JPWO2019208571A1 - アミダイト化合物及び該化合物を用いたポリヌクレオチドの製造方法 - Google Patents
アミダイト化合物及び該化合物を用いたポリヌクレオチドの製造方法 Download PDFInfo
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- JPWO2019208571A1 JPWO2019208571A1 JP2020515487A JP2020515487A JPWO2019208571A1 JP WO2019208571 A1 JPWO2019208571 A1 JP WO2019208571A1 JP 2020515487 A JP2020515487 A JP 2020515487A JP 2020515487 A JP2020515487 A JP 2020515487A JP WO2019208571 A1 JPWO2019208571 A1 JP WO2019208571A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 145
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 76
- 108091033319 polynucleotide Proteins 0.000 title claims abstract description 13
- 102000040430 polynucleotide Human genes 0.000 title claims abstract description 13
- 239000002157 polynucleotide Substances 0.000 title claims abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 25
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 23
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 23
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 23
- 125000006239 protecting group Chemical group 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- -1 ether compound Chemical class 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 42
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- 239000002253 acid Substances 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 21
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 20
- 239000007800 oxidant agent Substances 0.000 claims description 17
- 108091034117 Oligonucleotide Proteins 0.000 claims description 15
- 238000010532 solid phase synthesis reaction Methods 0.000 claims description 14
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 claims description 13
- BYJAJQGCMSBKPB-UHFFFAOYSA-N 3-hydroxybutanenitrile Chemical compound CC(O)CC#N BYJAJQGCMSBKPB-UHFFFAOYSA-N 0.000 claims description 12
- OVRKATYHWPCGPZ-UHFFFAOYSA-N 4-methyloxane Chemical compound CC1CCOCC1 OVRKATYHWPCGPZ-UHFFFAOYSA-N 0.000 claims description 10
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- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000008300 phosphoramidites Chemical class 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 8
- 239000000243 solution Substances 0.000 description 71
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- 238000006243 chemical reaction Methods 0.000 description 62
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- 239000000203 mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
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- 239000007788 liquid Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 9
- 229940045145 uridine Drugs 0.000 description 9
- 0 BC(C1OCC(C)(C)OCC(C)(C)OC(*)(CC)CC#N)OC2=C1O*OC2 Chemical compound BC(C1OCC(C)(C)OCC(C)(C)OC(*)(CC)CC#N)OC2=C1O*OC2 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
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- 239000000543 intermediate Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
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- 230000035484 reaction time Effects 0.000 description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
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- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 6
- 101001094831 Homo sapiens Phosphomannomutase 2 Proteins 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 102100035362 Phosphomannomutase 2 Human genes 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 5
- CKVRJOBUMGJKDE-UHFFFAOYSA-N phenylsulfanylmethoxymethylsulfanylbenzene Chemical compound C=1C=CC=CC=1SCOCSC1=CC=CC=C1 CKVRJOBUMGJKDE-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
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- RKVHNYJPIXOHRW-UHFFFAOYSA-N 3-bis[di(propan-2-yl)amino]phosphanyloxypropanenitrile Chemical compound CC(C)N(C(C)C)P(N(C(C)C)C(C)C)OCCC#N RKVHNYJPIXOHRW-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
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- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 4
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
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- 230000015572 biosynthetic process Effects 0.000 description 4
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- 230000000052 comparative effect Effects 0.000 description 4
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
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- 239000002244 precipitate Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229960000643 adenine Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
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- 238000010511 deprotection reaction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
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- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
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- RDZHCKRAHUPIFK-UHFFFAOYSA-N 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(I)C(=O)N(I)C1=O RDZHCKRAHUPIFK-UHFFFAOYSA-N 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
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- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- XSWODFNOUCZADO-UHFFFAOYSA-N 5-benzyl-1-sulfanyltetrazole Chemical compound SN1N=NN=C1CC1=CC=CC=C1 XSWODFNOUCZADO-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 2
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- 239000003223 protective agent Substances 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 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
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004954 trialkylamino group Chemical group 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- DJJCXFVJDGTHFX-XVFCMESISA-N uridine 5'-monophosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-XVFCMESISA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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Abstract
Description
nは1〜5の整数を表す。)
項1. 式(1)で示されるアミダイト化合物。
nは1〜5の整数を表す。)を表し、
Baは保護されていてもよい核酸塩基骨格を有する基を表し、
G1及びG2は同一又は相異なって水酸基の保護基を表し、
G3は同一又は相異なってアルキル基を表す。)
項2. Raがメチル基またはエチル基であり、Rbが水素原子である、項1に記載のアミダイト化合物。
項3. G1が以下の基である、項1又は2に記載のアミダイト化合物。
項4. G2が以下の基である、項1〜3のいずれか一項に記載のアミダイト化合物。
項6. 項1〜5のいずれか一項に記載のアミダイト化合物を固相合成反応に供する工程を含む、式(2):
Xは酸素原子又は硫黄原子を表し、
mは正の整数を表す。)
で示されるポリヌクレオチド骨格を含有する化合物の製造方法。
項7. 式(2)のポリヌクレオチド骨格を含有する化合物が、前記アミダイト化合物を用いる固相合成反応で生成する式(3):
Xは酸素原子又は硫黄原子を表し、
Rは同一又は相異なって、式:
nは1〜5の整数を表す。)を表し、
mは正の整数を表す。)
で示されるオリゴヌクレオチド骨格を有する化合物にテトラアルキルアンモニウムフルオライドを反応させる工程で生成した化合物である、項6に記載の製造方法。
項8. Raがメチル基またはエチル基であり、Rbが水素原子である、項7に記載の製造方法。
項9. n=1である、項6〜8のいずれか一項に記載の製造方法。
項10. 式(4)で示されるエーテル化合物。
項11. Raがメチル基またはエチル基であり、Rbが水素原子であり、Rcがメチルである、項10に記載のエーテル化合物。
項12. n=1である、項10または11に記載の化合物。
項13. 工程a:式(5):
で示される化合物とシアン化物イオンとを反応させる工程、及び
工程b:酸化剤及び酸存在下、溶媒中で、工程aで得られた式(6):
で示される3−ヒドロキシアルキルニトリルとビス(メチルチオメチル)エーテルとを反応させる工程、
を含む、式(7):
で示されるエーテル化合物の製造方法。
項14. Raがメチル基またはエチル基であり、Rbが水素原子である、項13に記載の製造方法。
項15. Raがメチル基であり、Rbが水素原子である、項13に記載の製造方法。
項16. 工程A:3−アミノクロトノニトリルを加水分解する工程、
工程B:工程Aで得られたシアノアセトンを還元して、3−ヒドロキシブタンニトリルを得る工程、および
工程C:酸化剤及び酸存在下、溶媒中で、工程Bで得られた3−ヒドロキシブタンニトリルとビス(メチルチオメチル)エーテルとを反応させる工程、
を含む、式(8):
項17. 式(9):
で示される化合物を、酸化剤の存在下、式(4):
RcはC1〜C6アルキル基、又はフェニル基である。
nは、1〜4の整数を表す。)
で示される化合物と、反応させることを特徴とする、式(10):
で示される化合物の製造方法。
項18. 反応溶媒として、テトラヒドロピランまたは4−メチルテトラヒドロピランを用いる、項17に記載の製造方法。
項19. 式(10)の化合物をさらに脱保護して、式(11):
で示される化合物を得る工程、
式(11)の化合物の5’の水酸基を選択的に保護して、式(12):
で示される化合物を得る工程、
式(12)の化合物を式(13):
で表されるホスホロジアミダイトと反応させる工程、
を含む、項1に記載の式(1)の化合物の製造方法。
項20. G4は、G4−1またはG4−2構造を有する項19に記載の製造方法。
nは1〜5の整数を表し、
Baは保護されていてもよい核酸塩基骨格を有する基を表し、
G4は、保護基を表す。)
で示される化合物。
項22. 式(11):
で示される化合物。
項23. 式(12):
で示される化合物。
項24.前記式(1)のアミダイト化合物のRNAの製造における使用。
nは1〜5の整数を表す。)を表し、
Baは保護されていてもよい核酸塩基骨格を有する基を表し、
G1及びG2は同一又は相異なって水酸基の保護基を表し、
G3は同一又は相異なってアルキル基を表す。)
R5は水素原子、アセチル基、イソブチリル基又はベンゾイル基を表し、
R6は水素原子、フェノキシアセチル基、4−tert−ブチルフェノキシアセチル基、4−イソプロピルフェノキシアセチル基、フェニルアセチル基、アセチル基又はイソブチリル基を表し、
R7は2−シアノエチル基を表し、
R8は水素原子、メチル基、ベンゾイル基、4−メトキシベンゾイル基又は4−メチルベンゾイル基を表し、
R9はジメチルアミノメチレン基を表す。)
のいずれかで表される基を表す。
nは1〜5の整数を表す。
RcはC1〜C6アルキル基、又はフェニル基である。)
シアン化物イオンとしては、例えば、シアン化ナトリウム、シアン化カリウム、シアン化銅、トリメチルシリルシアニドなどに由来するシアン化物イオンを使用することができる。
酸化剤としては、例えば、N−クロロスクシンイミド、N−ブロモスクシンイミド、N−ヨードスクシンイミド等のN−ハロゲン化スクシンイミド、1,3−ジヨード−5,5−ジメチルヒダントイン等のN−ハロゲン化ヒダントイン、および塩素、臭素、ヨウ素等のハロゲン等、並びにこれらの2種類以上の組み合わせが挙げられる。本発明においては、N−ハロゲン化スクシンイミドが好ましく用いられ、N−ヨードスクシンイミドが更に好ましく用いられる。
工程B:工程Aで得られたシアノアセトンを還元する工程、及び
工程C:酸化剤及び酸存在下、溶媒中で、工程Bで得られた3−ヒドロキシブタンニトリルとビス(メチルチオメチル)エーテルとを反応させる工程。
Xは酸素原子又は硫黄原子を表し、
mは正の整数を表す。)
Xは酸素原子又は硫黄原子を表し、
Rは同一又は相異なって、式:
nは1〜5の整数を表す。)
を表し、
mは正の整数を表す。)
本発明アミダイト化合物および式(4)で表されるエーテル化合物の製造における反応条件は特に限定されない。式(4)で表されるエーテル化合物はフローリアクターを用いて合成することもできる。
本発明アミダイト化合物に含まれる不純物を削減する目的で、パラジウムなどの遷移金属触媒存在下、水素による還元工程あるいはマグネシウム等による還元工程を追加することもできる。
式(9)の化合物において、Baは、前記と同じ意味を表し、G4は、典型的には、下記のG4−1またはG4−2構造を有する。
エーテル化工程は、式(9)の化合物を式(4)の化合物と反応させて実施される。この反応は、通常、酸化剤を添加して実施される。この工程において用いる酸化剤は、特に限定されないが、N−クロロスクシンイミド、N−ブロモスクシンイミド、N−ヨードスクシンイミド、ヨウ素、1,3−ジヨード−5、5‘−ジメチルヒダントイン、臭素および塩素からなる群から選択される少なくとも一つであることが好ましい。
前記工程1で得られた式(10)の化合物は、脱保護反応に供して式(11)の化合物に変換される。脱保護工程は、公知の方法で実施できるが、典型的には、溶媒中、フッ化水素/トリエチルアミンあるいはフッ化水素/ピリジンを作用させ、脱保護することができる。
前記工程で得られた式(11)の化合物は、保護工程に供され、保護基の導入は、公知の方法で実施できるが、典型的には、ピリジン中、化合物(11)に4,4’−ジメトキシトリチルクロリドを反応させて保護基が導入され、化合物(12)が製造される。
この工程は前記工程で得られた式(12)の化合物に、式(13)の化合物を反応させることによって実施される。典型的には、ジイソプロピルアンモニウムテトラゾリドの存在下、式(13)の化合物として2−シアノエチルーN,N,N’,N’−テトライソプロピルホスホロジアミダイトを反応させて行われる。アミダイト化は、特許第5554881号公報の実施例2〜5に記載された方法に準じて行うことができる。
本明細書中、以下の略号を使用する。
PMM=(((1−シアノプロパン−2−イル)オキシ)メトキシ)メチル基、BMM=(((1−シアノブタン−2−イル)オキシ)メトキシ)メチル基、TBM=(((1−シアノ−2−メチルプロパン−2−イル)オキシ)メトキシ)メチル基、PMM2=((2−シアノプロポキシ)メトキシ)メチル基、CPM=((1−シアノプロパン−2−イル)オキシ)メチル基;A=アデニン、G=グアニン、C=シトシン、U=ウラシル。
製造例1
1)3−ヒドロキシブタンニトリルの製造
1H-NMR (CDCl3): δ 4.93-4.84 (m, 2H) 4.75(s, 2H) 4.06-4.00 (m, 1H) 2.57 (t, 2H), 2.17(s, 3H) 1.35 (d, 3H)
1)シアノアセトンの製造
上記の実施例と同様にして(R)−PMM化剤、(S)−PMM化剤、BMM化剤、TBM化剤、PMM2化剤を製造した。また下記に記載の方法によってCPM化剤を製造した。
(R)−PMM化剤(シグマアルドリッチ社(R)-(+)-プロピレンオキシドより合成)
1H-NMR (CDCl3): δ4.92 (d,1H) 4.85(d,1H) 4.75 (s,2H) 4.03 (m,1H) 2.57 (m,2H) 2.17 (s,3H) 1.35 (d,3H)
(S)−PMM化剤(シグマアルドリッチ社(S)-(-)-プロピレンオキシドより合成)
1H-NMR (CDCl3): δ4.92 (d,1H) 4.85 (d,1H) 4.75 (s,2H) 4.03 (m,1H) 2.57 (m,2H) 2.17 (s,3H) 1.34 (d,3H)
BMM化剤
1H-NMR (CDCl3): δ4.95 (d,1H) 4.84 (d,1H) 4.76 (s,2H) 3.79 (m,1H) 2.60 (m,2H) 2.17 (s,3H) 1.70 (m,2H) 0.97 (t,3H)
PMM2化剤
1H-NMR (CDCl3): δ4.86 (s, 2H) 4.73 (s, 2H) 3.71-3.61 (m, 2H) 2.94-2.87 (m, 1H) 2.18 (s, 3H) 1.35 (d, 3H)
CPM化剤の製造
2000mlのナスフラスコに3−ヒドロキシブタンニトリル(3−HBN)51.0g(600mmol)、ジメチルスルホキシド640ml(9mol)を入れ、酢酸 350ml(6.1mol)、無水酢酸 600ml(6.3mol)を加えた。窒素ガス中室温で15分間撹拌した後、油浴(50℃)で12時間加熱撹拌した。GCで原料3−HBNの消失を確認して、室温まで放冷した。重曹 1600g(19.5mol)をイオン交換水8Lに懸濁して、上記の反応液を徐々に添加した。発泡が治まってから、分液ロートに移して酢酸エチル 500mlで抽出した。有機層をイオン交換水 1Lで洗浄し、硫酸マグネシウムで乾燥、減圧濃縮して91.0gの淡黄褐色油状物を得た。
当該油状物をシリカゲルカラムで精製した(SiO2 1000ml、n−Hexane:AcOEt=20:1でスラリーを作り、充填した。)。サンプルをカラムにチャージして、n−Hexane:AcOEt=20:1で溶出した。1000ml溶出後、200ml分取(15本)した。n−Hexane:AcOEt=3:1で溶出後、200ml分取(15本)した。目的物のフラクションを合わせて減圧濃縮し、真空ラインで減圧乾燥した。53.28gの無色油状物を得た。
1H-NMR (CDCl3): δ4.72 (d,1H) 4.64 (d,1H) 4.15 (m,1H) 2.56 (m,2H) 2.20 (s,3H) 1.31 (d,3H)
製造例9
核酸塩基部分がウラシルであるPMMアミダイトUの製造例を以下に示す。
核酸塩基部分がシトシンであるPMMアミダイトCの製造例を以下に示す。
核酸塩基部分がアデニンであるPMMアミダイトAの製造例を以下に示す。
製造例9〜11のアミダイトのスペクトルデータを以下に示す。
上記の実施例と同様にしてPMMアミダイトG、BMMアミダイトU、TBMアミダイトU、及び参考化合物であるPMM2アミダイトU、CPMアミダイトCを製造した。
製造したアミダイトのスペクトルデータを以下に示す。
上記製造例で作製したPMMアミダイトU、BMMアミダイトUおよびTBMアミダイトUを用いて、下記配列番号1の配列で示されるウリジン50量体を合成した。
5’−UUUUUUUUUU UUUUUUUUUU UUUUUUUUUU UUUUUUUUUU UUUUUUUUUU−3’(配列番号1)
(式中、Uはウリジンモノリン酸ナトリウム塩を意味する)
PMMアミダイトUを用いてウリジン50量体(分子量15246.53)を合成した結果、0.406μmolあたりのOD260は97.48ODであり、純度は84.3%であった。OD260の値から、1μmolあたりの収量は9604μg/μmolと算出された。結果を表4に示す。
同様にBMMアミダイトUを用いてウリジン50量体(分子量15246.53)を合成した結果、0.200μmolあたりのOD260は48.51ODであり、純度は72.5%であった。OD260の値から、1μmolあたりの収量は9702μg/μmolと算出された。結果を表4に示す。
同様にTBMアミダイトUを用いてウリジン50量体(分子量15246.53)を合成した結果、1.074μmolあたりのOD260は249.74ODであり、純度は66.2%であった。OD260の値から、1μmolあたりの収量は9301μg/μmolと算出された。結果を表4に示す。
一方、参考製造例で得られたPMM2アミダイトUを使用して、同様に固相合成を行い、ウリジン50量体を製造した結果、0.406μmolあたりのOD260は100.81ODであり、純度は50.4%であった。OD260の値から、1μmolあたりの収量は9932μg/μmolと算出された。結果を表4に示す。
特許第5554881号公報実施例2に記載されているウリジンEMMアミダイトを用いてウリジン50量体(分子量15246.53)を合成した結果、1.028μmolあたりのOD260は245.91ODであり、純度は55.8%であった。OD260の値から、1μmolあたりの収量は9568μg/μmolと算出された。結果を表4に示す。
核酸塩基部分がアデニンであるPMMアミダイトAの合成中間体PMM A−1の製造方法を以下に示す。
実施例4の方法において、溶媒として、4−メチルテトラヒドロピランの代わりに同量のテトラヒドロフラン(THF)を用いる以外は、同様の方法で反応させ、PMM A−1を得た。結果を表5に示す。
実施例4の方法において、溶媒として、4−メチルテトラヒドロピランの代わりに同量のジオキサンを用い、攪拌時間を3.5時間とする以外は、同様の方法で反応させ、PMM A−1を得た。結果を表5に示す。
以上の表5に示すように、合成中間体の製造収量の良好な結果を得ることができる。
配列(A):5’−AGCAGAGUACACACAGCAUAUACC-P-GGUAUAUGCUGUGUGUACUCUGCUUC-P-G−3’(配列番号2,3) 53mer
前記配列(A)において、Pは、以下の化学式において波線で区切られる部分構造で示される。
AGCAGAGUAC ACACAGCAUA UACC(配列番号2)
GGUAUAUGCU GUGUGUACUC UGCUUC(配列番号3)
前記粗生成物のOD260を測定した。OD260とは1mL溶液(pH=7.5)における10mm光路長あたりのUV260nmの吸光度を表す。一般的にRNAでは1OD=40μgであることが知られていることから、前記OD260の測定値に基づき、収量を算出した。実施例7及び比較例3については実施例7の収量に対する1μmolあたりの相対収量を求め、その結果を表6に示した。
上記PMMアミダイトU、PMMアミダイトC、PMMアミダイトA、PMMアミダイトGおよびWO2017/188042に記載の化合物(3)を使用し、上記配列(A)からなるオリゴヌクレオチドを合成した結果、純度は60.8%であった。純度と1μmolあたりの相対収量の結果を表6に示す。
US2012/0035246の実施例2に記載のEMMアミダイトU、実施例3に記載のEMMアミダイトC、実施例4に記載のEMMアミダイトA、実施例5に記載のEMMアミダイトGおよびWO2017/188042に記載の化合物(3)を使用し、上記配列(A)からなるオリゴヌクレオチドを合成した結果、純度は53.0%であった。純度と1μmolあたりの相対収量の結果を表6に示す。
配列表の配列番号2,3は、核酸の製造例2で製造した配列を構成するオリゴヌクレオチドの塩基配列を表す。
Claims (24)
- Raがメチル基またはエチル基であり、Rbが水素原子である、請求項1に記載のアミダイト化合物。
- G3がイソプロピル基である、請求項1〜4のいずれか一項に記載のアミダイト化合物。
- 式(2)のポリヌクレオチド骨格を含有する化合物が、前記アミダイト化合物を用いる固相合成反応で生成する式(3):
Xは酸素原子又は硫黄原子を表し、
Rは同一又は相異なって、式:
nは1〜5の整数を表す。)を表し、
mは正の整数を表す。)
で示されるオリゴヌクレオチド骨格を有する化合物にテトラアルキルアンモニウムフルオライドを反応させる工程で生成した化合物である、請求項6に記載の製造方法。 - Raがメチル基またはエチル基であり、Rbが水素原子である、請求項7に記載の製造方法。
- n=1である、請求項6〜8のいずれか一項に記載の製造方法。
- Raがメチル基またはエチル基であり、Rbが水素原子であり、Rcがメチルである、項10に記載のエーテル化合物。
- n=1である、請求項10または11に記載の化合物。
- Raがメチル基またはエチル基であり、Rbが水素原子である、請求項13に記載の製造方法。
- Raがメチル基であり、Rbが水素原子である、請求項13に記載の製造方法。
- 反応溶媒として、テトラヒドロピランまたは4−メチルテトラヒドロピランを用いる、請求項17に記載の製造方法。
- 前記式(1)のアミダイト化合物のRNAの製造における使用。
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