CA2437040C - Process for the preparation of phosphorothioate oligonucleotides - Google Patents
Process for the preparation of phosphorothioate oligonucleotides Download PDFInfo
- Publication number
- CA2437040C CA2437040C CA2437040A CA2437040A CA2437040C CA 2437040 C CA2437040 C CA 2437040C CA 2437040 A CA2437040 A CA 2437040A CA 2437040 A CA2437040 A CA 2437040A CA 2437040 C CA2437040 C CA 2437040C
- Authority
- CA
- Canada
- Prior art keywords
- oligonucleotide
- solid support
- process according
- acetonitrile
- solvent
- 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.)
- Expired - Lifetime
Links
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 106
- 238000000034 method Methods 0.000 title claims abstract description 49
- 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 abstract description 26
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 108
- 239000007787 solid Substances 0.000 claims abstract description 56
- 239000002904 solvent Substances 0.000 claims abstract description 39
- 238000005406 washing Methods 0.000 claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 125000005270 trialkylamine group Chemical group 0.000 claims abstract description 4
- -1 phosphate triester Chemical class 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002777 nucleoside Substances 0.000 claims description 18
- 150000008300 phosphoramidites Chemical class 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 238000003776 cleavage reaction Methods 0.000 claims description 10
- 230000007017 scission Effects 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- ZCQGVFNHUATAJY-UHFFFAOYSA-N methyl 2-[methyl(prop-2-enoyl)amino]acetate Chemical compound COC(=O)CN(C)C(=O)C=C ZCQGVFNHUATAJY-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229940088644 n,n-dimethylacrylamide Drugs 0.000 claims description 3
- YLGYACDQVQQZSW-UHFFFAOYSA-N n,n-dimethylprop-2-enamide Chemical compound CN(C)C(=O)C=C YLGYACDQVQQZSW-UHFFFAOYSA-N 0.000 claims description 3
- 150000003141 primary amines Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 238000007605 air drying Methods 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 239000012062 aqueous buffer Substances 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 125000003431 oxalo group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004492 methyl ester group Chemical group 0.000 claims 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 claims 1
- 239000002773 nucleotide Substances 0.000 abstract description 5
- 125000003729 nucleotide group Chemical group 0.000 abstract description 5
- 238000001035 drying Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 238000010532 solid phase synthesis reaction Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002515 oligonucleotide synthesis Methods 0.000 description 5
- 229920002401 polyacrylamide Polymers 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000005547 deoxyribonucleotide Substances 0.000 description 4
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 4
- 229960005215 dichloroacetic acid Drugs 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- 108091028664 Ribonucleotide Proteins 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 239000002336 ribonucleotide Substances 0.000 description 3
- 125000002652 ribonucleotide group Chemical group 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- JUDOLRSMWHVKGX-UHFFFAOYSA-N 1,1-dioxo-1$l^{6},2-benzodithiol-3-one Chemical compound C1=CC=C2C(=O)SS(=O)(=O)C2=C1 JUDOLRSMWHVKGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000005289 controlled pore glass Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000006642 detritylation reaction Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- AYGYHGXUJBFUJU-UHFFFAOYSA-N n-[2-(prop-2-enoylamino)ethyl]prop-2-enamide Chemical compound C=CC(=O)NCCNC(=O)C=C AYGYHGXUJBFUJU-UHFFFAOYSA-N 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- AKUNSTOMHUXJOZ-UHFFFAOYSA-N 1-hydroperoxybutane Chemical compound CCCCOO AKUNSTOMHUXJOZ-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- FSZBNXRNKJWUKH-UHFFFAOYSA-N 1-nitro-5-phenyltetrazole Chemical compound [O-][N+](=O)N1N=NN=C1C1=CC=CC=C1 FSZBNXRNKJWUKH-UHFFFAOYSA-N 0.000 description 1
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 1
- QUYTZULIGAMRMT-UHFFFAOYSA-N 2-cyanoethylperoxyphosphonamidous acid Chemical compound NP(O)OOCCC#N QUYTZULIGAMRMT-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- YWZHEXZIISFIDA-UHFFFAOYSA-N 5-amino-1,2,4-dithiazole-3-thione Chemical compound NC1=NC(=S)SS1 YWZHEXZIISFIDA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical compound NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000035657 Abasia Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229920000361 Poly(styrene)-block-poly(ethylene glycol) Polymers 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940124276 oligodeoxyribonucleotide Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- IXGZXXBJSZISOO-UHFFFAOYSA-N s-(2-phenylacetyl)sulfanyl 2-phenylethanethioate Chemical compound C=1C=CC=CC=1CC(=O)SSC(=O)CC1=CC=CC=C1 IXGZXXBJSZISOO-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2714353A CA2714353A1 (en) | 2000-12-05 | 2001-12-03 | Process for the preparation of phosphorothioate oligonucleotides |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0029610A GB0029610D0 (en) | 2000-12-05 | 2000-12-05 | Process |
| GB0029610.3 | 2000-12-05 | ||
| US09/740,031 | 2000-12-20 | ||
| US09/740,031 US6768005B2 (en) | 2000-12-20 | 2000-12-20 | Process |
| PCT/GB2001/005338 WO2002046205A2 (en) | 2000-12-05 | 2001-12-03 | Process for the preparation of phosphorothionate oligonucleotides |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2714353A Division CA2714353A1 (en) | 2000-12-05 | 2001-12-03 | Process for the preparation of phosphorothioate oligonucleotides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2437040A1 CA2437040A1 (en) | 2002-06-13 |
| CA2437040C true CA2437040C (en) | 2011-01-25 |
Family
ID=26245377
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2437040A Expired - Lifetime CA2437040C (en) | 2000-12-05 | 2001-12-03 | Process for the preparation of phosphorothioate oligonucleotides |
| CA2714353A Abandoned CA2714353A1 (en) | 2000-12-05 | 2001-12-03 | Process for the preparation of phosphorothioate oligonucleotides |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2714353A Abandoned CA2714353A1 (en) | 2000-12-05 | 2001-12-03 | Process for the preparation of phosphorothioate oligonucleotides |
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| US (1) | US7227017B2 (enExample) |
| EP (2) | EP1343802B1 (enExample) |
| JP (1) | JP2004517089A (enExample) |
| KR (1) | KR20040016826A (enExample) |
| CN (1) | CN1302005C (enExample) |
| AU (1) | AU2002220870A1 (enExample) |
| CA (2) | CA2437040C (enExample) |
| WO (1) | WO2002046205A2 (enExample) |
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| GB0229443D0 (en) * | 2002-12-18 | 2003-01-22 | Avecia Ltd | Process |
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| WO2009052034A1 (en) * | 2007-10-15 | 2009-04-23 | Honeywell International Inc. | Synthesis of oligonucleotides or phosphorothioate oligonucleotide with a capping agent of n-methylimidazole free of 1,3,5-trimethylhexahydro-1,3,5-triazine |
| WO2012059510A1 (en) * | 2010-11-02 | 2012-05-10 | Girindus America, Inc. | Back pressure control during solid-phase synthesis on polymeric supports |
| KR102237882B1 (ko) * | 2012-08-15 | 2021-04-07 | 아이오니스 파마수티컬즈, 인코포레이티드 | 변형된 캡핑 프로토콜을 이용하는 올리고머 화합물 제조 방법 |
| US9409139B2 (en) | 2013-08-05 | 2016-08-09 | Twist Bioscience Corporation | De novo synthesized gene libraries |
| CA2975852A1 (en) | 2015-02-04 | 2016-08-11 | Twist Bioscience Corporation | Methods and devices for de novo oligonucleic acid assembly |
| WO2016172377A1 (en) | 2015-04-21 | 2016-10-27 | Twist Bioscience Corporation | Devices and methods for oligonucleic acid library synthesis |
| AU2016324296A1 (en) | 2015-09-18 | 2018-04-12 | Twist Bioscience Corporation | Oligonucleic acid variant libraries and synthesis thereof |
| CN108698012A (zh) | 2015-09-22 | 2018-10-23 | 特韦斯特生物科学公司 | 用于核酸合成的柔性基底 |
| CN108603307A (zh) | 2015-12-01 | 2018-09-28 | 特韦斯特生物科学公司 | 功能化表面及其制备 |
| CA3034769A1 (en) | 2016-08-22 | 2018-03-01 | Twist Bioscience Corporation | De novo synthesized nucleic acid libraries |
| CN110248724B (zh) | 2016-09-21 | 2022-11-18 | 特韦斯特生物科学公司 | 基于核酸的数据存储 |
| CN110366613A (zh) | 2016-12-16 | 2019-10-22 | 特韦斯特生物科学公司 | 免疫突触的变体文库及其合成 |
| WO2018156792A1 (en) | 2017-02-22 | 2018-08-30 | Twist Bioscience Corporation | Nucleic acid based data storage |
| CN110913865A (zh) | 2017-03-15 | 2020-03-24 | 特韦斯特生物科学公司 | 免疫突触的变体文库及其合成 |
| WO2018231864A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
| IL271205B2 (en) | 2017-06-12 | 2025-02-01 | Twist Bioscience Corp | Methods for assembling continuous nucleic acids |
| US11407837B2 (en) | 2017-09-11 | 2022-08-09 | Twist Bioscience Corporation | GPCR binding proteins and synthesis thereof |
| KR102637566B1 (ko) | 2017-10-20 | 2024-02-16 | 트위스트 바이오사이언스 코포레이션 | 폴리뉴클레오타이드 합성을 위한 가열된 나노웰 |
| CN109956987B (zh) * | 2017-12-14 | 2022-05-17 | 南京金斯瑞生物科技有限公司 | 氨解方法及氨解组合物 |
| CN112041438B (zh) | 2018-01-04 | 2025-05-23 | 特韦斯特生物科学公司 | 基于dna的数字信息存储 |
| CA3100739A1 (en) | 2018-05-18 | 2019-11-21 | Twist Bioscience Corporation | Polynucleotides, reagents, and methods for nucleic acid hybridization |
| CA3124980A1 (en) | 2018-12-26 | 2020-07-02 | Twist Bioscience Corporation | Highly accurate de novo polynucleotide synthesis |
| CN113785057A (zh) | 2019-02-26 | 2021-12-10 | 特韦斯特生物科学公司 | 用于抗体优化的变异核酸文库 |
| KR20210143766A (ko) | 2019-02-26 | 2021-11-29 | 트위스트 바이오사이언스 코포레이션 | Glp1 수용체에 대한 변이체 핵산 라이브러리 |
| JP2022550497A (ja) | 2019-06-21 | 2022-12-02 | ツイスト バイオサイエンス コーポレーション | バーコードに基づいた核酸配列アセンブリ |
| AU2020355027A1 (en) | 2019-09-23 | 2022-04-21 | Twist Bioscience Corporation | Antibodies that bind CD3 Epsilon |
| CA3155629A1 (en) | 2019-09-23 | 2021-04-01 | Twist Bioscience Corporation | Variant nucleic acid libraries for crth2 |
| EP4263564A1 (en) * | 2020-12-18 | 2023-10-25 | Eli Lilly and Company | Oscillating fluidized bed oligonucleotide synthesizer |
| CN114573652B (zh) * | 2022-03-15 | 2025-02-07 | 安徽瑞拜药业有限公司 | 药用核酸合成工艺 |
| CN116854754B (zh) | 2023-09-01 | 2023-12-12 | 北京悦康科创医药科技股份有限公司 | 一种含有核糖环或其衍生结构的GalNAc化合物及其寡核苷酸缀合物 |
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-
2001
- 2001-12-03 EP EP01999571A patent/EP1343802B1/en not_active Expired - Lifetime
- 2001-12-03 CA CA2437040A patent/CA2437040C/en not_active Expired - Lifetime
- 2001-12-03 EP EP10009705A patent/EP2332954A3/en not_active Withdrawn
- 2001-12-03 CA CA2714353A patent/CA2714353A1/en not_active Abandoned
- 2001-12-03 KR KR10-2003-7007445A patent/KR20040016826A/ko not_active Abandoned
- 2001-12-03 CN CNB018201016A patent/CN1302005C/zh not_active Expired - Fee Related
- 2001-12-03 WO PCT/GB2001/005338 patent/WO2002046205A2/en not_active Ceased
- 2001-12-03 AU AU2002220870A patent/AU2002220870A1/en not_active Abandoned
- 2001-12-03 JP JP2002547942A patent/JP2004517089A/ja active Pending
-
2003
- 2003-06-05 US US10/454,841 patent/US7227017B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US20030229221A1 (en) | 2003-12-11 |
| EP1343802A2 (en) | 2003-09-17 |
| CN1479745A (zh) | 2004-03-03 |
| CN1302005C (zh) | 2007-02-28 |
| EP1343802B1 (en) | 2012-05-30 |
| JP2004517089A (ja) | 2004-06-10 |
| CA2437040A1 (en) | 2002-06-13 |
| KR20040016826A (ko) | 2004-02-25 |
| US7227017B2 (en) | 2007-06-05 |
| CA2714353A1 (en) | 2002-06-13 |
| WO2002046205A3 (en) | 2002-08-15 |
| WO2002046205A2 (en) | 2002-06-13 |
| EP2332954A3 (en) | 2011-12-21 |
| AU2002220870A1 (en) | 2002-06-18 |
| EP2332954A2 (en) | 2011-06-15 |
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