KR102375480B1 - 인 보호기 및 이의 제조 방법 및 용도 - Google Patents
인 보호기 및 이의 제조 방법 및 용도 Download PDFInfo
- Publication number
- KR102375480B1 KR102375480B1 KR1020167033381A KR20167033381A KR102375480B1 KR 102375480 B1 KR102375480 B1 KR 102375480B1 KR 1020167033381 A KR1020167033381 A KR 1020167033381A KR 20167033381 A KR20167033381 A KR 20167033381A KR 102375480 B1 KR102375480 B1 KR 102375480B1
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- South Korea
- Prior art keywords
- hydrogen
- alkyl
- halogen
- group
- nucleic acid
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 124
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical group [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 125000006239 protecting group Chemical group 0.000 claims abstract description 59
- 108091033319 polynucleotide Proteins 0.000 claims abstract description 40
- 102000040430 polynucleotide Human genes 0.000 claims abstract description 40
- 239000002157 polynucleotide Substances 0.000 claims abstract description 40
- 238000005859 coupling reaction Methods 0.000 claims abstract description 23
- 230000008878 coupling Effects 0.000 claims abstract description 22
- 238000010168 coupling process Methods 0.000 claims abstract description 22
- 150000001409 amidines Chemical class 0.000 claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 150000007523 nucleic acids Chemical class 0.000 claims description 105
- 102000039446 nucleic acids Human genes 0.000 claims description 100
- 108020004707 nucleic acids Proteins 0.000 claims description 100
- 239000002773 nucleotide Substances 0.000 claims description 92
- 125000003729 nucleotide group Chemical group 0.000 claims description 91
- 239000001257 hydrogen Substances 0.000 claims description 79
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- -1 naphthalene alcohol derivatives Chemical class 0.000 claims description 67
- 150000002431 hydrogen Chemical class 0.000 claims description 62
- 229910052736 halogen Inorganic materials 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 239000002777 nucleoside Substances 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 15
- 125000003835 nucleoside group Chemical group 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 238000012217 deletion Methods 0.000 claims description 13
- 230000037430 deletion Effects 0.000 claims description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 12
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 12
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 12
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 12
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000178 monomer Substances 0.000 claims description 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 9
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 229930024421 Adenine Natural products 0.000 claims description 6
- 229960000643 adenine Drugs 0.000 claims description 6
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 6
- 229940104302 cytosine Drugs 0.000 claims description 6
- 229940113082 thymine Drugs 0.000 claims description 6
- 229940035893 uracil Drugs 0.000 claims description 6
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 150000002790 naphthalenes Chemical group 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 239000012351 deprotecting agent Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000001369 canonical nucleoside group Chemical group 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 71
- 230000015572 biosynthetic process Effects 0.000 abstract description 65
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 48
- 239000000203 mixture Substances 0.000 abstract description 43
- 230000003647 oxidation Effects 0.000 abstract description 14
- 238000007254 oxidation reaction Methods 0.000 abstract description 14
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 6
- 239000011574 phosphorus Substances 0.000 abstract description 6
- 230000027832 depurination Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 90
- 239000000243 solution Substances 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 108091034117 Oligonucleotide Proteins 0.000 description 54
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 229910052786 argon Inorganic materials 0.000 description 45
- 108020004414 DNA Proteins 0.000 description 39
- 239000000460 chlorine Substances 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 35
- 0 B[C@@](C1)O[C@](C*)C1OP(N1CCCC1)O* Chemical compound B[C@@](C1)O[C@](C*)C1OP(N1CCCC1)O* 0.000 description 34
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- 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 33
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 238000004949 mass spectrometry Methods 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 238000003756 stirring Methods 0.000 description 17
- 239000000126 substance Substances 0.000 description 16
- 229940086542 triethylamine Drugs 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000006260 foam Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 150000008300 phosphoramidites Chemical class 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 239000000523 sample Substances 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000003776 cleavage reaction Methods 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 238000011160 research Methods 0.000 description 10
- 230000007017 scission Effects 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 9
- 229960004132 diethyl ether Drugs 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- UFJRJMFYONEIRK-UHFFFAOYSA-N 4-(1,1-dimethoxyethyl)morpholine Chemical compound COC(C)(OC)N1CCOCC1 UFJRJMFYONEIRK-UHFFFAOYSA-N 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 150000003212 purines Chemical class 0.000 description 7
- 150000003230 pyrimidines Chemical class 0.000 description 7
- HPZMWTNATZPBIH-UHFFFAOYSA-N 1-methyladenine Chemical compound CN1C=NC2=NC=NC2=C1N HPZMWTNATZPBIH-UHFFFAOYSA-N 0.000 description 6
- RFLVMTUMFYRZCB-UHFFFAOYSA-N 1-methylguanine Chemical compound O=C1N(C)C(N)=NC2=C1N=CN2 RFLVMTUMFYRZCB-UHFFFAOYSA-N 0.000 description 6
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-amino-7-methyl-1,7-dihydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 6
- BVIAOQMSVZHOJM-UHFFFAOYSA-N N(6),N(6)-dimethyladenine Chemical compound CN(C)C1=NC=NC2=C1N=CN2 BVIAOQMSVZHOJM-UHFFFAOYSA-N 0.000 description 6
- RQVWTMCUTHKGCM-UHFFFAOYSA-N S-Methyl benzenecarbothioate Chemical compound CSC(=O)C1=CC=CC=C1 RQVWTMCUTHKGCM-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000005289 controlled pore glass Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 238000002515 oligonucleotide synthesis Methods 0.000 description 6
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical class C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 description 5
- QMQXVNHINOVNSD-UHFFFAOYSA-N 2-[chloro(diphenyl)methyl]-5,5-dimethoxycyclohexa-1,3-diene Chemical compound C1=CC(OC)(OC)CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 QMQXVNHINOVNSD-UHFFFAOYSA-N 0.000 description 5
- 230000006820 DNA synthesis Effects 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- MFGWMAAZYZSWMY-UHFFFAOYSA-N (2-naphthyl)methanol Chemical compound C1=CC=CC2=CC(CO)=CC=C21 MFGWMAAZYZSWMY-UHFFFAOYSA-N 0.000 description 4
- XUFDMPZZAIRCGV-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylethanamine Chemical compound CCOC(C)(N(C)C)OCC XUFDMPZZAIRCGV-UHFFFAOYSA-N 0.000 description 4
- KMEMIMRPZGDOMG-UHFFFAOYSA-N 2-cyanoethoxyphosphonamidous acid Chemical compound NP(O)OCCC#N KMEMIMRPZGDOMG-UHFFFAOYSA-N 0.000 description 4
- XAASLEJRGFPHEV-UHFFFAOYSA-N 4-cyanobenzyl alcohol Chemical compound OCC1=CC=C(C#N)C=C1 XAASLEJRGFPHEV-UHFFFAOYSA-N 0.000 description 4
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 4
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 4
- YPEQTVHWPCYLSE-OPQQBVKSSA-N CN1CCCC1=NC1=NC(=O)N([C@@H]2O[C@H](CO)[C@@H](O)C2)C=C1 Chemical compound CN1CCCC1=NC1=NC(=O)N([C@@H]2O[C@H](CO)[C@@H](O)C2)C=C1 YPEQTVHWPCYLSE-OPQQBVKSSA-N 0.000 description 4
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 4
- 229930010555 Inosine Natural products 0.000 description 4
- MQFIKAWTCOXAAY-UHFFFAOYSA-N acetic acid;n-butylbutan-1-amine Chemical compound CC([O-])=O.CCCC[NH2+]CCCC MQFIKAWTCOXAAY-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 229960005305 adenosine Drugs 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000005549 deoxyribonucleoside Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 229960003786 inosine Drugs 0.000 description 4
- ZUINDAYECPXXNP-XINAWCOVSA-N methyl (2s,3r)-2-acetamido-3-hydroxybutanoate Chemical compound COC(=O)[C@H]([C@@H](C)O)NC(C)=O ZUINDAYECPXXNP-XINAWCOVSA-N 0.000 description 4
- 238000012163 sequencing technique Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 4
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical class O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000009598 prenatal testing Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003291 riboses Chemical class 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Chemical class [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005496 tempering Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
-
- 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
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- Molecular Biology (AREA)
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- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Saccharide Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
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| PCT/US2015/028624 WO2015168461A2 (en) | 2014-04-30 | 2015-04-30 | Phosphorous protecting groups and methods of preparation and use thereof |
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| KR20160147973A KR20160147973A (ko) | 2016-12-23 |
| KR102375480B1 true KR102375480B1 (ko) | 2022-03-16 |
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| WO2015168461A2 (en) | 2014-04-30 | 2015-11-05 | Agilent Technologies, Inc. | Phosphorous protecting groups and methods of preparation and use thereof |
| AU2017234150B2 (en) * | 2016-03-13 | 2021-09-16 | Wave Life Sciences Ltd. | Compositions and methods for phosphoramidite and oligonucleotide synthesis |
| JP7296882B2 (ja) | 2016-11-23 | 2023-06-23 | ウェイブ ライフ サイエンシズ リミテッド | ホスホラミダイト及びオリゴヌクレオチド合成のための組成物及び方法 |
| SG11201909019SA (en) | 2017-05-01 | 2019-10-30 | Theravance Biopharma R&D Ip Llc | Methods of treatment using a jak inhibitor compound |
| CN113508103A (zh) | 2019-02-28 | 2021-10-15 | 富士胶片株式会社 | 肽化合物的制造方法、保护基形成用试药及稠合多环芳香族烃化合物 |
| CN113490679A (zh) | 2019-02-28 | 2021-10-08 | 富士胶片株式会社 | 肽化合物的制造方法、保护基形成用试药及芳香族杂环化合物 |
| JP7814933B2 (ja) | 2019-08-29 | 2026-02-17 | 富士フイルム株式会社 | 核酸化合物の製造方法、及び、核酸化合物 |
| EP3805242A1 (en) * | 2019-10-07 | 2021-04-14 | Sterna Biologicals GmbH & Co. KG | Method for the production of a catalytically active dna molecule having improved activity and its use in a method of treating asthma |
| TW202317550A (zh) | 2021-06-25 | 2023-05-01 | 美商施萬生物製藥研發 Ip有限責任公司 | 作為jak抑制劑之咪唑吲唑化合物 |
| CN113461743B (zh) * | 2021-07-09 | 2023-03-17 | 中国石油大学(华东) | 6-甲硫基乙基嘌呤-2’-脱氧核苷及其制备方法和应用 |
| US12565641B2 (en) | 2021-10-15 | 2026-03-03 | Codexis, Inc. | Engineered terminal deoxynucleotidyl transferase variants |
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| JP2000507928A (ja) * | 1996-06-10 | 2000-06-27 | サントル・ナショナル・ドゥ・ラ・ルシェルシュ・シャンティフィック(セ・エヌ・エール・エス) | ホスホトリエステルオリゴヌクレオチド、アミダイト、およびそれらの調製法 |
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|---|---|---|---|---|
| US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
| JPS6251695A (ja) * | 1985-08-29 | 1987-03-06 | Yuki Gosei Yakuhin Kogyo Kk | ホスホロアミダイト類の合成法 |
| NL8700724A (nl) * | 1987-03-27 | 1988-10-17 | Univ Eindhoven Tech | Poly(deoxyribonucleotiden), farmaceutische samenstellingen, gebruik en bereiding van de poly(deoxyribonucleotiden). |
| US5948902A (en) | 1997-11-20 | 1999-09-07 | South Alabama Medical Science Foundation | Antisense oligonucleotides to human serine/threonine protein phosphatase genes |
| US6020475A (en) * | 1998-02-10 | 2000-02-01 | Isis Pharmeuticals, Inc. | Process for the synthesis of oligomeric compounds |
| US6531590B1 (en) * | 1998-04-24 | 2003-03-11 | Isis Pharmaceuticals, Inc. | Processes for the synthesis of oligonucleotide compounds |
| US6274725B1 (en) | 1998-06-02 | 2001-08-14 | Isis Pharmaceuticals, Inc. | Activators for oligonucleotide synthesis |
| US6222030B1 (en) | 1998-08-03 | 2001-04-24 | Agilent Technologies, Inc. | Solid phase synthesis of oligonucleotides using carbonate protecting groups and alpha-effect nucleophile deprotection |
| EP1176151B1 (en) | 2000-07-28 | 2014-08-20 | Agilent Technologies, Inc. | Synthesis of polynucleotides using combined oxidation/deprotection chemistry |
| US20060178507A1 (en) | 2004-12-30 | 2006-08-10 | Berry & Associates, Inc. | Fluorous oligonucleotide reagents and affinity purification of oligonucleotides |
| KR20130022437A (ko) * | 2011-08-22 | 2013-03-07 | 삼성전자주식회사 | 광분해성 화합물을 사용한, 비특이적 증폭의 감소를 위한 신규한 pcr 방법 |
| IN2015DN01765A (enExample) * | 2012-08-20 | 2015-05-29 | Univ California | |
| WO2015168461A2 (en) | 2014-04-30 | 2015-11-05 | Agilent Technologies, Inc. | Phosphorous protecting groups and methods of preparation and use thereof |
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2015
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000507928A (ja) * | 1996-06-10 | 2000-06-27 | サントル・ナショナル・ドゥ・ラ・ルシェルシュ・シャンティフィック(セ・エヌ・エール・エス) | ホスホトリエステルオリゴヌクレオチド、アミダイト、およびそれらの調製法 |
Non-Patent Citations (3)
| Title |
|---|
| F.Seela et al., Tetrahedron, 1999, Vol.55, pp.9481-9500* |
| H.Li et al., Bioorganic & Medicinal Chem. Letters, 2004, Vol.14, pp.6031-6034* |
| L.J.McBride et al., J. Am. Chem. Soc., 1986, Vol.108, pp.2040-2048* |
Also Published As
| Publication number | Publication date |
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| CN106255697B (zh) | 2020-04-28 |
| JP6730932B2 (ja) | 2020-07-29 |
| US11104699B2 (en) | 2021-08-31 |
| US20150315227A1 (en) | 2015-11-05 |
| CN106255697A (zh) | 2016-12-21 |
| JP2017518966A (ja) | 2017-07-13 |
| EP3137478A2 (en) | 2017-03-08 |
| US11584773B2 (en) | 2023-02-21 |
| WO2015168461A3 (en) | 2015-12-23 |
| EP3137478B1 (en) | 2021-09-22 |
| WO2015168461A2 (en) | 2015-11-05 |
| KR20160147973A (ko) | 2016-12-23 |
| US10196418B2 (en) | 2019-02-05 |
| US20190194242A1 (en) | 2019-06-27 |
| US20220002334A1 (en) | 2022-01-06 |
| EP3137478A4 (en) | 2018-03-07 |
| EP3943500A1 (en) | 2022-01-26 |
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