JP6490133B2 - 官能化核酸の合成のための方法 - Google Patents
官能化核酸の合成のための方法 Download PDFInfo
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- JP6490133B2 JP6490133B2 JP2017074528A JP2017074528A JP6490133B2 JP 6490133 B2 JP6490133 B2 JP 6490133B2 JP 2017074528 A JP2017074528 A JP 2017074528A JP 2017074528 A JP2017074528 A JP 2017074528A JP 6490133 B2 JP6490133 B2 JP 6490133B2
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- Prior art keywords
- compound
- alkyl
- alkylene
- aryl
- alkenyl
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- 238000000034 method Methods 0.000 title claims description 149
- 102000039446 nucleic acids Human genes 0.000 title claims description 76
- 108020004707 nucleic acids Proteins 0.000 title claims description 76
- 150000007523 nucleic acids Chemical class 0.000 title claims description 76
- 230000015572 biosynthetic process Effects 0.000 title description 28
- 238000003786 synthesis reaction Methods 0.000 title description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 112
- 230000000903 blocking effect Effects 0.000 claims description 95
- 125000000304 alkynyl group Chemical group 0.000 claims description 87
- 125000003342 alkenyl group Chemical group 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 75
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 239000003153 chemical reaction reagent Substances 0.000 claims description 71
- 230000008569 process Effects 0.000 claims description 69
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 150000002431 hydrogen Chemical class 0.000 claims description 56
- 125000005647 linker group Chemical group 0.000 claims description 48
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 42
- GWIKYPMLNBTJHR-UHFFFAOYSA-M thiosulfonate group Chemical group S(=S)(=O)[O-] GWIKYPMLNBTJHR-UHFFFAOYSA-M 0.000 claims description 41
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 40
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 40
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 38
- 239000007787 solid Substances 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 229940104302 cytosine Drugs 0.000 claims description 20
- 229940113082 thymine Drugs 0.000 claims description 20
- 229940035893 uracil Drugs 0.000 claims description 20
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 19
- 229930024421 Adenine Natural products 0.000 claims description 19
- 229960000643 adenine Drugs 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 108091034117 Oligonucleotide Proteins 0.000 claims description 17
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 16
- 150000001768 cations Chemical class 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 15
- NXDOFRNPJIPRIM-UHFFFAOYSA-N OP(OO[SiH3])=O Chemical compound OP(OO[SiH3])=O NXDOFRNPJIPRIM-UHFFFAOYSA-N 0.000 claims description 14
- 238000006884 silylation reaction Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 description 185
- -1 heterocyclo Chemical group 0.000 description 93
- 238000005481 NMR spectroscopy Methods 0.000 description 68
- 125000004432 carbon atom Chemical group C* 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 235000000346 sugar Nutrition 0.000 description 47
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- 229910019142 PO4 Inorganic materials 0.000 description 29
- 125000005842 heteroatom Chemical group 0.000 description 29
- 239000010452 phosphate Substances 0.000 description 29
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- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 26
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- 125000003729 nucleotide group Chemical group 0.000 description 22
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 21
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- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 15
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- 0 CC1=*(C)CC*1 Chemical compound CC1=*(C)CC*1 0.000 description 13
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- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 12
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 12
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 11
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- 239000000543 intermediate Substances 0.000 description 11
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000009833 condensation Methods 0.000 description 10
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- 125000000524 functional group Chemical group 0.000 description 10
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 10
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
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- 125000003710 aryl alkyl group Chemical group 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 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 description 8
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- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 6
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- QULMGWCCKILBTO-UHFFFAOYSA-N n-[dimethylamino(dimethyl)silyl]-n-methylmethanamine Chemical compound CN(C)[Si](C)(C)N(C)C QULMGWCCKILBTO-UHFFFAOYSA-N 0.000 description 6
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- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 6
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- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 6
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- WZRYXYRWFAPPBJ-PNHWDRBUSA-N methyl uridin-5-yloxyacetate Chemical compound O=C1NC(=O)C(OCC(=O)OC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 WZRYXYRWFAPPBJ-PNHWDRBUSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940124276 oligodeoxyribonucleotide Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- RUUFMHUAHUPZSS-UHFFFAOYSA-N oxido-oxo-sulfinophosphanium Chemical class P(=O)(=O)S(=O)O RUUFMHUAHUPZSS-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005597 polymer membrane Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 125000006853 reporter group Chemical group 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- RHFUOMFWUGWKKO-UHFFFAOYSA-N s2C Natural products S=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 RHFUOMFWUGWKKO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- XCOBLONWWXQEBS-UHFFFAOYSA-N trimethylsilyl 2,2,2-trifluoro-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(C(F)(F)F)=N[Si](C)(C)C XCOBLONWWXQEBS-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- YIZYCHKPHCPKHZ-UHFFFAOYSA-N uridine-5-acetic acid methyl ester Natural products COC(=O)Cc1cn(C2OC(CO)C(O)C2O)c(=O)[nH]c1=O YIZYCHKPHCPKHZ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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Description
i)構造IaのH−ホスホネートをシリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)シリルオキシホスホネートを構造IIaのチオスルホネート試薬と反応させて、構造IIIaのホスホロチオトリエステルをもたらすステップと、を含み、
構造IaのH−ホスホネートは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IIaのチオスルホネート試薬は、次の構造:
式中、
Xは、アルキル、シクロアルキル、またはヘテロアリールであり、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
構造IIIaのホスホロチオトリエステルは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200である、プロセスを提供する。
1,1,3,3−テトラメチル−1,3−ジフェニルジシラザン、
1,3−ジメチル−1,1,3,3−テトラフェニルジシラザン、
1−(トリメチルシリル)イミダゾール、
N−トリメチルシリル−N−メチルトリフルオロアセトアミド、
ビス(ジメチルアミノ)ジメチルシラン、
ブロモトリメチルシラン、
クロロジメチル(ペンタフルオロフェニル)シラン、
クロロトリエチルシラン、
クロロトリイソプロピルシラン、
クロロトリメチルシラン、
ジクロロジメチルシラン、
ヘキサメチルジシラザン、
N,N′−ビス(トリメチルシリル)尿素、
N,N−ビス(トリメチルシリル)メチルアミン、
N,N−ジメチルトリメチルシリルアミン、
N,O−ビス(トリメチルシリル)アセトアミド、
N,O−ビス(トリメチルシリル)カルバメート、
N,O−ビス(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−トリメチルシリルアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
N−tert−ブチルジメチルシリル−N−メチルトリフルオロアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
トリメチルシリルトリフラート、
トリエチルシリルトリフラート、
トリイソプロピルシリルトリフラート、または
tert−ブチルジメチルシリルトリフラートから選択される、プロセスを提供する。
i)構造Ibの非立体無作為性リン酸連結を含むH−ホスホネートを、シリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)シリルオキシホスホネートを、構造IIbのチオスルホネート試薬と反応させて、構造IIIbの非立体無作為性リン酸連結を含むホスホロチオトリエステルをもたらすステップと、を含み、
構造Ibの非立体無作為性リン酸連結を含むH−ホスホネートは、次の構造:
式中、
Wは、独立して、O、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IIbのチオスルホネート試薬は、次の構造:
式中、
Xは、アルキル、シクロアルキル、アリール、またはヘテロアリールであり、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
構造IIIbの非立体無作為性リン酸連結を含むキラルホスホロチオトリエステルは、次の構造:
式中、
Wは、独立して、O、NH、またはCH2から選択され、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200である、プロセスを提供する。
1,1,3,3−テトラメチル−1,3−ジフェニルジシラザン、
1,3−ジメチル−1,1,3,3−テトラフェニルジシラザン、
1−(トリメチルシリル)イミダゾール、
N−トリメチルシリル−N−メチルトリフルオロアセトアミド、
ビス(ジメチルアミノ)ジメチルシラン、
ブロモトリメチルシラン、
クロロジメチル(ペンタフルオロフェニル)シラン、
クロロトリエチルシラン、
クロロトリイソプロピルシラン、
クロロトリメチルシラン、
ジクロロジメチルシラン、
ヘキサメチルジシラザン、
N,N′−ビス(トリメチルシリル)尿素、
N,N−ビス(トリメチルシリル)メチルアミン、
N,N−ジメチルトリメチルシリルアミン、
N,O−ビス(トリメチルシリル)アセトアミド、
N,O−ビス(トリメチルシリル)カルバメート、
N,O−ビス(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−トリメチルシリルアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
N−tert−ブチルジメチルシリル−N−メチルトリフルオロアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
トリメチルシリルトリフラート、
トリエチルシリルトリフラート、
トリイソプロピルシリルトリフラート、または
tert−ブチルジメチルシリルトリフラートから選択される、プロセスを提供する。
i)構造IcのH−ホスホネートを、シリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)シリルオキシホスホネートを、構造IVcのビス(チオスルホネート)試薬と反応させて、構造Vcのチオスルホネート基を含むホスホロチオトリエステルをもたらすステップと、
iii)構造Vcのチオスルホネート基を含むホスホロチオトリエステルを、構造VIcの求核試薬と反応させて、構造IIIcのホスホロチオトリエステルをもたらすステップと、を含み、
構造IcのH−ホスホネートは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IVcのビス(チオスルホネート)試薬は、次の構造:
式中、
Xは、アルキレン、アルケニレン、アリーレン、またはヘテロアリーレンであり、
各R6は、独立して、アルキル、シクロアルキル、アリール、またはヘテロアリールであり、
構造VIcの求核試薬は、次の構造:
R7−SHを有し、式中、R7は、アルキル、アルケニル、アリール、ヘテロシクロ、アミノアルキル、または(ヘテロシクロ)アルキルから選択され、
構造IIIcのホスホロチオトリエステルは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
Rは、R7−S−S−X−であり、
R7は、アルキル、アルケニル、アリール、ヘテロシクロ、アミノアルキル、または(ヘテロシクロ)アルキルであり、
Xは、アルキレン、アルケニレン、アリーレン、またはヘテロアリーレンであり、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IcのH−ホスホネートのリン酸連結は、ホスホロチオトリエステルが構造Vcのチオスルホネート基を含み、構造IIIcのホスホロチオトリエステルが、任意で、非立体無作為性リン酸連結を含んでもよい、プロセスを提供する。
1,1,3,3−テトラメチル−1,3−ジフェニルジシラザン、
1,3−ジメチル−1,1,3,3−テトラフェニルジシラザン、
1−(トリメチルシリル)イミダゾール、
N−トリメチルシリル−N−メチルトリフルオロアセトアミド、
ビス(ジメチルアミノ)ジメチルシラン、
ブロモトリメチルシラン、
クロロジメチル(ペンタフルオロフェニル)シラン、
クロロトリエチルシラン、
クロロトリイソプロピルシラン、
クロロトリメチルシラン、
ジクロロジメチルシラン、
ヘキサメチルジシラザン、
N,N′−ビス(トリメチルシリル)尿素、
N,N−ビス(トリメチルシリル)メチルアミン、
N,N−ジメチルトリメチルシリルアミン、
N,O−ビス(トリメチルシリル)アセトアミド、
N,O−ビス(トリメチルシリル)カルバメート、
N,O−ビス(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−トリメチルシリルアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
N−tert−ブチルジメチルシリル−N−メチルトリフルオロアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
トリメチルシリルトリフラート、
トリエチルシリルトリフラート、
トリイソプロピルシリルトリフラート、または
tert−ブチルジメチルシリルトリフラートから選択される、プロセスを提供する。
参照による組み込み
特定の化学用語
一実施形態において、「シクロアルキル」は、置換される。別段の指定がない限り、「シクロアルキル」は、非置換である。
一実施形態において、「ヘテロアリール」は、置換される。別段の指定がない限り、「ヘテロアリール」は、非置換である。
特定の核酸に関する用語
新規な官能化核酸および核酸プロドラッグの調製のための合成方法
i)構造IaのH−ホスホネートをシリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)シリルオキシホスホネートを構造IIaのチオスルホネート試薬と反応させて、構造IIIaのホスホロチオトリエステルをもたらすステップと、を含み、
構造IaのH−ホスホネートは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IIaのチオスルホネート試薬は、次の構造:
式中、
Xは、アルキル、シクロアルキル、またはヘテロアリールであり、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
構造IIIaのホスホロチオトリエステルは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200である、プロセスを提供する。
1,1,3,3−テトラメチル−1,3−ジフェニルジシラザン、
1,3−ジメチル−1,1,3,3−テトラフェニルジシラザン、
1−(トリメチルシリル)イミダゾール、
N−トリメチルシリル−N−メチルトリフルオロアセトアミド、
ビス(ジメチルアミノ)ジメチルシラン、
ブロモトリメチルシラン、
クロロジメチル(ペンタフルオロフェニル)シラン、
クロロトリエチルシラン、
クロロトリイソプロピルシラン、
クロロトリメチルシラン、
ジクロロジメチルシラン、
ヘキサメチルジシラザン、
N,N′−ビス(トリメチルシリル)尿素、
N,N−ビス(トリメチルシリル)メチルアミン、
N,N−ジメチルトリメチルシリルアミン、
N,O−ビス(トリメチルシリル)アセトアミド、
N,O−ビス(トリメチルシリル)カルバメート、
N,O−ビス(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−トリメチルシリルアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
N−tert−ブチルジメチルシリル−N−メチルトリフルオロアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
トリメチルシリルトリフラート、
トリエチルシリルトリフラート、
トリイソプロピルシリルトリフラート、または
tert−ブチルジメチルシリルトリフラートから選択される、プロセスを提供する。
i)構造Ibの非立体無作為性リン酸連結を含むH−ホスホネートを、シリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)シリルオキシホスホネートを、構造IIbのチオスルホネート試薬と反応させて、構造IIIbの非立体無作為性リン酸連結を含むホスホロチオトリエステルをもたらすステップと、を含み、
構造Ibの非立体無作為性リン酸連結を含むH−ホスホネートは、次の構造:
式中、
Wは、独立して、O、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IIbのチオスルホネート試薬は、次の構造:
式中、
Xは、アルキル、シクロアルキル、アリール、またはヘテロアリールであり、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
構造IIIbの非立体無作為性リン酸連結を含むキラルホスホロチオトリエステルは、次の構造:
式中、
Wは、独立して、O、NH、またはCH2から選択され、
Rは、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、またはR1−R2であり、
R1は、−S−アルケニレン−、−S−アルキレン−、−S−アルキレン−アリール−アルキレン−、−S−CO−アリール−アルキレン−、または−S−CO−アルキレン−アリール−アルキレン−から選択され、
R2は、ヘテロシクロ−アルキレン−S−、ヘテロシクロ−アルケニレン−S−、アミノアルキル−S−、または(アルキル)4N−アルキレン−S−から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200である、プロセスを提供する。
1,1,3,3−テトラメチル−1,3−ジフェニルジシラザン、
1,3−ジメチル−1,1,3,3−テトラフェニルジシラザン、
1−(トリメチルシリル)イミダゾール、
N−トリメチルシリル−N−メチルトリフルオロアセトアミド、
ビス(ジメチルアミノ)ジメチルシラン、
ブロモトリメチルシラン、
クロロジメチル(ペンタフルオロフェニル)シラン、
クロロトリエチルシラン、
クロロトリイソプロピルシラン、
クロロトリメチルシラン、
ジクロロジメチルシラン、
ヘキサメチルジシラザン、
N,N′−ビス(トリメチルシリル)尿素、
N,N−ビス(トリメチルシリル)メチルアミン、
N,N−ジメチルトリメチルシリルアミン、
N,O−ビス(トリメチルシリル)アセトアミド、
N,O−ビス(トリメチルシリル)カルバメート、
N,O−ビス(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−トリメチルシリルアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
N−tert−ブチルジメチルシリル−N−メチルトリフルオロアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
トリメチルシリルトリフラート、
トリエチルシリルトリフラート、
トリイソプロピルシリルトリフラート、または
tert−ブチルジメチルシリルトリフラートから選択される、プロセスを提供する。
i)構造IcのH−ホスホネートを、シリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)シリルオキシホスホネートを、構造IVcのビス(チオスルホネート)試薬と反応させて、構造Vcのチオスルホネート基を含むホスホロチオトリエステルをもたらすステップと、
iii)構造Vcのチオスルホネート基を含むホスホロチオトリエステルを、構造VIcの求核試薬と反応させて、構造IIIcのホスホロチオトリエステルをもたらすステップと、を含み、
構造IcのH−ホスホネートは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、`
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IVcのビス(チオスルホネート)試薬は、次の構造:
式中、
Xは、アルキレン、アルケニレン、アリーレン、またはヘテロアリーレンであり、
各R6は、独立して、アルキル、シクロアルキル、アリール、またはヘテロアリールであり、
構造VIcの求核試薬は、次の構造:
R7−SHを有し、式中、R7は、アルキル、アルケニル、アリール、ヘテロシクロ、アミノアルキル、または(ヘテロシクロ)アルキルから選択され、
構造IIIcのホスホロチオトリエステルは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
Rは、R7−S−S−X−であり、
R7は、アルキル、アルケニル、アリール、ヘテロシクロ、アミノアルキル、または(ヘテロシクロ)アルキルであり、
Xは、アルキレン、アルケニレン、アリーレン、またはヘテロアリーレンであり、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、カルバメート、−P(O)(Re)2、または−HP(O)(Re)であり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IcのH−ホスホネートのリン酸連結は、ホスホロチオトリエステルが構造Vcのチオスルホネート基を含み、構造IIIcのホスホロチオトリエステルが、任意で、非立体無作為性リン酸連結を含んでもよい、プロセスを提供する。
1,1,3,3−テトラメチル−1,3−ジフェニルジシラザン、
1,3−ジメチル−1,1,3,3−テトラフェニルジシラザン、
1−(トリメチルシリル)イミダゾール、
N−トリメチルシリル−N−メチルトリフルオロアセトアミド、
ビス(ジメチルアミノ)ジメチルシラン、
ブロモトリメチルシラン、
クロロジメチル(ペンタフルオロフェニル)シラン、
クロロトリエチルシラン、
クロロトリイソプロピルシラン、
クロロトリメチルシラン、
ジクロロジメチルシラン、
ヘキサメチルジシラザン、
N,N′−ビス(トリメチルシリル)尿素、
N,N−ビス(トリメチルシリル)メチルアミン、
N,N−ジメチルトリメチルシリルアミン、
N,O−ビス(トリメチルシリル)アセトアミド、
N,O−ビス(トリメチルシリル)カルバメート、
N,O−ビス(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−(トリメチルシリル)トリフルオロアセトアミド、
N−メチル−N−トリメチルシリルアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
N−tert−ブチルジメチルシリル−N−メチルトリフルオロアセトアミド、
N−メチル−N−トリメチルシリルヘプタフルオロブチルアミド、
トリメチルシリルトリフラート、
トリエチルシリルトリフラート、
トリイソプロピルシリルトリフラート、または
tert−ブチルジメチルシリルトリフラートから選択される、プロセスを提供する。
修飾オリゴヌクレオチド
本発明の方法に使用される反応条件および試薬。
条件
固体支持体上での合成
連結部分
合成のための溶媒
ブロッキング基を除去するための酸性化条件
ブロッキング部分または基の除去
オリゴヌクレオシドホスホロチオエート連結の立体化学
核酸塩基および修飾核酸塩基
ヌクレオチド/ヌクレオシドの修飾糖
ブロッキング基
実施例
実施例1−メタンチオスルホネート試薬の合成
1H NMR(399MHz,CDCl3)δ4.86(s,2H),3.45(s,6H);13C NMR(100MHz,CDCl3)δ52.15,41.50。
1H NMR(399MHz,CDCl3)δ3.55(s,4H),3.40(s,6H);13C NMR(100MHz,CDCl3)δ50.67,35.96。
TMS開裂が完了した後、溶媒を真空下で除去し、残渣をDCM中に再溶解し、その溶液を水で洗浄し、乾燥させ(MgSO4)、濾過し、真空で濃縮する。
粗製アルコールをピリジン(5ml)中に再溶解し、TsCl(0.55mmol)を添加する。室温で18時間後、溶媒を除去し、残渣をDCM中に再溶解し、その溶液を水で洗浄し、乾燥させ(MgSO4)、濾過し、真空で濃縮する。カラムクロマトグラフィーによる精製によって、純粋な化合物37を得る。
実施例3−ビス(メタンチオスルホネート)試薬を使用した、ホスホロチオトリエステルの代替的合成
実施例4−H−固相でホスホロチオトリエステルをもたらすためのホスホネートのチオアルキル化
実施例5−溶液相でホスホロチオトリエステルをもたらすためのH−ホスホネートのチオアルキル化
実施例6−H−ホスホネートの立体選択的チオアルキル化
Claims (20)
- 構造IIIaのホスホロチオトリエステルの製造方法であって、
i)構造IaのH−ホスホネートをシリル化試薬と反応させて、シリルオキシホスホネートをもたらすステップと、
ii)前記シリルオキシホスホネートを構造IIaのチオスルホネート試薬と反応させて、構造IIIaのオリゴヌクレオチドをもたらすステップと、を含み、
構造Iaの前記H−ホスホネートは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、又はカルバメートであり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200であり、
構造IIaの前記チオスルホネート試薬は、次の構造:
Xは、アルキル、シクロアルキル、またはヘテロアリールであり、
Rは、R1−R2であり、
R1は、−アルケニレン−S−、−アルキレン−S−、−アルキレン−アリール−アルキレン−S−、−アルキレン−アリール−CO−S−、または−アルキレン−アリール−アルキレン−CO−S−から選択され、
R2は、−S−アルキレン−ヘテロシクロ、−S−アルケニレン−ヘテロシクロ、−S−アミノアルキル、または−S−アルキレン−N(アルキル)4から選択され、
構造IIIaの前記オリゴヌクレオチドは、次の構造:
式中、
Wは、独立して、O、S、NH、またはCH2から選択され、
Rは、R1−R2であり、
R1は、−アルケニレン−S−、−アルキレン−S−、−アルキレン−アリール−アルキレン−S−、−アルキレン−アリール−CO−S−、または−アルキレン−アリール−アルキレン−CO−S−から選択され、
R2は、−S−アルキレン−ヘテロシクロ、−S−アルケニレン−ヘテロシクロ、−S−アミノアルキル、または−S−アルキレン−N(アルキル)4から選択され、
R3は、−OH、−SH、−NRdRd、−N3、ハロゲン、水素、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−P(O)(Re)2、−HP(O)(Re)、−ORa、または−SRcであり、
Y1は、O、NRd、S、またはSeであり、
Raは、ブロッキング基であり、
Rcは、ブロッキング基であり、
各場合のRdは、独立して、水素、アルキル、アルケニル、アルキニル、アリール、アシル、置換シリル、又はカルバメートであり、
各場合のReは、独立して、水素、アルキル、アリール、アルケニル、アルキニル、アルキル−Y2−、アルケニル−Y2−、アルキニル−Y2−、アリール−Y2−、もしくはヘテロアリール−Y2−、またはNa+1、Li+1、もしくはK+1であるカチオンであり、
Y2は、O、NRd、またはSであり、
各場合のR4は、独立して、水素、−OH、−SH、−NRdRd、−N3、ハロゲン、アルキル、アルケニル、アルキニル、アルキル−Y1−、アルケニル−Y1−、アルキニル−Y1−、アリール−Y1−、ヘテロアリール−Y1−、−ORb、または−SRcであり、Rbは、ブロッキング基であり、
各場合のBaは、独立して、ブロックまたは非ブロックのアデニン、シトシン、グアニン、チミン、ウラシル、または修飾核酸塩基であり、
R5は、水素、ブロッキング基、固体支持体に結合した連結部分、または核酸に結合した連結部分であり、
nは、1〜約200である、方法。 - 請求項1に記載の方法であって,R1は、−アルケニレン−S−又は−アルキレン−S−から選択される基である方法。
- 請求項1に記載の方法であって,R2は、−S−アルキレン−ヘテロシクロである方法。
- 請求項1〜5のいずれかに記載の方法であって,Xはアルキルである,方法。
- 請求項6に記載の方法であって,Xはメチルである,方法。
- 請求項11に記載のチオスルホネート試薬であって,R1は、−アルケニレン−S−又は−アルキレン−S−から選択される基であるチオスルホネート試薬。
- 請求項11に記載のチオスルホネート試薬であって,R2は、−S−アルキレン−ヘテロシクロであるチオスルホネート試薬。
- 請求項11〜15のいずれかに記載のチオスルホネート試薬であって,Xはアルキルである,チオスルホネート試薬。
- 請求項16に記載のチオスルホネート試薬であって,Xはメチルである,チオスルホネート試薬。
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IL230522B (en) | 2018-02-28 |
BR112014001244A2 (pt) | 2017-02-21 |
US20180222936A1 (en) | 2018-08-09 |
SG10201700554VA (en) | 2017-03-30 |
EP3248982A1 (en) | 2017-11-29 |
KR20140068884A (ko) | 2014-06-09 |
CN107365339A (zh) | 2017-11-21 |
US20140194610A1 (en) | 2014-07-10 |
JP2014522862A (ja) | 2014-09-08 |
RU2014105311A (ru) | 2015-08-27 |
CN103796657A (zh) | 2014-05-14 |
EP2734208A1 (en) | 2014-05-28 |
US10280192B2 (en) | 2019-05-07 |
CA2842358A1 (en) | 2013-01-24 |
JP2017141272A (ja) | 2017-08-17 |
MX2014000716A (es) | 2014-05-22 |
DK2734208T3 (en) | 2017-06-19 |
AU2012284265A1 (en) | 2014-02-06 |
EP2734208A4 (en) | 2015-03-18 |
EP2734208B1 (en) | 2017-03-01 |
ES2626488T8 (es) | 2017-08-14 |
CA2842358C (en) | 2020-07-14 |
US9605019B2 (en) | 2017-03-28 |
JP6128529B2 (ja) | 2017-05-17 |
AU2012284265B2 (en) | 2017-08-17 |
US20170029457A1 (en) | 2017-02-02 |
ES2626488T3 (es) | 2017-07-25 |
HK1198479A1 (en) | 2015-05-08 |
CN103796657B (zh) | 2017-07-11 |
MX347361B (es) | 2017-04-12 |
WO2013012758A1 (en) | 2013-01-24 |
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