KR100898083B1 - 올리고뉴클레오티드 합성의 활성화제 - Google Patents
올리고뉴클레오티드 합성의 활성화제 Download PDFInfo
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- KR100898083B1 KR100898083B1 KR1020037016969A KR20037016969A KR100898083B1 KR 100898083 B1 KR100898083 B1 KR 100898083B1 KR 1020037016969 A KR1020037016969 A KR 1020037016969A KR 20037016969 A KR20037016969 A KR 20037016969A KR 100898083 B1 KR100898083 B1 KR 100898083B1
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- oligonucleotide
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- 239000012190 activator Substances 0.000 title claims abstract description 19
- 238000002515 oligonucleotide synthesis Methods 0.000 title description 7
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 136
- 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 claims abstract description 73
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims abstract description 48
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- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 238000009739 binding Methods 0.000 claims description 22
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 15
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 5
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 4
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- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
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- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004961 1-arylpyrazolyl group Chemical group 0.000 claims description 2
- 239000007822 coupling agent Substances 0.000 claims description 2
- MQCHTHJRANYSEJ-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]-1-(3-methylphenyl)benzimidazole-5-carboxamide Chemical class CC1=CC=CC(N2C3=CC=C(C=C3N=C2)C(=O)NCC=2C(=CC=CC=2)Cl)=C1 MQCHTHJRANYSEJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000004713 phosphodiesters Chemical class 0.000 claims description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical class C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical class C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
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- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims 1
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- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical group [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims 1
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- 150000002780 morpholines Chemical class 0.000 claims 1
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- 125000001424 substituent group Chemical group 0.000 abstract description 6
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- 150000003536 tetrazoles Chemical class 0.000 description 14
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000009833 condensation Methods 0.000 description 9
- 230000005494 condensation Effects 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
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- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 229940043279 diisopropylamine Drugs 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 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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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
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- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical group NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
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- 229920000573 polyethylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 125000000075 primary alcohol group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229920002477 rna polymer Polymers 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
- XTDHBAVVPOKCKF-UHFFFAOYSA-N s-(benzoyltrisulfanyl) benzenecarbothioate Chemical compound C=1C=CC=CC=1C(=O)SSSSC(=O)C1=CC=CC=C1 XTDHBAVVPOKCKF-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/18—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
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Abstract
Description
고체 지지체 | 합성 규모 | 활성화제 | 아미다이트 몰당량 | 활성화제: 아미다이트 | 황화제의 당량 |
CPG-비즈(beads) | 746μmol | 테트라졸 | 2.0 equ. | 4.3 | 3.2 |
CPG-비즈 | 737μmol | 염-복합체 | 2.0 equ. | 4.0 | 3.3 |
CPG-비즈 | 737μmol | 염-복합체 | 1.5 equ. | 3.3 | 3.3 |
경질 PS | 626μmol | 염-복합체 | 2.0 equ. | 4.0 | 3.8 |
경질 PS | 600μmol | 테트라졸 | 2.0 equ. | 4.3 | 4.0 |
고체 지지체 | 규모 | 활성화제 | 아미다이트 몰당량 | 총 OD 유닛 | CGE에 의한 FLP | HPLC에 의한 FLP | 분자량 |
CPG 비즈 | 746 μmol | 테트라졸 | 2.0 equ | 84504 | 74 % | 77 % | 5688 |
CPG 비즈 | 737 μmol | 염복합체 | 2.0 equ | 82134 | 77 % | 79 % | 5687 |
CPG 비즈 | 737 μmol | 염복합체 | 1.5 equ | 82320 | 77 % | 79 % | 5689 |
경질 PS | 626 μmol | 염복합체 | 2.0 equ | 80712 | 76 % | 76 % | 5686 |
경질 PS | 600 μmol | 테트라졸 | 2.0 equ | 75006 | 73 % | 71 % | 5687 |
FLP = 전장 생성물, CGE = 모세관 겔 전기영동, HPLC =이온교환 HPLC |
Claims (64)
- 결합 시약(coupling agent)인 하기 화학식 1의 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온의 존재 하에서 유리 히드록시기 또는 티올기를 갖는 뉴클레오시드 또는 신생 올리고뉴클레오티드와 뉴클레오시드 포스포라미다이트를 결합(coupling)하는 것을 포함하는 포스포라미다이트 화학반응을 이용하여 올리고뉴클레오티드를 합성하는 방법:[화학식 1]상기 화학식 1에서,p는 0 또는 1 내지 4의 정수이고,X7은 O 또는 S이며;R은 독립적으로 할로, 치환 또는 비치환된 지방족기, -NR11R12, -OR13, -OC(O)R13, -C(O)OR13, 시아노, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로시클릴, -CHO, -COR13, -NHCOR13, 치환 또는 비치환된 아랄킬, 또는 -SR13이거나; 두 개의 인접한 R기는 그들이 부착된 탄소원자와 함께 포화 또는 불포화의 6원환을 형성하고; 여기에서,R11 및 R12는 각각 독립적으로 -H, 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 아랄킬기이거나; 그들이 부착된 질소와 함께 헤테로시클릴기를 형성하며;R13은 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 또는 치환 또는 비치환된 아랄킬기이다.
- 삭제
- 제 1 항에 있어서, 유기 염기가 결합반응동안 결합시약과 함께 존재하는 것을 특징으로 하는 방법.
- 제 3 항에 있어서, 상기 유기 염기는 아민인 것을 특징으로 하는 방법.
- 제 4 항에 있어서, 상기 아민은 3급 아민인 것을 특징으로 하는 방법.
- 제 5 항에 있어서, 상기 3급 아민은 트리알킬아민, 치환 또는 비치환된 N-알킬피롤리딘, 치환 또는 비치환된 N-아릴피롤리딘, 치환 또는 비치환된 N-알킬피롤, 치환 또는 비치환된 N-아릴피롤, 치환 또는 비치환된 N-알킬몰폴린, 치환 또는 비치환된 N-아릴몰폴린, 치환 또는 비치환된 N-알킬피페리딘, 치환 또는 비치환된 N-아릴피페리딘, 치환 또는 비치환된 N,N-디알킬피페라진, 치환 또는 비치환된 N,N-디아릴피페라진, 치환 또는 비치환된 N-알킬-N-아릴피페라진, 치환 또는 비치환된 퀴누클리딘, 및 치환 또는 비치환된 1,8-디아자바이사이클로[5.4.0]운데크-7엔으로 구성된 그룹에서 선택되는 것을 특징으로 하는 방법.
- 제 4 항에 있어서, 상기 아민은 치환 또는 비치환된 아자헤테로시클릴 화합물인 것을 특징으로 하는 방법.
- 제 7 항에 있어서, 상기 아자헤테로시클릴 화합물은 치환 또는 비치환된 피리미딘, 치환 또는 비치환된 1-알킬피라졸, 치환 또는 비치환된 1-아릴피라졸, 치환 또는 비치환된 피라진, 치환 또는 비치환된 N-알킬퓨린, 치환 또는 비치환된 N-아릴퓨린, 치환 또는 비치환된 N-알킬피롤, 치환 또는 비치환된 N-아릴피롤, 치환 또는 비치환된 피리딘, 치환 또는 비치환된 N-알킬이미다졸, 치환 또는 비치환된 N-아릴이미다졸, 치환 또는 비치환된 퀴놀린, 치환 또는 비치환된 이소퀴놀린, 치환 또는 비치환된 퀴녹살린, 치환 또는 비치환된 퀴나졸린, 치환 또는 비치환된 N-알킬인돌, 치환 또는 비치환된 N-아릴인돌, 치환 또는 비치환된 N-알킬벤즈이미다졸, 치환 또는 비치환된 N-아릴벤즈이미다졸, 치환 또는 비치환된 트리아진, 치환 또는 비치환된 트리아졸, 치환 또는 비치환된 1-알킬-7-아자인돌, 치환 또는 비치환된 1-아릴-7-아자인돌, 치환 또는 비치환된 피롤리딘, 치환 또는 비치환된 몰폴린, 치환 또는 비치환된 피페리딘, 및 치환 또는 비치환된 피페라진으로 구성된 그룹에서 선택되는 것을 특징으로 하는 방법.
- 제 8 항에 있어서, 상기 아자헤테로시클릴 화합물은 피리딘, 3-메틸피리딘, 또는 N-메틸이미다졸인 것을 특징으로 하는 방법.
- 제 1 항, 및 제 3 항 내지 제 9 항 중 어느 한 항에 있어서, 상기 뉴클레오시드 포스포라미다이트는 모노머인 것을 특징으로 하는 방법.
- 제 1 항, 및 제 3 항 내지 제 9 항 중 어느 한 항에 있어서, 상기 뉴클레오시드 포스포라미다이트는 다이머인 것을 특징으로 하는 방법.
- 제 10 항에 있어서, 상기 포스포라미다이트는 하기 화학식 2a 또는 화학식 2b의 3'-포스포라미다이트인 것을 특징으로 하는 방법:[화학식 2a][화학식 2b]상기 화학식에서,각각의 X1은 독립적으로 -O- 또는 -S-이고;각각의 X2는 독립적으로 -O-, -S-, 또는 -NR14-이고;각각의 X3는 독립적으로 -O-, -S-, -CH2-, 또는 -(CH2)2- 이고;R1은 알콜 보호기 또는 티오 보호기이고;R2는 -H, 치환 또는 비치환된 지방족기, -F, -OR6, -NR7R8, 또는 -SR9이고;R3는 -OCH2CH2CN, -SCH2CH2CN, 치환 또는 비치환된 지방족기, -OR10, -SR10, -O-CH2CH2-Si(CH3)2C6H5, -O-CH2CH2-S(O)2-CH2CH3, -O-CH2CH2-C6H4-NO2, -S-CH2CH2-Si(CH3)2C6H5, -S-CH2CH2-S(O)2-CH2CH3, 또는 -S-CH2CH2-C6H4-NO2이고;R4 및 R5는 각각 독립적으로 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 아랄킬기이거나;R4 및 R5는 그들이 부착되어 있는 질소와 함께 헤테로시클릴기를 형성하고;R6는 -H, 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 아랄킬기, 히드록시 보호기 또는 -(CH2)q-NR18R19이고;R7 및 R8은 각각 독립적으로 H, 치환 또는 비치환된 지방족기, 또는 아민 보호기이거나;R7 및 R8은 그들이 부착되어 있는 질소와 함께 헤테로시클릴기를 형성하고;R9은 H, 치환 또는 비치환된 지방족기, 또는 티오 보호기이고;R10은 각각의 경우에 독립적으로 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 또는 치환 또는 비치환된 아랄킬기이고;R14는 -H, 알킬기, 아릴기, 또는 아랄킬기이고;R18 및 R19는 각각 독립적으로 -H, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 헤테로아릴기, 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아랄킬기, 치환 또는 비치환된 헤테로아랄킬기, 또는 아민 보호기이거나;R18 및 R19는 그들이 부착된 질소와 함께 헤테로시클릴기를 형성하고;q는 1 내지 6의 정수이며;각각의 B는 독립적으로 -H, 천연 또는 비천연의 핵염기, 보호된 천연 또는 비천연의 핵염기, 헤테로고리, 또는 보호된 헤테로고리이다.
- 제 1 항, 및 제 3 항 내지 제 9 항 중 어느 한 항에 있어서, 상기 X7은 O이고 p는 0인 것을 특징으로 하는 방법.
- 제 1 항, 및 제 3 항 내지 제 9 항 중 어느 한 항에 있어서, 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온:뉴클레오시드 포스포라미다이트의 몰비는 0.2:1 내지 5:1의 범위인 것을 특징으로 하는 방법.
- 하기 화학식 4의 올리고뉴클레오티드 또는 뉴클레오시드를 하기 화학식 2a의 뉴클레오시드 포스포라미다이트 및 하기 화학식 1의 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온과 접촉시키는 단계를 포함하는, 하기 화학식 4의 N-mer 올리고뉴클레오티드 또는 뉴클레오시드를 하기 화학식 2a의 뉴클레오시드 포스포라미다이트와 축합시켜 5'-말단이 3가의 인 결합을 갖는 하기 화학식 5의 (n+1) 올리고뉴클레오티드를 형성하는 방법:[화학식 4]상기 화학식 4에서,각각의 X1은 독립적으로 -O- 또는 -S-이고;각각의 X2는 독립적으로 -O-, -S-, 또는 -NR14-이고;각각의 X3는 독립적으로 -O-, -S-, -CH2-, 또는 -(CH2)2-이고;각각의 X4는 독립적으로 -O-, 또는 -S-이고;X5는 -OH 또는 -SH 이고;각각의 R2는 독립적으로 -H, 치환 또는 비치환된 지방족기, -F, -OR6, -NR7R8, 또는 -SR9이고;각각의 R3는 독립적으로 -OCH2CH2CN, -SCH2CH2CN, 치환 또는 비치환된 지방족기, -OR10, -SR10, -O-CH2CH2-Si(CH3)2C6H5, -O-CH2CH2-S(O)2-CH2CH3, -O-CH2CH2-C6H4-NO2, -S-CH2CH2-Si(CH3)2C6H5, -S-CH2CH2-S(O)2-CH2CH3, 또는 -S-CH2CH2-C6H4-NO2이고;각각의 R6는 독립적으로 -H, 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 아랄킬기, 히드록시 보호기 또는 -(CH2)q-NR18R19이고;R7 및 R8은 각각 독립적으로 H, 치환 또는 비치환된 지방족기, 또는 아민 보호기이거나;R7 및 R8은 그들이 부착되어 있는 질소와 함께 헤테로시클릴기를 형성하고;R9은 H, 치환 또는 비치환된 지방족기, 또는 티오 보호기이고;R10은 각각의 경우에 독립적으로 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 또는 치환 또는 비치환된 아랄킬기이고;각각의 R14는 독립적으로 -H, 알킬기, 아릴기, 또는 아랄킬기이고;R16은 히드록시 보호기, 티오 보호기, 아미노 보호기, -(CH2)q-NR18R19, 고체 기판, 또는 고체 기판에 부착되어 있는 분리 가능한 링커이고;R18 및 R19는 각각 독립적으로 -H, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 헤테로아릴기, 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아랄킬기, 치환 또는 비치환된 헤테로아랄킬기, 또는 아민 보호기이거나;R18 및 R19는 그들이 부착된 질소와 함께 헤테로시클릴기를 형성하고;q는 1 내지 6의 정수이고;각각의 B는 독립적으로 -H, 천연 또는 비천연의 핵염기, 보호된 천연 또는 비천연의 핵염기, 헤테로고리, 또는 보호된 헤테로고리이며;n은 0 또는 양의 정수이다;[화학식 2a]상기 화학식 2a에서,R2, R3, X1, X2, X3, 및 B는 앞서 이미 정의한 바와 같고;R1은 알콜 보호기 또는 티오 보호기이고;R4 및 R5는 각각 독립적으로 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 아랄킬기이거나;R4 및 R5는 그들이 부착되어 있는 질소와 함께 헤테로시클릴기를 형성한다;[화학식 1]상기 화학식 1에서,p는 0 또는 1 내지 4의 정수이고,X7은 O 또는 S이며;R은 독립적으로 할로, 치환 또는 비치환된 지방족기, -NR11R12, -OR13, -OC(O)R13, -C(O)OR13, 시아노, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로시클릴, -CHO, -COR13, -NHCOR13, 치환 또는 비치환된 아랄킬, 또는 -SR13이거나; 두 개의 인접한 R기는 그들이 부착된 탄소원자와 함께 포화 또는 불포화의 6원환을 형성하고; 여기에서,R11 및 R12는 각각 독립적으로 -H, 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 치환 또는 비치환된 아랄킬기이거나; 그들이 부착된 질소와 함께 헤테로시클릴기를 형성하며;R13은 치환 또는 비치환된 지방족기, 치환 또는 비치환된 아릴기, 또는 치환 또는 비치환된 아랄킬기이다:[화학식 5]
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- 제 15 항에 있어서, 올리고뉴클레오티드 또는 뉴클레오시드를 포스포라미다이트 및 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온과 접촉시킬 때, 유기 염기가 존재하는 것을 특징으로 하는 방법.
- 제 17 항에 있어서, 상기 유기 염기 및 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온의 농도는 0.01 M 내지 2 M인 것을 특징으로 하는 방법.
- 제 15 항, 제 17 항, 및 제 18 항 중 어느 한 항에 있어서, 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온:뉴클레오시드 포스포라미다이트의 몰비는 0.2:1 내지 5:1의 범위인 것을 특징으로 하는 방법.
- 제 15 항, 제 17 항, 및 제 18 항 중 어느 한 항에 있어서,a) 5'-말단이 3가의 인 결합을 갖는 (n+1) 올리고뉴클레오티드를 산화제 또는 황화제(sulfurizing agent)와 접촉시켜, 5가의 인 백본(back bone)을 갖는 하기 화학식 6의 올리고뉴클레오티드를 형성하는 단계;[화학식 6]b) 선택적으로, X5 기를 산 클로라이드 또는 무수물과 반응시킴으로써, 포스포라미다이트와 반응하지 않는 X5 기를 캡핑(capping)시키는 단계;c) 5가의 인 백본을 갖는 (n+1) 올리고뉴클레오티드를 시약과 반응시켜 R1을 제거함으로써 탈보호하는 단계;d) 선택적으로, 결합단계, 산화 또는 황화 단계, 캡핑 단계, 및 탈보호 단계를 1 회 이상 반복하는 단계를 더 포함하는 것을 특징으로 하는 방법.
- 제 15 항, 제 17 항, 및 제 18 항 중 어느 한 항에 있어서, R16은 고체 기판에 부착되는 분리 가능한 링커인 것을 특징으로 하는 방법.
- 제 20 항에 있어서,a) 상기 올리고뉴클레오티드는 각각의 결합 단계 후에 산화되어, 제조된 올리고뉴클레오티드는 포스포디에스테르 올리고뉴클레오티드이고;b) 상기 올리고뉴클레오티드는 각각의 결합 단계 후에 황화되어, 제조된 올리고뉴클레오티드는 포스포로티오에이트 올리고뉴클레오티드이거나;c) 상기 올리고뉴클레오티드는 하나 이상의 결합 단계 후에 산화되고 하나 이상의 결합 단계 후에 황화되어, 제조된 올리고뉴클레오티드는 키메릭 올리고뉴클레오티드인 것을 특징으로 하는 방법.
- 제 15 항, 제 17 항, 및 제 18 항 중 어느 한 항에 있어서, 상기 X7은 O이고 p는 0인 것을 특징으로 하는 방법.
- 제 21 항에 있어서, 상기 올리고뉴클레오티드는 이후에 정제되는 것을 특징으로 하는 방법.
- 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온과 N-알킬이미다졸의 혼합물을 포함하는 활성화제의 존재 하에서, 뉴클레오시드 포스포라미다이트를 유리 히드록시기를 포함하는 뉴클레오시드 또는 신생 올리고뉴클레오티드와 결합시키는 것을 포함하는 올리고뉴클레오티드의 합성방법.
- 제 27 항에 있어서, 상기 뉴클레오시드 포스포라미다이트는 뉴클레오시드 3'-포스포라미다이트이고, 상기 뉴클레오시드 또는 신생 올리고뉴클레오티드는 유리 5'-히드록시기를 포함하는 것을 특징으로 하는 방법.
- 제 27 항 또는 제 28 항에 있어서, 상기 N-알킬이미다졸은 N-메틸이미다졸인 것을 특징으로 하는 방법.
- 제 27 항 또는 제 28 항에 있어서, 상기 포스포라미다이트는 화학식 -P(OCH2CH2CN)N(CH(CH3)2)2의 모이어티를 포함하는 것을 특징으로 하는 방법.
- 제 27 항 또는 제 28 항에 있어서, 상기 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온 및 N-알킬이미다졸 각각의 농도는 0.1 내지 0.25M인 것을 특징으로 하는 방법.
- 제 27 항 또는 제 28 항에 있어서, 상기 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온 : N-알킬이미다졸의 몰비는 1:1 내지 1:1.5:1인 것을 특징으로 하는 방법.
- 제 27 항 또는 제 28 항에 있어서, 상기 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온 : 포스포라미다이트의 몰비는 0.5:1 내지 2:1인 것을 특징으로 하는 방법.
- N-C1-6알킬이미다졸 및 하기 화학식 1의 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온을 포함하는 염 복합체:[화학식 1]상기 화학식 1에서,p는 0 또는 1 내지 4의 정수이고,X7은 O 또는 S이며;R은 각각 독립적으로 할로, 선형 또는 분지형 C1-8알킬, -NR11R12, -OR13, -OC(O)R13, -C(O)OR13, 시아노, -CHO, -COR13, -NHCOR13, 또는 -SR13이고;상기 R11 및 R12는 각각 독립적으로 -H, 선형 또는 분지형 C1-8알킬이며;R13은 선형 또는 분지형 C1-8알킬이다.
- 제 34 항에 있어서, p는 0이고, X7은 O이고 N-알킬이미다졸은 N-메틸이미다졸인 것을 특징으로 하는 염 복합체.
- 제 14 항에 있어서, X7은 O 이고 p는 0 인 것을 특징으로 하는 방법.
- 제 22 항에 있어서, 상기 올리고뉴클레오티드는 이후에 정제되는 것을 특징으로 하는 방법.
- 제 31 항에 있어서, 상기 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온 : N-알킬이미다졸의 몰비는 1:1 내지 1:1.5:1 이고, 상기 1,1-디옥소-1,2-디하이드로-1λ6-벤조[d]이소티아졸-3-온:포스포라미다이트의 몰비는 0.5:1 내지 2:1인 것을 특징으로 하는 방법.
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US8569367B2 (en) | 2004-11-16 | 2013-10-29 | Allergan, Inc. | Ophthalmic compositions and methods for treating eyes |
US7339052B2 (en) * | 2005-02-08 | 2008-03-04 | Honeywell International Inc. | Phosphoramidite activator for oligonucleotide synthesis |
WO2006116476A1 (en) | 2005-04-27 | 2006-11-02 | Sigma-Aldrich Co. | Activators for oligonucleotide and phosphoramidite synthesis |
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KR200457843Y1 (ko) * | 2010-05-26 | 2012-01-10 | 김원제 | 향기 발산 기능을 가지는 악취 차단 커버 |
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US9907826B2 (en) | 2011-12-07 | 2018-03-06 | Allergan, Inc. | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system |
CN104278030A (zh) * | 2013-07-05 | 2015-01-14 | 上海交通大学医学院 | 小分子化合物Antagomir-31制备方法及应用 |
MD3331891T2 (ro) | 2015-08-05 | 2022-04-30 | Eisai R&D Man Co Ltd | Procedeu de obţinere a unui oligomer de fosforodiamidat substanțial diastereomeric pur, a unui oligomer de fosforodiamidat obţinut printr-un astfel de procedeu și a unei compoziții farmaceutice care conţine un astfel de oligomer de fosforodiamidat |
US10072261B1 (en) * | 2016-03-25 | 2018-09-11 | Agilent Technologies, Inc. | Double coupling method for oligonucleotide synthesis |
AU2017312116A1 (en) | 2016-08-17 | 2019-03-07 | Solstice Biologics, Ltd. | Polynucleotide constructs |
EP3645546A4 (en) | 2017-06-30 | 2021-12-01 | Solstice Biologics, Ltd. | CHIRAL PHOSPHORAMIDITIS AUXILIARIES AND THEIR METHODS OF USE |
WO2019158007A1 (zh) * | 2018-02-13 | 2019-08-22 | 深圳华大生命科学研究院 | 合成寡核苷酸的方法及系统 |
BR112021025026A2 (pt) * | 2019-06-11 | 2022-01-25 | Hoffmann La Roche | Processo para a produção de um oligonucleotídeo |
JPWO2021141072A1 (ko) | 2020-01-08 | 2021-07-15 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5034534A (en) | 1988-07-15 | 1991-07-23 | E. I. Du Pont De Nemours And Company | Process for producing saccharin, saccharin analogues or their salts |
WO1999062922A1 (en) * | 1998-06-02 | 1999-12-09 | Isis Pharmaceuticals, Inc. | Activators for oligonucleotide synthesis |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US757650A (en) | 1903-09-30 | 1904-04-19 | Wilfrid Chausse | Means for cleaning the third rails of electrical railways. |
US3325475A (en) | 1964-11-16 | 1967-06-13 | Maumee Chemical Company | Organic amine salts of saccharin |
JPS4822628B1 (ko) * | 1967-04-15 | 1973-07-07 | ||
IT8148047A0 (it) | 1981-03-18 | 1981-03-18 | Manetti & Roberts Italo Brit | Composti organici derivati da 2-ami no-5-(o-solfamidofenil)-1,3,4-tiadiazolo loro applicazione terapeutica e procedimento per la loro preparazione |
DE3430805A1 (de) | 1984-03-08 | 1985-09-19 | Bayer Ag, 5090 Leverkusen | Mikrobizide mittel |
DE3639901A1 (de) | 1986-11-22 | 1988-06-01 | Bayer Ag | Saccharin-salze von substituierten aminen |
JPH04330093A (ja) * | 1990-07-20 | 1992-11-18 | Takeda Chem Ind Ltd | オリゴリボヌクレオチドの製造法 |
US5639875A (en) | 1995-02-01 | 1997-06-17 | Hybridon, Inc. | Methods for H-phosphonate syntheis of oligonucleotides using triphosgene |
WO1998016540A1 (en) * | 1996-10-15 | 1998-04-23 | Proligo Llc | Improved coupling activators for oligonucleotide synthesis |
US5896999A (en) | 1996-10-16 | 1999-04-27 | United Parcel Service Of America, Inc. | Sorting system |
US5955600A (en) * | 1996-12-27 | 1999-09-21 | Isis Pharmaceuticals, Inc. | Method for the synthesis of nucleotide or oligonucleotide phosphoramidites |
US6096881A (en) | 1997-05-30 | 2000-08-01 | Hybridon, Inc. | Sulfur transfer reagents for oligonucleotide synthesis |
AR036122A1 (es) | 2001-07-03 | 2004-08-11 | Avecia Biotechnology Inc | Un complejo de sal que comprende un n-alquilimidazol y una 1,1-dioxo-1,2-dihidro-1l6-benzo [d]-isotiazol-3-ona y un metodo para sintetizar oligonucleotidos utilizando la quimica de fosforamidita |
EP1554300B1 (en) * | 2002-10-15 | 2007-05-23 | Avecia Biotechnology, Inc. | Phosphitylation process |
GB0229443D0 (en) * | 2002-12-18 | 2003-01-22 | Avecia Ltd | Process |
-
2002
- 2002-06-28 AR ARP020102444A patent/AR036122A1/es unknown
- 2002-07-01 RU RU2004102903/04A patent/RU2004102903A/ru not_active Application Discontinuation
- 2002-07-01 WO PCT/GB2002/003029 patent/WO2003004512A1/en active IP Right Grant
- 2002-07-01 AT AT02748994T patent/ATE317395T1/de not_active IP Right Cessation
- 2002-07-01 ES ES02748994T patent/ES2258151T3/es not_active Expired - Lifetime
- 2002-07-01 KR KR1020037016969A patent/KR100898083B1/ko active IP Right Grant
- 2002-07-01 CA CA2452205A patent/CA2452205C/en not_active Expired - Lifetime
- 2002-07-01 HU HU0400151A patent/HUP0400151A2/hu unknown
- 2002-07-01 CN CNB02817156XA patent/CN100430411C/zh not_active Expired - Lifetime
- 2002-07-01 EP EP02748994A patent/EP1404696B1/en not_active Expired - Lifetime
- 2002-07-01 US US10/482,441 patent/US7501505B2/en not_active Expired - Lifetime
- 2002-07-01 IL IL15940202A patent/IL159402A0/xx unknown
- 2002-07-01 PL PL02367623A patent/PL367623A1/xx not_active Application Discontinuation
- 2002-07-01 JP JP2003510678A patent/JP4574167B2/ja not_active Expired - Lifetime
- 2002-07-01 DE DE60209128T patent/DE60209128T2/de not_active Expired - Lifetime
- 2002-07-01 DK DK02748994T patent/DK1404696T3/da active
-
2008
- 2008-10-06 US US12/287,116 patent/US8093397B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5034534A (en) | 1988-07-15 | 1991-07-23 | E. I. Du Pont De Nemours And Company | Process for producing saccharin, saccharin analogues or their salts |
WO1999062922A1 (en) * | 1998-06-02 | 1999-12-09 | Isis Pharmaceuticals, Inc. | Activators for oligonucleotide synthesis |
Also Published As
Publication number | Publication date |
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DE60209128T2 (de) | 2006-10-05 |
RU2004102903A (ru) | 2005-07-10 |
EP1404696B1 (en) | 2006-02-08 |
US20060041114A1 (en) | 2006-02-23 |
JP4574167B2 (ja) | 2010-11-04 |
WO2003004512A1 (en) | 2003-01-16 |
CN1549820A (zh) | 2004-11-24 |
DK1404696T3 (da) | 2006-06-06 |
ES2258151T3 (es) | 2006-08-16 |
PL367623A1 (en) | 2005-03-07 |
DE60209128D1 (de) | 2006-04-20 |
JP2004533488A (ja) | 2004-11-04 |
IL159402A0 (en) | 2004-06-01 |
CA2452205C (en) | 2011-11-08 |
HUP0400151A2 (en) | 2007-08-28 |
KR20040015758A (ko) | 2004-02-19 |
CN100430411C (zh) | 2008-11-05 |
US8093397B2 (en) | 2012-01-10 |
CA2452205A1 (en) | 2003-01-16 |
US20090085006A1 (en) | 2009-04-02 |
ATE317395T1 (de) | 2006-02-15 |
EP1404696A1 (en) | 2004-04-07 |
AR036122A1 (es) | 2004-08-11 |
US7501505B2 (en) | 2009-03-10 |
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