CN119143828A - 寡核苷酸的汇聚液相合成 - Google Patents
寡核苷酸的汇聚液相合成 Download PDFInfo
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- CN119143828A CN119143828A CN202411234221.5A CN202411234221A CN119143828A CN 119143828 A CN119143828 A CN 119143828A CN 202411234221 A CN202411234221 A CN 202411234221A CN 119143828 A CN119143828 A CN 119143828A
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- 239000007791 liquid phase Substances 0.000 title claims abstract description 51
- 108091034117 Oligonucleotide Proteins 0.000 title abstract description 302
- 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 abstract description 51
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- 125000006242 amine protecting group Chemical group 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
- 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 claims description 13
- 230000002209 hydrophobic effect Effects 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 238000010533 azeotropic distillation Methods 0.000 claims description 8
- 239000002516 radical scavenger Substances 0.000 claims description 8
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 239000004793 Polystyrene Chemical group 0.000 claims description 4
- PDXRQENMIVHKPI-UHFFFAOYSA-N cyclohexane-1,1-diol Chemical compound OC1(O)CCCCC1 PDXRQENMIVHKPI-UHFFFAOYSA-N 0.000 claims description 4
- 229920002223 polystyrene Chemical group 0.000 claims description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000005373 siloxane group Chemical group [SiH2](O*)* 0.000 claims 1
- 239000012634 fragment Substances 0.000 abstract description 180
- 238000006243 chemical reaction Methods 0.000 abstract description 109
- 238000005859 coupling reaction Methods 0.000 abstract description 75
- 230000008878 coupling Effects 0.000 abstract description 35
- 238000010168 coupling process Methods 0.000 abstract description 35
- 239000002773 nucleotide Substances 0.000 abstract description 32
- 125000003729 nucleotide group Chemical group 0.000 abstract description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 567
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 421
- 239000000203 mixture Substances 0.000 description 303
- 239000000243 solution Substances 0.000 description 219
- 239000000047 product Substances 0.000 description 179
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
- 238000004128 high performance liquid chromatography Methods 0.000 description 139
- 239000007787 solid Substances 0.000 description 135
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 108
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 103
- 239000012043 crude product Substances 0.000 description 99
- 239000011541 reaction mixture Substances 0.000 description 99
- -1 2-dimethylpentyl Chemical group 0.000 description 96
- 238000002360 preparation method Methods 0.000 description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 75
- 235000019439 ethyl acetate Nutrition 0.000 description 70
- 239000002904 solvent Substances 0.000 description 70
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 69
- 239000011734 sodium Substances 0.000 description 67
- 239000007858 starting material Substances 0.000 description 60
- 239000012267 brine Substances 0.000 description 58
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 58
- 239000012044 organic layer Substances 0.000 description 56
- 238000001556 precipitation Methods 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 46
- 238000006642 detritylation reaction Methods 0.000 description 41
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 37
- 239000010410 layer Substances 0.000 description 36
- 125000006239 protecting group Chemical group 0.000 description 35
- 239000002777 nucleoside Substances 0.000 description 34
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 33
- 239000002585 base Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 30
- 239000012071 phase Substances 0.000 description 30
- 150000003949 imides Chemical class 0.000 description 29
- 229920000642 polymer Polymers 0.000 description 29
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- 239000003795 chemical substances by application Substances 0.000 description 26
- 238000004587 chromatography analysis Methods 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 24
- 238000005915 ammonolysis reaction Methods 0.000 description 23
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
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- 239000013256 coordination polymer Substances 0.000 description 21
- 238000000605 extraction Methods 0.000 description 21
- 125000005843 halogen group Chemical group 0.000 description 21
- 125000000623 heterocyclic group Chemical group 0.000 description 21
- 239000007800 oxidant agent Substances 0.000 description 21
- ZAMCTDDIJFNXOH-UHFFFAOYSA-N tributylazanium;acetate Chemical compound CC(O)=O.CCCCN(CCCC)CCCC ZAMCTDDIJFNXOH-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 239000011877 solvent mixture Substances 0.000 description 20
- GVZJRBAUSGYWJI-UHFFFAOYSA-N 2,5-bis(3-dodecylthiophen-2-yl)thiophene Chemical compound C1=CSC(C=2SC(=CC=2)C2=C(C=CS2)CCCCCCCCCCCC)=C1CCCCCCCCCCCC GVZJRBAUSGYWJI-UHFFFAOYSA-N 0.000 description 19
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- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 18
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- 229910052799 carbon Inorganic materials 0.000 description 17
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 15
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- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 14
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
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- 125000002346 iodo group Chemical group I* 0.000 description 1
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- LAQFLZHBVPULPL-UHFFFAOYSA-N methyl(phenyl)silicon Chemical compound C[Si]C1=CC=CC=C1 LAQFLZHBVPULPL-UHFFFAOYSA-N 0.000 description 1
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- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
-
- 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
- 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
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
-
- 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
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- 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)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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| US201962845160P | 2019-05-08 | 2019-05-08 | |
| US62/845,160 | 2019-05-08 | ||
| PCT/US2020/032070 WO2020227618A2 (en) | 2019-05-08 | 2020-05-08 | Convergent liquid phase syntheses of oligonucleotides |
| CN202080044020.2A CN114206897B (zh) | 2019-05-08 | 2020-05-08 | 寡核苷酸的汇聚液相合成 |
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| CN202080044020.2A Division CN114206897B (zh) | 2019-05-08 | 2020-05-08 | 寡核苷酸的汇聚液相合成 |
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| CN202080044020.2A Active CN114206897B (zh) | 2019-05-08 | 2020-05-08 | 寡核苷酸的汇聚液相合成 |
| CN202411234328.XA Pending CN119462804A (zh) | 2019-05-08 | 2020-05-08 | 寡核苷酸的汇聚液相合成 |
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| CN202080044020.2A Active CN114206897B (zh) | 2019-05-08 | 2020-05-08 | 寡核苷酸的汇聚液相合成 |
| CN202411234328.XA Pending CN119462804A (zh) | 2019-05-08 | 2020-05-08 | 寡核苷酸的汇聚液相合成 |
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| EP (1) | EP3966219A2 (https=) |
| JP (2) | JP7824080B2 (https=) |
| KR (1) | KR20220007104A (https=) |
| CN (3) | CN119143828A (https=) |
| AU (1) | AU2020268415B2 (https=) |
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| EP2831232A4 (en) | 2012-03-30 | 2015-11-04 | Univ Washington | METHOD FOR MODULATING TAU EXPRESSION TO REDUCE PROBLEMS AND MODIFY A NEURODEGENERATIVE SYNDROME |
| TW202246503A (zh) | 2013-07-19 | 2022-12-01 | 美商百健Ｍａ公司 | 用於調節τ蛋白表現之組合物 |
| KR20230106665A (ko) | 2020-11-11 | 2023-07-13 | 바이오젠 엠에이 인코포레이티드 | 올리고뉴클레오티드, 시약, 및 그의 제조 방법 |
| TW202310854A (zh) * | 2021-07-23 | 2023-03-16 | 美商百健Ｍａ公司 | 用於減少ｔａｕ表現之方法 |
| WO2024083746A1 (en) | 2022-10-17 | 2024-04-25 | Bachem Holding Ag | Method and composition for oligonucleotide synthesis |
| WO2024089953A1 (ja) * | 2022-10-27 | 2024-05-02 | 住友化学株式会社 | オリゴヌクレオチドの製造方法 |
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| GB202305283D0 (en) * | 2023-04-11 | 2023-05-24 | Exactmer Ltd | Liquid-phase process for preparing oligonucleotides |
| JP7433684B1 (ja) * | 2023-05-24 | 2024-02-20 | 塩野フィネス株式会社 | 疑似固相保護基、それを用いたヌクレオシド保護体又はオリゴヌクレオチド保護体、オリゴアミダイト前駆体の製造方法 |
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| CA2096658A1 (en) | 1990-11-20 | 1992-05-21 | Sankyo Company, Limited | Anti-sense nucleic acid derivative |
| US5510476A (en) | 1994-07-07 | 1996-04-23 | Isis Pharmaceuticals, Inc. | Carbocation scavenging during oligonucleotide synthesis |
| AU738032B2 (en) | 1995-10-19 | 2001-09-06 | Proligo Llc | Method for solution phase synthesis of oligonucleotides |
| EP1386925A1 (en) * | 2002-07-31 | 2004-02-04 | Girindus AG | Method for preparing oligonucleotides |
| EP3470072A1 (en) | 2005-06-23 | 2019-04-17 | Biogen MA Inc. | Compositions and methods for modulation of smn2 splicing |
| CN102282155B (zh) | 2008-12-02 | 2017-06-09 | 日本波涛生命科学公司 | 磷原子修饰的核酸的合成方法 |
| JP5548852B2 (ja) | 2009-05-29 | 2014-07-16 | 国立大学法人東京農工大学 | 疎水性基結合ヌクレオシド、疎水性基結合ヌクレオシド溶液、及び疎水性基結合オリゴヌクレオチド合成方法 |
| ES2699827T3 (es) | 2009-06-17 | 2019-02-13 | Biogen Ma Inc | Composiciones y métodos para la modulación de corte y empalme de SMN2 en un sujeto |
| US20120184724A1 (en) * | 2009-09-22 | 2012-07-19 | Agilent Technologies, Inc. | Protected monomers and methods of deprotection for rna synthesis |
| JP5705512B2 (ja) | 2010-11-26 | 2015-04-22 | 農工大ティー・エル・オー株式会社 | 高分散性液相支持体を用いたオリゴヌクレオチド合成法 |
| DK2711370T3 (en) * | 2011-05-17 | 2018-02-26 | Ajinomoto Kk | PROCEDURE FOR THE PREPARATION OF OLIGONUCLEOTIDES |
| US8846885B2 (en) | 2012-02-17 | 2014-09-30 | Ajinomoto Co., Inc. | Oligonucleotide with protected base |
| EP2816053B1 (en) | 2012-02-17 | 2021-03-24 | Ajinomoto Co., Inc. | Base-protected oligonucleotide |
| US9284344B2 (en) * | 2012-05-30 | 2016-03-15 | Hokkaido System Science Co., Ltd. | Oligonucleotide synthesis method using highly dispersible liquid-phase support |
| US10214555B2 (en) * | 2012-11-14 | 2019-02-26 | Takeda Pharmaceutical Company Limitjed | Method for liquid-phase synthesis of nucleic acid |
| HUE050704T2 (hu) | 2014-04-01 | 2020-12-28 | Biogen Ma Inc | Összetételek a SOD-1 expressziójának modulálására |
| CN113717239B (zh) | 2015-01-21 | 2024-12-24 | 味之素株式会社 | 沉淀促进剂以及使用其的沉淀方法 |
| CN116063365A (zh) | 2015-12-16 | 2023-05-05 | 味之素株式会社 | 寡核苷酸的制备方法以及核苷、核苷酸或寡核苷酸 |
| WO2017111137A1 (ja) * | 2015-12-22 | 2017-06-29 | 味の素株式会社 | オリゴヌクレオチドの製造方法 |
| AU2016381992B2 (en) | 2015-12-28 | 2024-01-04 | Chugai Seiyaku Kabushiki Kaisha | Method for promoting efficiency of purification of Fc region-containing polypeptide |
| TW201906855A (zh) | 2017-05-02 | 2019-02-16 | 日商日產化學工業股份有限公司 | 寡核苷酸之製造方法 |
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2020
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- 2020-05-08 EP EP20729413.3A patent/EP3966219A2/en active Pending
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- 2020-05-08 WO PCT/US2020/032070 patent/WO2020227618A2/en not_active Ceased
- 2020-05-08 EA EA202193010A patent/EA202193010A1/ru unknown
- 2020-05-08 JP JP2021565931A patent/JP7824080B2/ja active Active
- 2020-05-08 AU AU2020268415A patent/AU2020268415B2/en active Active
- 2020-05-08 CN CN202080044020.2A patent/CN114206897B/zh active Active
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- 2020-05-08 MX MX2021013587A patent/MX2021013587A/es unknown
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| US12378276B2 (en) | 2025-08-05 |
| WO2020227618A2 (en) | 2020-11-12 |
| AU2020268415A8 (en) | 2022-01-20 |
| IL287798A (en) | 2022-01-01 |
| JP2025138846A (ja) | 2025-09-25 |
| AU2020268415A1 (en) | 2021-12-23 |
| MA55891A (fr) | 2022-03-16 |
| EA202193010A1 (ru) | 2022-03-18 |
| CN114206897B (zh) | 2024-09-20 |
| CN114206897A (zh) | 2022-03-18 |
| IL287798B2 (en) | 2025-09-01 |
| IL319933A (en) | 2025-05-01 |
| BR112021022219A2 (pt) | 2022-03-22 |
| CN119462804A (zh) | 2025-02-18 |
| WO2020227618A8 (en) | 2020-12-24 |
| JP7824080B2 (ja) | 2026-03-04 |
| IL287798B1 (en) | 2025-05-01 |
| CA3139545A1 (en) | 2020-11-12 |
| KR20220007104A (ko) | 2022-01-18 |
| WO2020227618A3 (en) | 2021-01-14 |
| AU2020268415B2 (en) | 2026-04-23 |
| EP3966219A2 (en) | 2022-03-16 |
| US20220348602A1 (en) | 2022-11-03 |
| MX2021013587A (es) | 2022-02-11 |
| JP2022531876A (ja) | 2022-07-12 |
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