DE19627898A1 - Festphasensynthese von Oligonucleotiden - Google Patents
Festphasensynthese von OligonucleotidenInfo
- Publication number
- DE19627898A1 DE19627898A1 DE19627898A DE19627898A DE19627898A1 DE 19627898 A1 DE19627898 A1 DE 19627898A1 DE 19627898 A DE19627898 A DE 19627898A DE 19627898 A DE19627898 A DE 19627898A DE 19627898 A1 DE19627898 A1 DE 19627898A1
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- alkoxy
- aryl
- formula
- independently
- Prior art date
- 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.)
- Withdrawn
Links
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 37
- 238000010532 solid phase synthesis reaction Methods 0.000 title claims abstract description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 title claims description 24
- -1 p-nitrophenylethyl Chemical group 0.000 claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000007787 solid Substances 0.000 claims abstract description 22
- 125000003277 amino group Chemical group 0.000 claims abstract description 15
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 15
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 14
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 14
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 13
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 13
- 125000003729 nucleotide group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002773 nucleotide Substances 0.000 claims abstract description 10
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 125000006245 phosphate protecting group Chemical group 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 111
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 26
- 125000006239 protecting group Chemical group 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 150000003536 tetrazoles Chemical class 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 12
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 8
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- 230000007017 scission Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229940104302 cytosine Drugs 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 102000039446 nucleic acids Human genes 0.000 claims description 6
- 108020004707 nucleic acids Proteins 0.000 claims description 6
- 150000007523 nucleic acids Chemical class 0.000 claims description 6
- 229930024421 Adenine Natural products 0.000 claims description 5
- 229960000643 adenine Drugs 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 5
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 4
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229940113082 thymine Drugs 0.000 claims description 4
- 229940035893 uracil Drugs 0.000 claims description 4
- 239000003298 DNA probe Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid group Chemical group C(CCC(=O)O)(=O)O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 2
- ZSUSGBQRHRZDAP-UHFFFAOYSA-N 2,2-diethylbutan-1-amine Chemical group CCC(CC)(CC)CN ZSUSGBQRHRZDAP-UHFFFAOYSA-N 0.000 claims description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 2
- 108020000948 Antisense Oligonucleotides Proteins 0.000 claims description 2
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 2
- 108020003215 DNA Probes Proteins 0.000 claims description 2
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 2
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
- CGHIBGNXEGJPQZ-UHFFFAOYSA-N 1-hexyne Chemical compound CCCCC#C CGHIBGNXEGJPQZ-UHFFFAOYSA-N 0.000 claims 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 125000002327 selenol group Chemical group [H][Se]* 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 125000005336 allyloxy group Chemical group 0.000 abstract 1
- 125000000371 nucleobase group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 239000006260 foam Substances 0.000 description 15
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 14
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 11
- 229910052681 coesite Inorganic materials 0.000 description 10
- 229910052906 cristobalite Inorganic materials 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- 235000012239 silicon dioxide Nutrition 0.000 description 10
- 229910052682 stishovite Inorganic materials 0.000 description 10
- 229910052905 tridymite Inorganic materials 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 150000002431 hydrogen Chemical group 0.000 description 8
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 8
- 239000002777 nucleoside Substances 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- FYXKZNLBZKRYSS-UHFFFAOYSA-N benzene-1,2-dicarbonyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C(Cl)=O FYXKZNLBZKRYSS-UHFFFAOYSA-N 0.000 description 7
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 7
- 235000019256 formaldehyde Nutrition 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 6
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 102000053602 DNA Human genes 0.000 description 5
- 230000027832 depurination Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229940014800 succinic anhydride Drugs 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 4
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- 238000002515 oligonucleotide synthesis Methods 0.000 description 4
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 4
- 229920002477 rna polymer Polymers 0.000 description 4
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- 230000008025 crystallization Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
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- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 1
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- GALWCMOWYUPKMY-UHFFFAOYSA-N n-[[di(propan-2-yl)amino]-[2-(4-nitrophenyl)ethoxy]phosphanyl]-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C(C)C)P(N(C(C)C)C(C)C)OCCC1=CC=C([N+]([O-])=O)C=C1 GALWCMOWYUPKMY-UHFFFAOYSA-N 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 239000001384 succinic acid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19627898A DE19627898A1 (de) | 1996-07-11 | 1996-07-11 | Festphasensynthese von Oligonucleotiden |
| ES97111426T ES2188826T3 (es) | 1996-07-11 | 1997-07-07 | Sintesis en fase solida de oligonucleotidos. |
| DE59709128T DE59709128D1 (de) | 1996-07-11 | 1997-07-07 | Festphasensynthese von Oligonucleotiden |
| DK97111426T DK0818460T3 (da) | 1996-07-11 | 1997-07-07 | Fastfasesyntese af oligonucleotider |
| AT97111426T ATE231162T1 (de) | 1996-07-11 | 1997-07-07 | Festphasensynthese von oligonucleotiden |
| EP97111426A EP0818460B1 (de) | 1996-07-11 | 1997-07-07 | Festphasensynthese von Oligonucleotiden |
| PT97111426T PT818460E (pt) | 1996-07-11 | 1997-07-07 | Sintese em fase solida de oligonucleotidos |
| AU28552/97A AU716391B2 (en) | 1996-07-11 | 1997-07-09 | Solid phase synthesis of oligonucleotides |
| JP18514297A JP4435878B2 (ja) | 1996-07-11 | 1997-07-10 | オリゴヌクレオチドの固相合成 |
| NO19973217A NO317853B1 (no) | 1996-07-11 | 1997-07-10 | Fastfasesyntese av oligonukleotider |
| CA002210031A CA2210031C (en) | 1996-07-11 | 1997-07-10 | Solid phase synthesis of oligonucleotides |
| US08/893,614 US5936077A (en) | 1996-07-11 | 1997-07-11 | Solid phase synthesis of oligonucleotides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19627898A DE19627898A1 (de) | 1996-07-11 | 1996-07-11 | Festphasensynthese von Oligonucleotiden |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19627898A1 true DE19627898A1 (de) | 1998-01-15 |
Family
ID=7799510
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19627898A Withdrawn DE19627898A1 (de) | 1996-07-11 | 1996-07-11 | Festphasensynthese von Oligonucleotiden |
| DE59709128T Expired - Lifetime DE59709128D1 (de) | 1996-07-11 | 1997-07-07 | Festphasensynthese von Oligonucleotiden |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE59709128T Expired - Lifetime DE59709128D1 (de) | 1996-07-11 | 1997-07-07 | Festphasensynthese von Oligonucleotiden |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5936077A (https=) |
| EP (1) | EP0818460B1 (https=) |
| JP (1) | JP4435878B2 (https=) |
| AT (1) | ATE231162T1 (https=) |
| AU (1) | AU716391B2 (https=) |
| CA (1) | CA2210031C (https=) |
| DE (2) | DE19627898A1 (https=) |
| DK (1) | DK0818460T3 (https=) |
| ES (1) | ES2188826T3 (https=) |
| NO (1) | NO317853B1 (https=) |
| PT (1) | PT818460E (https=) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000046231A1 (en) * | 1999-02-05 | 2000-08-10 | Amersham Pharmacia Biotech Inc. | Method for deprotecting oligonucleotides |
| EP1028124A3 (en) * | 1999-02-04 | 2000-09-06 | Isis Pharmaceuticals, Inc. | Improved process for the synthesis of oligomeric compounds |
| US6664388B2 (en) | 2001-03-08 | 2003-12-16 | Applera Corporation | Reagents for oligonucleotide cleavage and deprotection |
| DE102006016473A1 (de) * | 2005-12-08 | 2007-06-14 | Continental Teves Ag & Co. Ohg | Druckregelventil |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6274725B1 (en) * | 1998-06-02 | 2001-08-14 | Isis Pharmaceuticals, Inc. | Activators for oligonucleotide synthesis |
| EP1095054B1 (en) | 1998-07-09 | 2006-10-25 | Biocept, Inc. | Method of using an improved peptide nucleic acid universal library to optimize dna sequence hybridation |
| DE19842164B4 (de) * | 1998-09-15 | 2004-06-03 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Verfahren zur Qualitätskontrolle beim Aufbau von Oligomerrastern |
| US6175001B1 (en) * | 1998-10-16 | 2001-01-16 | The Scripps Research Institute | Functionalized pyrimidine nucleosides and nucleotides and DNA's incorporating same |
| WO2006025154A1 (ja) * | 2004-08-30 | 2006-03-09 | Gifu University | 修飾オリゴヌクレオチド |
| US8513404B2 (en) * | 2008-04-24 | 2013-08-20 | Nitto Denko Avecia, Inc. | Process for the manufacture of oligonucleotides |
| JP6794258B2 (ja) * | 2013-09-30 | 2020-12-02 | ジェロン・コーポレーションＧｅｒｏｎ Ｃｏｒｐｏｒａｔｉｏｎ | オリゴヌクレオチドについてのホスホロジアミデート骨格結合 |
| WO2017066782A1 (en) * | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Hydrophobic mrna cap analogs |
| WO2017066781A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified phosphate linkage |
| US11866754B2 (en) | 2015-10-16 | 2024-01-09 | Modernatx, Inc. | Trinucleotide mRNA cap analogs |
| JP2019532027A (ja) | 2016-08-17 | 2019-11-07 | ソルスティス バイオロジクス，リミティッド | ポリヌクレオチド構築物 |
| WO2019006455A1 (en) | 2017-06-30 | 2019-01-03 | Solstice Biologics, Ltd. | AUXILIARIES OF CHIRAL PHOSPHORAMIDITIS AND METHODS OF USE THEREOF |
| KR20190090301A (ko) * | 2018-01-24 | 2019-08-01 | 에스티팜 주식회사 | 신규한 뉴클레오사이드 또는 뉴클레오타이드 유도체 및 이들의 용도 |
| CN115772201B (zh) * | 2021-09-08 | 2024-11-26 | 苏州金唯智生物科技有限公司 | 一种固相合成rna的后处理方法及其应用 |
| CN117362370B (zh) * | 2023-12-07 | 2024-03-05 | 北京百力格生物科技有限公司 | 核苷亚磷酰胺单体及其制备方法和应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI115214B (fi) * | 1992-01-22 | 2005-03-31 | Hoechst Ag | Menetelmä oligonukleotidianalogien valmistamiseksi ja niiden käyttö |
| US5623068A (en) * | 1994-03-07 | 1997-04-22 | Beckman Instruments, Inc. | Synthesis of DNA using substituted phenylacetyl-protected nucleotides |
-
1996
- 1996-07-11 DE DE19627898A patent/DE19627898A1/de not_active Withdrawn
-
1997
- 1997-07-07 ES ES97111426T patent/ES2188826T3/es not_active Expired - Lifetime
- 1997-07-07 AT AT97111426T patent/ATE231162T1/de active
- 1997-07-07 PT PT97111426T patent/PT818460E/pt unknown
- 1997-07-07 DE DE59709128T patent/DE59709128D1/de not_active Expired - Lifetime
- 1997-07-07 EP EP97111426A patent/EP0818460B1/de not_active Expired - Lifetime
- 1997-07-07 DK DK97111426T patent/DK0818460T3/da active
- 1997-07-09 AU AU28552/97A patent/AU716391B2/en not_active Ceased
- 1997-07-10 JP JP18514297A patent/JP4435878B2/ja not_active Expired - Fee Related
- 1997-07-10 NO NO19973217A patent/NO317853B1/no not_active IP Right Cessation
- 1997-07-10 CA CA002210031A patent/CA2210031C/en not_active Expired - Fee Related
- 1997-07-11 US US08/893,614 patent/US5936077A/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1028124A3 (en) * | 1999-02-04 | 2000-09-06 | Isis Pharmaceuticals, Inc. | Improved process for the synthesis of oligomeric compounds |
| US7041816B2 (en) | 1999-02-04 | 2006-05-09 | Isis Pharmaceuticals, Inc. | Process for the synthesis of oligomeric compounds |
| US7186822B2 (en) | 1999-02-04 | 2007-03-06 | Isis Pharmaceuticals, Inc. | Process for the synthesis of oligomeric compounds |
| US7199236B2 (en) | 1999-02-04 | 2007-04-03 | Isis Pharmaceuticals, Inc. | Process for the synthesis of oligomeric compounds |
| US7227016B2 (en) | 1999-02-04 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Process for the synthesis of oligomeric compounds |
| WO2000046231A1 (en) * | 1999-02-05 | 2000-08-10 | Amersham Pharmacia Biotech Inc. | Method for deprotecting oligonucleotides |
| US6664388B2 (en) | 2001-03-08 | 2003-12-16 | Applera Corporation | Reagents for oligonucleotide cleavage and deprotection |
| DE102006016473A1 (de) * | 2005-12-08 | 2007-06-14 | Continental Teves Ag & Co. Ohg | Druckregelventil |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0818460B1 (de) | 2003-01-15 |
| CA2210031A1 (en) | 1998-01-11 |
| DE59709128D1 (de) | 2003-02-20 |
| EP0818460A2 (de) | 1998-01-14 |
| DK0818460T3 (da) | 2003-05-05 |
| CA2210031C (en) | 2008-04-22 |
| NO973217D0 (no) | 1997-07-10 |
| ES2188826T3 (es) | 2003-07-01 |
| NO973217L (no) | 1998-01-12 |
| JPH1072486A (ja) | 1998-03-17 |
| US5936077A (en) | 1999-08-10 |
| NO317853B1 (no) | 2004-12-20 |
| AU716391B2 (en) | 2000-02-24 |
| AU2855297A (en) | 1998-01-22 |
| PT818460E (pt) | 2003-06-30 |
| JP4435878B2 (ja) | 2010-03-24 |
| ATE231162T1 (de) | 2003-02-15 |
| EP0818460A3 (de) | 1999-02-24 |
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