69626915T2 DE69626915T DE69626915T DE69626915T2 DE 69626915 T2 DE69626915 T2 DE 69626915T2 DE 69626915 T DE69626915 T DE 69626915T DE 69626915 T DE69626915 T DE 69626915T DE 69626915 T2 DE69626915 T2 DE 69626915T2

Authority

DE

Germany

Prior art keywords

methyl

ethyl

carbon atoms

dihydro

dipyrido

Prior art date

1995-10-06

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

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• 238000011282 treatment Methods 0.000 title claims abstract description 12
• 208000031886 HIV Infections Diseases 0.000 title claims abstract description 9
• 230000002265 prevention Effects 0.000 title claims abstract description 7
• 208000037357 HIV infectious disease Diseases 0.000 title abstract 2
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 title abstract 2
• POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical class N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 253
• 125000004432 carbon atom Chemical group C* 0.000 claims description 149
• -1 ethylamino, acetamido, acetyl Chemical group 0.000 claims description 120
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 72
• 125000000217 alkyl group Chemical group 0.000 claims description 69
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
• 229910052757 nitrogen Inorganic materials 0.000 claims description 39
• 229910052736 halogen Inorganic materials 0.000 claims description 38
• 150000002367 halogens Chemical group 0.000 claims description 38
• 239000001257 hydrogen Substances 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 36
• 125000003545 alkoxy group Chemical group 0.000 claims description 34
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 32
• 229910052799 carbon Inorganic materials 0.000 claims description 32
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
• 125000004429 atom Chemical group 0.000 claims description 27
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
• 125000004414 alkyl thio group Chemical group 0.000 claims description 26
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 150000002431 hydrogen Chemical group 0.000 claims description 18
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 18
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 18
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 18
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 16
• 125000002541 furyl group Chemical group 0.000 claims description 16
• 125000004076 pyridyl group Chemical group 0.000 claims description 16
• 125000001544 thienyl group Chemical group 0.000 claims description 16
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 239000001301 oxygen Substances 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 239000000460 chlorine Chemical group 0.000 claims description 12
• 229910052801 chlorine Chemical group 0.000 claims description 12
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
• 150000003839 salts Chemical class 0.000 claims description 10
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
• 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 8
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
• 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 8
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 8
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 8
• JISVFSBNJCUDHU-UHFFFAOYSA-N 2-chloro-11-ethyl-5-methyl-8-(2-pyridin-4-ylethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1CCC1=CC=NC=C1 JISVFSBNJCUDHU-UHFFFAOYSA-N 0.000 claims description 7
• 150000001336 alkenes Chemical class 0.000 claims description 7
• 125000001589 carboacyl group Chemical group 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 239000011593 sulfur Substances 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• ULVUURBFDYVMPY-UHFFFAOYSA-N 11-ethyl-2-fluoro-5-methyl-8-(2-pyridin-4-ylethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1CCC1=CC=NC=C1 ULVUURBFDYVMPY-UHFFFAOYSA-N 0.000 claims description 4
• VCLGTWSYOLHYCH-UHFFFAOYSA-N 2-chloro-11-ethyl-5-methyl-8-(2-pyridin-4-yloxyethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1CCOC1=CC=NC=C1 VCLGTWSYOLHYCH-UHFFFAOYSA-N 0.000 claims description 4
• TYPYIAOCHCKFIA-UHFFFAOYSA-N 2-chloro-11-ethyl-5-methyl-8-(phenylsulfanylmethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1CSC1=CC=CC=C1 TYPYIAOCHCKFIA-UHFFFAOYSA-N 0.000 claims description 4
• MGZRDDUEGVRPHN-UHFFFAOYSA-N 2-chloro-11-ethyl-8-(2-hydroxy-2-pyridin-4-ylethyl)-5-methyldipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1CC(O)C1=CC=NC=C1 MGZRDDUEGVRPHN-UHFFFAOYSA-N 0.000 claims description 4
• 150000001204 N-oxides Chemical class 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000000466 oxiranyl group Chemical group 0.000 claims description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
• 125000004953 trihalomethyl group Chemical group 0.000 claims description 4
• RCZBRRIUHGFFMJ-UHFFFAOYSA-N 11-ethyl-2-fluoro-8-(2-hydroxy-2-pyridin-4-ylethyl)-5-methyldipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1CC(O)C1=CC=NC=C1 RCZBRRIUHGFFMJ-UHFFFAOYSA-N 0.000 claims description 3
• AHAQASQWEHMCHG-UHFFFAOYSA-N 2-chloro-11-ethyl-5-methyl-8-(pyridin-4-ylsulfanylmethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1CSC1=CC=NC=C1 AHAQASQWEHMCHG-UHFFFAOYSA-N 0.000 claims description 3
• 239000005864 Sulphur Substances 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 238000002360 preparation method Methods 0.000 claims description 3
• YUHUGAAISLIFCE-UHFFFAOYSA-N 11-ethyl-2-fluoro-5-methyl-8-(2-pyridin-4-yloxyethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1CCOC1=CC=NC=C1 YUHUGAAISLIFCE-UHFFFAOYSA-N 0.000 claims description 2
• SPXQUPQCZUOOCQ-UHFFFAOYSA-N 11-ethyl-2-fluoro-5-methyl-8-(phenylsulfanylmethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1CSC1=CC=CC=C1 SPXQUPQCZUOOCQ-UHFFFAOYSA-N 0.000 claims description 2
• YKGOEDBDALKHFV-UHFFFAOYSA-N 11-ethyl-2-fluoro-5-methyl-8-(pyridin-4-ylmethoxymethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1COCC1=CC=NC=C1 YKGOEDBDALKHFV-UHFFFAOYSA-N 0.000 claims description 2
• BMCALDMFEXQQRY-UHFFFAOYSA-N 11-ethyl-2-fluoro-5-methyl-8-(pyridin-4-yloxymethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1COC1=CC=NC=C1 BMCALDMFEXQQRY-UHFFFAOYSA-N 0.000 claims description 2
• MHYFAWNAKSZSLJ-UHFFFAOYSA-N 11-ethyl-2-fluoro-5-methyl-8-(pyridin-4-ylsulfanylmethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1CSC1=CC=NC=C1 MHYFAWNAKSZSLJ-UHFFFAOYSA-N 0.000 claims description 2
• SSBKOEBEWJHUQR-UHFFFAOYSA-N 2-chloro-11-ethyl-5-methyl-8-(pyridin-4-yloxymethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1COC1=CC=NC=C1 SSBKOEBEWJHUQR-UHFFFAOYSA-N 0.000 claims description 2
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
• DHUJHUFQRGWMTJ-UHFFFAOYSA-N 8-[(3-aminophenoxy)methyl]-11-ethyl-2-fluoro-5-methyldipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(F)=CC=C3N(C)C(=O)C2=CC=1COC1=CC=CC(N)=C1 DHUJHUFQRGWMTJ-UHFFFAOYSA-N 0.000 claims description 2
• GGICVMHKERQRRS-UHFFFAOYSA-N 8-[(3-aminophenoxy)methyl]-2-chloro-11-ethyl-5-methyldipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1COC1=CC=CC(N)=C1 GGICVMHKERQRRS-UHFFFAOYSA-N 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 125000004423 acyloxy group Chemical group 0.000 claims description 2
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
• 150000001408 amides Chemical class 0.000 claims description 2
• 125000003277 amino group Chemical group 0.000 claims description 2
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
• 125000005002 aryl methyl group Chemical group 0.000 claims description 2
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 2
• 239000011737 fluorine Chemical group 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
• 125000003566 oxetanyl group Chemical group 0.000 claims description 2
• 125000004434 sulfur atom Chemical group 0.000 claims description 2
• OJNIFBJDBPQXIY-UHFFFAOYSA-N 2-chloro-11-ethyl-5-methyl-8-(pyridin-4-ylmethoxymethyl)dipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound C=1N=C2N(CC)C3=NC(Cl)=CC=C3N(C)C(=O)C2=CC=1COCC1=CC=NC=C1 OJNIFBJDBPQXIY-UHFFFAOYSA-N 0.000 claims 1
• 238000013329 compounding Methods 0.000 claims 1
• 150000004908 diazepines Chemical class 0.000 claims 1
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 336
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 139
• 238000000034 method Methods 0.000 description 133
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
• 239000000203 mixture Substances 0.000 description 73
• 239000011541 reaction mixture Substances 0.000 description 73
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 72
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 70
• 239000000047 product Substances 0.000 description 67
• 239000000243 solution Substances 0.000 description 66
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
• 238000003818 flash chromatography Methods 0.000 description 58
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
• 238000000746 purification Methods 0.000 description 41
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
• 238000006243 chemical reaction Methods 0.000 description 37
• 229910052786 argon Inorganic materials 0.000 description 36
• 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 35
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 34
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
• 102100034343 Integrase Human genes 0.000 description 32
• 229920006395 saturated elastomer Polymers 0.000 description 31
• 239000002904 solvent Substances 0.000 description 30
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• 238000001953 recrystallisation Methods 0.000 description 29
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 27
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
• 239000013078 crystal Substances 0.000 description 26
• 241000725303 Human immunodeficiency virus Species 0.000 description 25
• 239000003208 petroleum Substances 0.000 description 24
• 238000010828 elution Methods 0.000 description 23
• NSXKHLFKMRRCOE-UHFFFAOYSA-N 2-chloro-8-(chloromethyl)-11-ethyl-5-methyldipyrido[2,4-d:2',3'-h][1,4]diazepin-6-one Chemical compound CN1C(=O)C2=CC(CCl)=CN=C2N(CC)C2=NC(Cl)=CC=C21 NSXKHLFKMRRCOE-UHFFFAOYSA-N 0.000 description 22
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
• 229910052938 sodium sulfate Inorganic materials 0.000 description 20
• 235000011152 sodium sulphate Nutrition 0.000 description 20
• 238000003556 assay Methods 0.000 description 19
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 19
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 17
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 238000005859 coupling reaction Methods 0.000 description 15
• 230000008569 process Effects 0.000 description 15
• 210000004027 cell Anatomy 0.000 description 14
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
• 235000019341 magnesium sulphate Nutrition 0.000 description 14
• 235000017557 sodium bicarbonate Nutrition 0.000 description 14
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
• 108020004414 DNA Proteins 0.000 description 13
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
• 239000011780 sodium chloride Substances 0.000 description 13
• 239000012312 sodium hydride Substances 0.000 description 13
• 229910000104 sodium hydride Inorganic materials 0.000 description 13
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
• 238000005984 hydrogenation reaction Methods 0.000 description 12
• MYJWRKKBBZLUSJ-UHFFFAOYSA-N 11-ethyl-8-iodo-5-methyldipyrido[2,3-d:2',3'-h][1,4]diazepin-6-one Chemical compound CN1C(=O)C2=CC(I)=CN=C2N(CC)C2=NC=CC=C21 MYJWRKKBBZLUSJ-UHFFFAOYSA-N 0.000 description 11
• 102000004190 Enzymes Human genes 0.000 description 11
• 108090000790 Enzymes Proteins 0.000 description 11
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
• 239000012298 atmosphere Substances 0.000 description 11
• 239000012267 brine Substances 0.000 description 11
• 239000003921 oil Substances 0.000 description 11
• 235000019198 oils Nutrition 0.000 description 11
• 235000011121 sodium hydroxide Nutrition 0.000 description 11
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