BR112020024782A2 - compostos de tetra-hidro-1h-pirazino[2,1-a]isoindolilquinolina para o tratamento de doença autoimune - Google Patents

Info

Publication number

BR112020024782A2

BR112020024782A2 BR112020024782-0A BR112020024782A BR112020024782A2 BR 112020024782 A2 BR112020024782 A2 BR 112020024782A2 BR 112020024782 A BR112020024782 A BR 112020024782A BR 112020024782 A2 BR112020024782 A2 BR 112020024782A2

Authority

BR

Brazil

Prior art keywords

methyl

amino

carbonitrile

tetrahydro

isoindol

Prior art date

2018-06-05

Links

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• 238000011282 treatment Methods 0.000 title claims description 15
• 208000023275 Autoimmune disease Diseases 0.000 title description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title description 2
• FKZVEJFZKRENLL-UHFFFAOYSA-N 2-(2H-isoindol-1-yl)quinoline Chemical class C1=CC=CC2=CNC(C=3N=C4C=CC=CC4=CC=3)=C21 FKZVEJFZKRENLL-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 358
• 150000003839 salts Chemical class 0.000 claims abstract description 47
• 238000000034 method Methods 0.000 claims abstract description 15
• -1 1,2,3,4,6,6a-hexahydropyrrolo [3,4-c] pyrrolyl Chemical group 0.000 claims description 482
• CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical compound C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 claims description 250
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 180
• 238000002360 preparation method Methods 0.000 claims description 179
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 162
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 65
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 61
• KIDIJBYYGAEULX-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound N#CC1=CC=CC2=CC=NN12 KIDIJBYYGAEULX-UHFFFAOYSA-N 0.000 claims description 58
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 50
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 44
• 125000001424 substituent group Chemical group 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 33
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
• 125000004193 piperazinyl group Chemical group 0.000 claims description 31
• 238000006243 chemical reaction Methods 0.000 claims description 30
• 239000003054 catalyst Substances 0.000 claims description 28
• 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims description 26
• 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 26
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 25
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 25
• 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 25
• 229910052805 deuterium Inorganic materials 0.000 claims description 25
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
• 125000002393 azetidinyl group Chemical group 0.000 claims description 24
• 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 23
• 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 23
• 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 22
• 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 claims description 20
• 229910000024 caesium carbonate Inorganic materials 0.000 claims description 18
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 18
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 18
• 125000005960 1,4-diazepanyl group Chemical group 0.000 claims description 17
• 125000003386 piperidinyl group Chemical group 0.000 claims description 17
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 16
• MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 15
• 239000005557 antagonist Substances 0.000 claims description 13
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 13
• 239000003153 chemical reaction reagent Substances 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 125000005962 1,4-oxazepanyl group Chemical group 0.000 claims description 11
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 11
• 208000005777 Lupus Nephritis Diseases 0.000 claims description 10
• 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 claims description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 9
• 150000004820 halides Chemical class 0.000 claims description 9
• 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 8
• JFSVAISMOVUTDY-ZGBKXNSBSA-N 5-[(4R,10bS)-8-[(3R,4R)-4-amino-3-hydroxy-3-methylpyrrolidin-1-yl]-9-fluoro-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound N[C@H]1[C@](CN(C1)C=1C=C2CN3[C@@H](C2=CC1F)CN(C[C@H]3C)C3=C1C=CC=NC1=C(C=C3)C#N)(C)O JFSVAISMOVUTDY-ZGBKXNSBSA-N 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
• 238000011321 prophylaxis Methods 0.000 claims description 7
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• 238000006411 Negishi coupling reaction Methods 0.000 claims description 4
• 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
• 235000015320 potassium carbonate Nutrition 0.000 claims description 4
• GJFFVYGPVOUSJN-UHFFFAOYSA-N 5-(8-piperazin-1-yl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl)quinoline-8-carbonitrile Chemical compound C1N(CCNC1)C1=CC=C2C3CN(CCN3CC2=C1)C1=CC=C(C#N)C2=NC=CC=C12 GJFFVYGPVOUSJN-UHFFFAOYSA-N 0.000 claims description 3
• FMKLASALOBGCFV-PDQLQIGBSA-N 5-[(4R,10bS)-8-(3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl)-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound O1C2C(N(CC1)C1=CC=C3[C@H]4CN(C[C@H](N4CC3=C1)C)C1=CC=C(C#N)C3=NC=CC=C13)CNC2 FMKLASALOBGCFV-PDQLQIGBSA-N 0.000 claims description 3
• STWJRRQLEOCSIF-LJWPGGNMSA-N 5-[(4R,10bS)-8-(3a-methoxy-1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound N1CC2CN(CC2(OC)C1)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 STWJRRQLEOCSIF-LJWPGGNMSA-N 0.000 claims description 3
• PZQRPNMBTICEBQ-VOIUYBSRSA-N 5-[(4R,10bS)-8-(azetidin-3-yl)-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound N1CC(C1)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 PZQRPNMBTICEBQ-VOIUYBSRSA-N 0.000 claims description 3
• JFSVAISMOVUTDY-AUROACQKSA-N 5-[(4R,10bS)-8-[(3S,4S)-4-amino-3-hydroxy-3-methylpyrrolidin-1-yl]-9-fluoro-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound N[C@@H]1[C@@](CN(C1)C=1C=C2CN3[C@@H](C2=CC1F)CN(C[C@H]3C)C3=C1C=CC=NC1=C(C=C3)C#N)(C)O JFSVAISMOVUTDY-AUROACQKSA-N 0.000 claims description 3
• CCCDSOYAGIVCTL-NDKUEENFSA-N 5-[(4R,10bS)-8-[(8aR)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound C1N2[C@H](CNC1)CN(C2=O)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 CCCDSOYAGIVCTL-NDKUEENFSA-N 0.000 claims description 3
• CCCDSOYAGIVCTL-QGUBCYKSSA-N 5-[(4R,10bS)-8-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound C1CN2[C@@H](CN1)CN(C2=O)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 CCCDSOYAGIVCTL-QGUBCYKSSA-N 0.000 claims description 3
• LQZJUWWESWCREX-UHFFFAOYSA-N 7-(8-piperazin-1-yl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl)-1,3-benzothiazole-4-carbonitrile Chemical compound C1CN(CCN1)C1=CC=C2C3CN(CCN3CC2=C1)C1=CC=C(C#N)C=2N=CSC1=2 LQZJUWWESWCREX-UHFFFAOYSA-N 0.000 claims description 3
• 238000006619 Stille reaction Methods 0.000 claims description 3
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 3
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 125000004553 quinoxalin-5-yl group Chemical group N1=CC=NC2=C(C=CC=C12)* 0.000 claims description 3
• FDIVMIYSWNDEGF-NFQMXDRXSA-N 5-[(4R,10bS)-4-methyl-8-(2-morpholin-4-ylethylamino)-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@H]2N1CC1=CC(=CC=C21)NCCN2CCOCC2)C2=C1C=CC=NC1=C(C=C2)C#N FDIVMIYSWNDEGF-NFQMXDRXSA-N 0.000 claims description 2
• ZBUAVGQJZANEJQ-UVWOLYCHSA-N 5-[(4R,10bS)-4-methyl-8-(morpholin-3-ylmethylamino)-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@H]2N1CC1=CC(=CC=C21)NCC2NCCOC2)C2=C1C=CC=NC1=C(C=C2)C#N ZBUAVGQJZANEJQ-UVWOLYCHSA-N 0.000 claims description 2
• DCYVKDHFBSFDBY-IQGLISFBSA-N 5-[(4R,10bS)-4-methyl-8-(piperazine-1-carbonyl)-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound N1(C(=O)C2=CC=C3[C@H]4CN(C[C@H](N4CC3=C2)C)C2=CC=C(C#N)C3=NC=CC=C23)CCNCC1 DCYVKDHFBSFDBY-IQGLISFBSA-N 0.000 claims description 2
• XCLLBSFSZAOMFX-VOIUYBSRSA-N 5-[(4R,10bS)-8-(azetidin-3-ylamino)-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound C1C(CN1)NC1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 XCLLBSFSZAOMFX-VOIUYBSRSA-N 0.000 claims description 2
• IZNJCGCCGDJMIO-RUQDXMQKSA-N 5-[(4R,10bS)-8-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound N1(C[C@H]([C@@H](C1)OC)N)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 IZNJCGCCGDJMIO-RUQDXMQKSA-N 0.000 claims description 2
• FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
• 125000005103 alkyl silyl group Chemical group 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
• 238000006467 substitution reaction Methods 0.000 claims description 2
• NCDGOROIOUEVHZ-ZTNKVBRBSA-N 5-[(4R,10bS)-8-[(3S,4S)-3-hydroxy-4-(methylamino)pyrrolidin-1-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]quinoline-8-carbonitrile Chemical compound [C@H]1(O)CN(C[C@@H]1NC)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC=C(C#N)C2=NC=CC=C12 NCDGOROIOUEVHZ-ZTNKVBRBSA-N 0.000 claims 1
• 239000013543 active substance Substances 0.000 claims 1
• MQUPWTBHHPUUMC-UHFFFAOYSA-N isoindole Chemical compound C1=CC=C[C]2C=NC=C21 MQUPWTBHHPUUMC-UHFFFAOYSA-N 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 72
• 238000001819 mass spectrum Methods 0.000 description 188
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 109
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
• 238000005481 NMR spectroscopy Methods 0.000 description 71
• 239000000243 solution Substances 0.000 description 71
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 66
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
• 229910001868 water Inorganic materials 0.000 description 62
• 238000005160 1H NMR spectroscopy Methods 0.000 description 61
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 51
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 48
• 239000011541 reaction mixture Substances 0.000 description 45
• NSILYQWHARROMG-MRVPVSSYSA-N tert-butyl (3r)-3-(hydroxymethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1 NSILYQWHARROMG-MRVPVSSYSA-N 0.000 description 42
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
• 210000004027 cell Anatomy 0.000 description 39
• 235000019439 ethyl acetate Nutrition 0.000 description 37
• 239000012044 organic layer Substances 0.000 description 36
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• 239000012267 brine Substances 0.000 description 30
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
• 238000003818 flash chromatography Methods 0.000 description 29
• 238000012360 testing method Methods 0.000 description 28
• 239000000741 silica gel Substances 0.000 description 26
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 239000000706 filtrate Substances 0.000 description 18
• 229910004809 Na2 SO4 Inorganic materials 0.000 description 17
• 239000012043 crude product Substances 0.000 description 17
• 239000007832 Na2SO4 Substances 0.000 description 16
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
• PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 16
• 229910052938 sodium sulfate Inorganic materials 0.000 description 16
• 235000011152 sodium sulphate Nutrition 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 238000003556 assay Methods 0.000 description 15
• PIGDOXPNNMFBNA-HTQZYQBOSA-N tert-butyl n-[(3r,4r)-4-methoxypyrrolidin-3-yl]carbamate Chemical compound CO[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C PIGDOXPNNMFBNA-HTQZYQBOSA-N 0.000 description 15
• 230000004913 activation Effects 0.000 description 14
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
• 239000000460 chlorine Substances 0.000 description 12
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
• 206010034972 Photosensitivity reaction Diseases 0.000 description 11
• 208000007578 phototoxic dermatitis Diseases 0.000 description 11
• 231100000018 phototoxicity Toxicity 0.000 description 11
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 10
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
• 229940079593 drug Drugs 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
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