JP5868324B2 - 不斉補助基 - Google Patents
不斉補助基 Download PDFInfo
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- JP5868324B2 JP5868324B2 JP2012535064A JP2012535064A JP5868324B2 JP 5868324 B2 JP5868324 B2 JP 5868324B2 JP 2012535064 A JP2012535064 A JP 2012535064A JP 2012535064 A JP2012535064 A JP 2012535064A JP 5868324 B2 JP5868324 B2 JP 5868324B2
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- 150000001875 compounds Chemical class 0.000 claims description 70
- 108020004707 nucleic acids Proteins 0.000 claims description 68
- 150000007523 nucleic acids Chemical class 0.000 claims description 68
- 102000039446 nucleic acids Human genes 0.000 claims description 68
- 229910052698 phosphorus Inorganic materials 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 15
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 8
- 239000011574 phosphorus Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- -1 dimethoxytrityl Chemical group 0.000 description 282
- 125000001424 substituent group Chemical group 0.000 description 122
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
- 239000000243 solution Substances 0.000 description 65
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 50
- 125000000217 alkyl group Chemical group 0.000 description 46
- 238000000034 method Methods 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 125000003118 aryl group Chemical group 0.000 description 34
- 125000003545 alkoxy group Chemical group 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 125000000304 alkynyl group Chemical group 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 125000003342 alkenyl group Chemical group 0.000 description 25
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
- 238000004007 reversed phase HPLC Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 19
- 229920005989 resin Polymers 0.000 description 19
- 239000011347 resin Substances 0.000 description 19
- 125000003710 aryl alkyl group Chemical group 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 125000004437 phosphorous atom Chemical group 0.000 description 15
- 125000006239 protecting group Chemical group 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000000178 monomer Substances 0.000 description 14
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 230000002378 acidificating effect Effects 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 11
- 229910052731 fluorine Inorganic materials 0.000 description 11
- 125000001153 fluoro group Chemical group F* 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 11
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 10
- 229960005215 dichloroacetic acid Drugs 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 9
- 125000005647 linker group Chemical group 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 125000001544 thienyl group Chemical group 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 239000007790 solid phase Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 8
- 150000003613 toluenes Chemical class 0.000 description 8
- VKIGAWAEXPTIOL-UHFFFAOYSA-N 2-hydroxyhexanenitrile Chemical compound CCCCC(O)C#N VKIGAWAEXPTIOL-UHFFFAOYSA-N 0.000 description 7
- 239000008351 acetate buffer Substances 0.000 description 7
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 5
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 5
- WXLCDTBTIVJDCE-UHFFFAOYSA-N 1,4-oxazepine Chemical compound O1C=CC=NC=C1 WXLCDTBTIVJDCE-UHFFFAOYSA-N 0.000 description 5
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 5
- JGQPSDIWMGNAPE-UHFFFAOYSA-N 2,1-benzothiazole Chemical compound C1=CC=CC2=CSN=C21 JGQPSDIWMGNAPE-UHFFFAOYSA-N 0.000 description 5
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 description 5
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 5
- 229930024421 Adenine Natural products 0.000 description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229960000643 adenine Drugs 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 238000001425 electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- GTTBQSNGUYHPNK-UHFFFAOYSA-N hydroxymethylphosphonic acid Chemical compound OCP(O)(O)=O GTTBQSNGUYHPNK-UHFFFAOYSA-N 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- TVZOVEUMXMVYGZ-UHFFFAOYSA-N propylaminophosphonic acid Chemical compound CCCNP(O)(O)=O TVZOVEUMXMVYGZ-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000010532 solid phase synthesis reaction Methods 0.000 description 5
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 4
- SLLFVLKNXABYGI-UHFFFAOYSA-N 1,2,3-benzoxadiazole Chemical compound C1=CC=C2ON=NC2=C1 SLLFVLKNXABYGI-UHFFFAOYSA-N 0.000 description 4
- QPPOMEOQNLTFRU-UHFFFAOYSA-N 1,4-thiazepine Chemical compound S1C=CC=NC=C1 QPPOMEOQNLTFRU-UHFFFAOYSA-N 0.000 description 4
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 150000007960 acetonitrile Chemical class 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 238000007630 basic procedure Methods 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 4
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 3
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 3
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000007806 chemical reaction intermediate Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000001293 nucleolytic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- JRPHGDYSKGJTKZ-UHFFFAOYSA-K selenophosphate Chemical compound [O-]P([O-])([O-])=[Se] JRPHGDYSKGJTKZ-UHFFFAOYSA-K 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 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 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 2
- JNHRIRHWRWHOKI-WHFBIAKZSA-N (3r,4r)-4-hydroxypyrrolidine-3-carbonitrile Chemical compound O[C@H]1CNC[C@@H]1C#N JNHRIRHWRWHOKI-WHFBIAKZSA-N 0.000 description 2
- KJBQDFYSFZZSMZ-LLVKDONJSA-N (3s)-3-phenylpiperidin-3-ol Chemical compound C=1C=CC=CC=1[C@@]1(O)CCCNC1 KJBQDFYSFZZSMZ-LLVKDONJSA-N 0.000 description 2
- AFQYBBFSDHKQJV-SNVBAGLBSA-N (3s)-3-phenylpyrrolidin-3-ol Chemical compound C=1C=CC=CC=1[C@@]1(O)CCNC1 AFQYBBFSDHKQJV-SNVBAGLBSA-N 0.000 description 2
- ZDIRWPHDIWKANE-NTSWFWBYSA-N (3s,4s)-3-hydroxypiperidine-4-carbonitrile Chemical compound O[C@@H]1CNCC[C@H]1C#N ZDIRWPHDIWKANE-NTSWFWBYSA-N 0.000 description 2
- JNHRIRHWRWHOKI-RFZPGFLSSA-N (3s,4s)-4-hydroxypyrrolidine-3-carbonitrile Chemical compound O[C@@H]1CNC[C@H]1C#N JNHRIRHWRWHOKI-RFZPGFLSSA-N 0.000 description 2
- SOIZBCZOBJUNFN-OAHLLOKOSA-N (4r)-4-phenyl-2,3-dihydro-1h-isoquinolin-4-ol Chemical compound C1([C@]2(C3=CC=CC=C3CNC2)O)=CC=CC=C1 SOIZBCZOBJUNFN-OAHLLOKOSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 2
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 2
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical compound C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 description 2
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PFUGUPWABHMPQO-UHFFFAOYSA-N 1,4-dioxane;tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl.C1COCCO1 PFUGUPWABHMPQO-UHFFFAOYSA-N 0.000 description 2
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- NPRYXVXVLCYBNS-UHFFFAOYSA-N 2-pyrrolidin-1-ylacetonitrile Chemical compound N#CCN1CCCC1 NPRYXVXVLCYBNS-UHFFFAOYSA-N 0.000 description 2
- RYVNIFSIEDRLSJ-UHFFFAOYSA-N 5-(hydroxymethyl)cytosine Chemical compound NC=1NC(=O)N=CC=1CO RYVNIFSIEDRLSJ-UHFFFAOYSA-N 0.000 description 2
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005163 aryl sulfanyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000000707 boryl group Chemical group B* 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 125000001651 cyanato group Chemical group [*]OC#N 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- MYRTYDVEIRVNKP-UHFFFAOYSA-N divinylbenzene Substances C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 125000005638 hydrazono group Chemical group 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical group [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 125000006606 n-butoxy group Chemical group 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000006608 n-octyloxy group Chemical group 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 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
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 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
- 125000005484 neopentoxy group Chemical group 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005005 perfluorohexyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 108090000765 processed proteins & peptides Chemical group 0.000 description 1
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 1
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 125000000213 sulfino group Chemical group [H]OS(*)=O 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IEGAWSYJCQMVBM-HTQZYQBOSA-N tert-butyl (3s,4s)-3-cyano-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](C#N)C1 IEGAWSYJCQMVBM-HTQZYQBOSA-N 0.000 description 1
- OAQOKUKHQIGNCJ-UHFFFAOYSA-N tert-butyl 3-hydroxy-3-phenylpiperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1(O)C1=CC=CC=C1 OAQOKUKHQIGNCJ-UHFFFAOYSA-N 0.000 description 1
- SUVXRTSOZHJSGE-UHFFFAOYSA-N tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1(O)C1=CC=CC=C1 SUVXRTSOZHJSGE-UHFFFAOYSA-N 0.000 description 1
- JSOMVCDXPUXKIC-UHFFFAOYSA-N tert-butyl 3-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C1 JSOMVCDXPUXKIC-UHFFFAOYSA-N 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
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 125000005300 thiocarboxy group Chemical group C(=S)(O)* 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- ZEMGGZBWXRYJHK-UHFFFAOYSA-N thiouracil Chemical compound O=C1C=CNC(=S)N1 ZEMGGZBWXRYJHK-UHFFFAOYSA-N 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
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Description
より具体的には、上記の4種の化合物のうちFormula Q及びFormula Rで表される化合物を用いて導入された不斉補助基は、強い酸性条件、例えば1% トリフルオロ酢酸(TFA)/ジクロロメタンを用いてカチオンを発生させることにより下記のSN1機構で脱離させることができる。しかしながら、この酸性条件はアシル型の保護基で塩基部位を保護したアデニン塩基(一般的にはアデニン塩基にはアシル型の保護基が導入されている)の脱離(デプリネーション)が生じる条件であることから、この不斉補助基を用いる場合にはアデニン塩基をアミジン型、トリチル型、又はジアシル型などの保護基で保護しなければならないという問題が生じる(下記のスキーム中、Bsは核酸塩基、Meはメチル基、Phはフェニル基を示す)。
本発明はこれらの知見を基にして完成されたものである。
(a)下記一般式(V):
で表される核酸誘導体と、上記一般式(IV)で表されるヌクレオチド誘導体(ただし、R1、R2、R3、R4、R5、及びYは上記と同義であり;R21は水酸基の保護基を示し;R22は水素原子、アルコキシ基、フッ素原子、又は保護された水酸基を示し;Bsは核酸塩基を示す)とを反応させて、上記一般式(III)(ただし、R1、R2、R3、R4、R5、Y、及びnは上記と同義であり;R11は水酸基の保護基を示し;R12、R13、及びR14はそれぞれ独立に水素原子、アルコキシ基、フッ素原子、又は保護された水酸基を示し;R15は必要に応じてリンカーを介して結合した固相担体を示し;Bsは核酸塩基を示す)で表される核酸誘導体を製造する工程;
(b)上記工程(a)により得られた一般式(III)で表される核酸誘導体からR11で表される水酸基の保護基を除去し、必要に応じて、得られた核酸誘導体と一般式(IV)で表されるヌクレオチド誘導体とを反応させる工程を繰り返す工程;
(c)酸性条件下において一般式(II)で表される不斉補助基を除去して下記一般式(VI):
(d)上記工程(c)で得られた核酸誘導体のリン原子を修飾した後、必要に応じて保護基を脱離する工程
を含む方法が提供される。
また、工程(d)におけるリン原子の修飾としては、Xで表される基(Xは置換基を有していてもよいアルキルチオ基、置換基を有していてもよいアルケニルチオ基、置換基を有していてもよいアルキニルチオ基、置換基を有していてもよいアリールチオ基、チオール基、置換基を有していてもよいアルコキシ基、-BH3、-Se-、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアシル基、又は-N(R116)(R117)(R116及びR117はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、又は置換基を有していてもよいアリール基を示す)で表される基を示す)をリン原子上に導入することができる。
(a)下記一般式(XIII'):
で表される核酸誘導体と、上記一般式(XIV)で表されるヌクレオチド誘導体(ただし、R121は水酸基の保護基を示し;R122は水素原子、アルコキシ基、フッ素原子、又は保護された水酸基を示す)とを反応させた後に、求電子剤を用いてX(Xはチオール基、-BH3、-Se-を示す)を導入し、R121が示す水酸基の保護基を除去することにより下記一般式(XV):
(b)上記工程(a)により得られた上記一般式(XV)で表される核酸誘導体から塩基性条件下において一般式(XII)で表される不斉補助基を除去して下記一般式(XVII):
を含む方法が提供される。
アルキルチオ基、アルケニルチオ基、アルキニルチオ基、及びアリールチオ基のアルキル部分、アルケニル部分、アルキニル部分、及びアリール部分としては上記に説明したアルキル基、アルケニル基、アルキニル基、及びアリール基を用いることができる。
一般式(I)において、R1及びR2はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアラルキル基、又は置換基を有していてもよいアリール基を示す。好ましくはR1及びR2はそれぞれ独立に水素原子又はアルキル基を示し、R1及びR2がともに水素原子であることがさらに好ましい。
R4及びR5はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアラルキル基、又は置換基を有していてもよいアリール基を示す。好ましくはR4及びR5はそれぞれ独立に水素原子又はアルキル基を示し、R4及びR5がともに水素原子であることがさらに好ましい。
Y2は単結合又は-C(R8)(R9)-を示す。R8及びR9はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアラルキル基、又は置換基を有していてもよいアリール基を示す。Y2は単結合であることが好ましく、この場合、Yは-C(R6)(R7)-を示すか、又は置換基を有していてもよいo-アリールジイル基を示す。
この方法は、背景技術において国際公開WO 2010/064146の反応工程を説明したスキーム中のRoute Bで示したサイクルと同様に行うことができる。
一般式(XI)において、R101及びR102はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアリール基を示す。R101及びR102は水素原子又はアルキル基であることが好ましく、R101及びR102がともに水素原子であることがより好ましい。
この方法は、背景技術において国際公開WO 2010/064146の反応工程を説明したスキーム中のRoute Aで示したサイクルと同様に行うことができる。
1H NMR (300 MHz, CDCl3) δ 8.01 (1H, d, J = 7.8 Hz), 7.81 (1H, t, J = 7.2 Hz), 7.71 (1H, t, J = 7.2 Hz), 7.56 (1H, d, J = 7.8 Hz), 7.52-7.40 (5H, m); 13C NMR (75.5 MHz, CDCl3) δ 167.3, 146.6, 135.8, 133.6, 131.4, 130.7, 129.3, 126.3, 125.7, 123.9, 123.2, 115.8, 79.6.
1H NMR (300 MHz, CDCl3) δ 7.22-7.18 (9H, m), 4.42 (1H, d, J = 11.7 Hz), 4.09 (1H, d, J = 11.7 Hz), 3.53 (1H, d, J = 12.0 Hz), 3.23 (1H, d, J = 12.0 Hz), 1.64 (2H, brs); 13C NMR (75.5 MHz, CDCl3) δ 145.4, 143.1, 140.8, 133.0, 128.2, 128.1, 127.5, 127.0, 125.7, 125.6, 77.3, 64.4, 51.7; ESI TOF-MS m/z Calcd for C15H16NO [M+H]+ 226.12, found 226.15.
1H NMR (300 MHz, CD3OD) δ 7.53 (2H, d, J = 6.9 Hz), 7.34 (2H, t, J = 6.9 Hz), 7.25 (1H, d, J = 6.9 Hz), 4.20-3.88 (1H, m), 3.88-3.71 (1H, m), 3.42-3.18 (1H, m), 3.08-2.93 (1H, m), 2.13-1.77 (3H, m), 1.58-1.47 (1H, m), 1.46 (9H, s); 13C NMR (75.5 MHz, CD3OD) δ 157.2, 147.5, 129.2, 128.1, 126.3, 81.0, 79.5, 72.4, 37.8, 28.7, 22.3.
1H NMR (300 MHz, CD3OD) δ 7.53-7.46 (2H, m), 7.37-7.29 (2H, m), 7.26-7.18 (1H, m), 3.08-2.99 (1H, m), 2.93-2.85 (1H, m), 2.81-2.72 (1H, m), 2.68-2.56 (1H, m), 2.13-1.80 (3H, m), 1.61-1.51 (1H, m); 13C NMR (75.5 MHz, CD3OD) δ 148.7, 129.2, 127.9, 125.8, 71.8, 57.4, 46.3, 37.2, 23.4; ESI TOF-MS m/z Calcd for C11H16NO [M+H]+ 178.12, found 178.14.
1H NMR (300 MHz, CDCl3) δ 7.52-7.28 (5H, m), 3.80-3.54 (4H, m), 2.42-2.10 (2H, m), 1.93 (1H, brs), 1.48 (9H, s).
1H NMR (300 MHz, CDCl3) δ 7.52-7.46 (2H, m), 7.41-7.24 (3H, m), 3.34 (1H, dt, J = 10.8, 7.8 Hz), 3.20-3.09 (2H, m), 3.03 (1H, d, J = 12.0 Hz), 2.27 (1H, ddd, J = 13.4, 9.3, 7.5 Hz), 2.18-2.06 (1H, m), 1.95 (1H, brs); 13C NMR (75.5 MHz, CD3OD) δ 146.0, 129.2, 128.0, 126.4, 83.1, 61.9, 46.8, 42.9; ESI TOF-MS m/z Calcd for C10H14NO [M+H]+ 164.11, found 164.13.
1H NMR (300 MHz, CDCl3) δ 4.64 (1H, q, J = 4.5 Hz),3.87-3.62 (3H, m), 3.47-3.31 (1H, m), 3.15-2.99 (1H, m), 2.46 (1H, brs), 1.47 (9H, s); ESI TOF-MS m/z Calcd for C10H14NO [M+H]+ 164.11, found 164.13.
1H NMR (300 MHz, CD3OD) δ 4.49 (1H, dt, J = 6.0, 3.6 Hz), 3.39 (1H, dd, J = 11.9, 8.1 Hz), 3.08 (1H, dd, 12.3, 5.4 Hz), 3.00 (1H, dd, J = 11.9, 5.7 Hz), 2.92-2.85 (1H, m), 2.80 (1H, dd, J = 12.3, 3.6 Hz); 13C NMR (100 MHz, CD3OD) δ 121.7, 77.5, 55.5, 50.8, 39.1; ESI TOF-MS m/z Calcd for C5H9N2O [M+H]+ 113.07, found 113.07.
(a)酸除去型不斉補助基を用いるX-ホスホネートDNAの固相合成の基本手順(一般式 I)
HCP若しくはCPGにサクシニルリンカー若しくはオキザリルリンカーを介して結合した5'-O-(DMTr)ヌクレオシド(0.5μmol)を3%ジクロロ酢酸/ジクロロメタン溶液で処理し、5'-DMTr基を除去し、ジクロロメタンで洗浄し、真空下で乾燥する。鎖長延長反応は以下の(a)、(b)の工程を繰り返し行なうことで達成する。(a)縮合反応(5分)は、事前に活性化した対応するモノマー溶液をアルゴン雰囲気下で行なう。縮合後、固相担体を脱水アセトニトリルと脱水ジクロロメタンで洗浄する。(b) 5'-O-DMTrと不斉補助基の除去は3%ジクロロメタン/(ジクロロメタン−トリエチルシラン(体積比で1:1))溶液で処理することで同時に行い、続いてジクロロメタン及び脱水アセトニトリルで洗浄する。鎖長延長後、樹脂上にできたオリゴヌクレオシドHホスホネートはXホスホネートDNAに下に示す方法で変換する。
上記の方法で得られた、HCP若しくはCPGにサクシニルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、10重量%S8/(二琉化炭素−ピリジン−トリエチルアミン)溶液(体積比35:35:1)に室温で3時間処理し、続いて二硫化炭素、ピリジン、アセトニトリルで洗浄する。樹脂を25%アンモニア水で室温12時間処理し、水で洗浄する。水溶液を集め、減圧下濃縮し、残渣を逆相HPLCで精製し、立体を制御したホスホロチオエートDNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートに対し、脱水ジメチルホルムアミド、N,O-ビス(トリメチルシリル)アセトアミド、ボランジメチルスルフィドを加える。15分後、樹脂をジメチルホルムアミド、アセトニトリル、メタノールの順に洗浄する。樹脂をアンモニア/メタノール溶液で室温12時間処理し、メタノールで洗浄する。メタノール溶液を集め、減圧下濃縮し、残渣を逆相HPLCで精製し、立体を制御したボラノホスフェートDNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、0.1Mトリメチルシリルクロリド/(ピリジン:1−メチル−2−ピロリドン(体積比1:9))溶液で室温10分間、ガス状のホルムアルデヒドで室温30分間処理し、次に1−メチル−2−ピロリドン、アセトニトリルで洗浄する。樹脂を25%アンモニア水で室温12時間処理し、水で洗浄する。水溶液を集め、減圧下濃縮し、残渣を逆相HPLCで精製し、立体を制御したヒドロキシメチルホスホネートDNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、四塩化炭素-1、4-ジオキサン(体積比4:1)の飽和アンモニア溶液に0℃で30分間処理し、1、4-ジオキサンで洗浄する。有機溶媒を集め、減圧下濃縮乾燥し、25%アンモニア水で室温12時間処理し、水で洗浄する。水溶液を集め、減圧下濃縮し、残渣を逆相HPLCで精製し、立体を制御したホスホロアミデートDNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、四塩化炭素−プロピルアミン(体積比9:1)溶液に室温で1時間処理し、メタノールで洗浄する。有機溶媒を集め、減圧下濃縮乾燥し、25%アンモニア水で室温12時間処理し、水で洗浄する。水溶液を集め、減圧下濃縮し、残渣を逆相HPLCで精製し、立体を制御したN−プロピルホスホロアミデートDNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、四塩化炭素-2-ジメチルアニモエチルアミン(体積比9:1)溶液に室温で1時間処理し、アセトニトリルで洗浄する。有機溶媒を集め、減圧下濃縮乾燥し、25%アンモニア水で室温12時間処理し、水で洗浄する。水溶液を集め、減圧下濃縮し、残渣を逆相HPLCで精製し、立体を制御したN-[(2-ジメチルアミノ)エチル]ホスホロアミデートDNAを得る。
(a)酸除去型不斉補助基を用いるX-ホスホネートRNAの固相合成の基本手順(一般式 I)
HCP若しくはCPGにサクシニルリンカー若しくはオキザリルリンカーを介して結合した5'-O-(DMTr)ヌクレオシド(0.5μmol)を3%ジクロロ酢酸/ジクロロメタン溶液で処理し、5'-DMTr基を除去し、ジクロロメタンで洗浄し、真空下で乾燥する。鎖長延長反応は以下の(a)、(b)の工程を繰り返し行なうことで達成する。(a)縮合反応(15分)は、事前に活性化した対応するモノマー溶液*をアルゴン雰囲気下で行なう。縮合後、固相担体を脱水アセトニトリルと脱水ジクロロメタンで洗浄する。(b) 5'-O-DMTrと不斉補助基の除去は3%ジクロロメタン/(ジクロロメタン−トリエチルシラン(体積比で1:1))溶液で処理することで同時に行い、続いてジクロロメタン及び脱水アセトニトリルで洗浄する。鎖長延長後、樹脂上にできたオリゴヌクレオシドHホスホネートはXホスホネートRNAに下に示す方法で変換する。
上記の方法で得られた、HCP若しくはCPGにサクシニルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、10重量%S8/(二琉化炭素−ピリジン−トリエチルアミン)溶液(体積比35:35:1)に室温で3時間処理し、続いて二硫化炭素、ピリジン、エタノールで洗浄する。次に樹脂を25%アンモニア水−エタノール溶液(体積比3:1)で室温2時間処理し、樹脂をフィルターでろ別する。ろ液を25%アンモニア水−エタノール溶液(体積比3:1)で希釈し、フラスコ内に密閉し、室温で12時間処理する。溶液を減圧下濃縮し、残渣を逆相HPLCで精製する。目的とする2'位がTBS基で保護されたホスホロチオエートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したホスホロチオエートRNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートに対し、脱水ジメチルホルムアミド、N,O-ビス(トリメチルシリル)アセトアミド、ボランジメチルスルフィドを加える。15分後、樹脂をジメチルホルムアミド、アセトニトリル、エタノールの順に洗浄する。次に樹脂を25%アンモニア水−エタノール溶液(体積比3:1)で室温2時間処理し、樹脂をフィルターでろ別する。ろ液を25%アンモニア水−エタノール溶液(体積比3:1)で希釈し、フラスコ内に密閉し、室温で12時間処理する。溶液を減圧下濃縮し、残渣を逆相HPLCで精製する。目的とする2'位がTBS基で保護されたボラノホスフェートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したボラノホスフェートRNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、0.1Mトリメチルシリルクロリド/(ピリジン:1−メチル−2−ピロリドン(体積比1:9))溶液で室温10分間、ガス状のホルムアルデヒドで室温30分間処理し、次に1−メチル−2−ピロリドン、エタノールで洗浄する。次に樹脂を25%アンモニア水−エタノール溶液(体積比3:1)で室温2時間処理し、樹脂をフィルターでろ別する。ろ液を25%アンモニア水−エタノール溶液(体積比3:1)で希釈し、フラスコ内に密閉し、室温で12時間処理する。溶液を減圧下濃縮し、残渣を逆相HPLCで精製する。目的とする2'位がTBS基で保護されたヒドロキシメチルホスホネートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したヒドロキシメチルホスホネートRNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、四塩化炭素-1、4-ジオキサン(体積比4:1)の飽和アンモニア溶液に0℃で30分間処理し、1、4-ジオキサンで洗浄する。有機溶媒を集め、減圧下濃縮乾燥する。25%アンモニア水−エタノール溶液(体積比3:1)で希釈し、フラスコ内に密閉し、室温で12時間処理する。溶液を減圧下濃縮し、残渣を逆相HPLCで精製する。目的とする2'位がTBS基で保護されたホスホロアミデートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したホスホロアミデートRNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、四塩化炭素−プロピルアミン(体積比9:1)溶液に室温で1時間処理し、メタノールで洗浄する。有機溶媒を集め、減圧下濃縮乾燥する。25%アンモニア水−エタノール溶液(体積比3:1)で希釈し、フラスコ内に密閉し、室温で12時間処理する。溶液を減圧下濃縮し、残渣を逆相HPLCで精製する。目的とする2'位がTBS基で保護されたN−プロピルホスホロアミデートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したN−プロピルホスホロアミデートRNAを得る。
上記の方法で得られた、HCP若しくはCPGにオキザリルリンカーを介して結合したオリゴヌクレオシドHホスホネートを、四塩化炭素-2-ジメチルアニモエチルアミン(体積比9:1)溶液に室温で1時間処理し、アセトニトリルで洗浄する。有機溶媒を集め、減圧下濃縮乾燥する。25%アンモニア水−エタノール溶液(体積比3:1)で希釈し、フラスコ内に密閉し、室温で12時間処理する。溶液を減圧下濃縮し、残渣を逆相HPLCで精製する。目的とする2'位がTBS基で保護されたN-[(2-ジメチルアミノ)エチル]ホスホロアミデートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したN-[(2-ジメチルアミノ)エチル]ホスホロアミデートRNAを得る。
(a)塩基除去型不斉補助基を用いるX-ホスホネートDNAの固相合成の基本手順(一般式 XI)
HCP若しくはCPGにサクシニルリンカー若しくはオキザリルリンカーを介して結合した5'-O-(DMTr)ヌクレオシド(0.5μmol)を合成に用いる。鎖長延長反応はTable1に記す工程を繰返し行なうことで達成する。鎖長延長後、不斉補助基は無水10%DBU/アセトニトリル溶液を用い室温15分で除去し、アセトニトリルで洗浄する。次に5'-O-DMTr基を3%ジクロロ酢酸/ジクロロメタン溶液で除去し、ジクロロメタンで洗浄する。HCP若しくはCPG上のオリゴマーをOリングの付いたスクリューキャップ式のエッペンドルフチューブに移す。0.5マイクロモルのオリゴヌクレオチドを含む固相担体を25%のアンモニア水(1mL)に懸濁させ、55℃で12時間処理し、核酸塩基部位の保護基を除去し、同時にHCP若しくはCPGからオリゴマーを遊離させる。遠心分離後、上清を丸底フラスコへ移し、固相担体を水(0.5mLで2回)で洗浄する。遠心分離後、集めた上清を減圧下乾燥する。残渣を水(1mL)で希釈し、Sep-Pak PLUS tC18にロードし、水で平衡化する。まず塩を除くために水(20mL)を流し、次に脱塩済みの立体を制御したXホスホネートDNAを50%アセトニトリル水溶液(10mL)で溶出させ、逆相UPLCとMALDI-TOF MSで分析する。
(a)酸除去型不斉補助基を用いるX-ホスホネートRNAの固相合成の基本手順(一般式 XI)
HCP若しくはCPGにサクシニルリンカー若しくはオキザリルリンカーを介して結合した5'-O-(DMTr)リボヌクレオシド(0.5μmol)を合成に用いる。鎖長延長反応はTable2に記す工程を繰返し行なうことで達成する。鎖長延長後、不斉補助基は無水10%DBU/アセトニトリル溶液を用い室温15分で除去し、アセトニトリルで洗浄する。次に5'-O-DMTr基を3%ジクロロ酢酸/ジクロロメタン溶液で除去し、ジクロロメタンで洗浄する。HCP若しくはCPG上のオリゴマーをOリングの付いたスクリューキャップ式のエッペンドルフチューブに移す。0.5マイクロモルのオリゴヌクレオチドを含む固相担体を25%のアンモニア水−エタノール混合液(体積比3:1、1mL)に懸濁させ、室温で48時間処理し、核酸塩基部位の保護基を除去し、同時にHCP若しくはCPGからオリゴマーを遊離させる。遠心分離後、上清を丸底フラスコへ移し、固相担体を水(0.5mLで2回)で洗浄する。遠心分離後、集めた上清を減圧下乾燥し、残渣を逆相HPLCで精製する。2'位をTBS基で保護したXホスホネートRNAを含むフラクションを集め、凍結乾燥する。残渣を1モル濃度テトラブチルアンモニウムフルオリドの脱水テトラヒドロフラン溶液を用い室温で24時間処理する。0.05モル濃度のトリエチルアンモニウムアセテートバッファー(pH6.9)を加え、テトラヒドロフランを濃縮除去する。残渣をSep-Pak PLUS tC18で脱塩し、逆相HPLCで精製し、立体を制御したXホスホネートRNAを得る。
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