CN117510562B - Synthesis method of medical intermediate 2' -O-propynyl-uridine - Google Patents
Synthesis method of medical intermediate 2' -O-propynyl-uridine Download PDFInfo
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- CN117510562B CN117510562B CN202410023958.6A CN202410023958A CN117510562B CN 117510562 B CN117510562 B CN 117510562B CN 202410023958 A CN202410023958 A CN 202410023958A CN 117510562 B CN117510562 B CN 117510562B
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- CN
- China
- Prior art keywords
- uridine
- propynyl
- reaction
- propynyloxy
- silane
- Prior art date
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- -1 2' -O-propynyl-uridine Chemical compound 0.000 title claims abstract description 49
- 238000001308 synthesis method Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000002829 reductive effect Effects 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 13
- 238000000746 purification Methods 0.000 claims abstract description 10
- VNWSRGIEWIGHJI-UHFFFAOYSA-N prop-1-ynoxysilane Chemical compound CC#CO[SiH3] VNWSRGIEWIGHJI-UHFFFAOYSA-N 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- ZYDKYFIXEYSNPO-UHFFFAOYSA-N tert-butyl-dimethyl-prop-2-ynoxysilane Chemical group CC(C)(C)[Si](C)(C)OCC#C ZYDKYFIXEYSNPO-UHFFFAOYSA-N 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- QCPXVCYHAUXYFF-UHFFFAOYSA-N trimethyl(prop-1-ynoxy)silane Chemical compound CC#CO[Si](C)(C)C QCPXVCYHAUXYFF-UHFFFAOYSA-N 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000011261 inert gas Substances 0.000 claims description 6
- 239000000543 intermediate Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052754 neon Inorganic materials 0.000 claims description 2
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 239000000758 substrate Substances 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 29
- UUGITDASWNOAGG-CCXZUQQUSA-N cyclouridine Chemical compound O=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 UUGITDASWNOAGG-CCXZUQQUSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 11
- 230000006872 improvement Effects 0.000 description 10
- 239000007787 solid Substances 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 8
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 8
- 229940045145 uridine Drugs 0.000 description 8
- 108091034117 Oligonucleotide Proteins 0.000 description 7
- 108020004459 Small interfering RNA Proteins 0.000 description 7
- 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 7
- 230000000052 comparative effect Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 229910015900 BF3 Inorganic materials 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 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 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
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- 230000015556 catabolic process Effects 0.000 description 2
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- 125000003636 chemical group Chemical group 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
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- 230000009368 gene silencing by RNA Effects 0.000 description 2
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- 150000002500 ions Chemical class 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- TURAMGVWNUTQKH-UHFFFAOYSA-N propa-1,2-dien-1-one Chemical group C=C=C=O TURAMGVWNUTQKH-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 108020004394 Complementary RNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
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- 102000004190 Enzymes Human genes 0.000 description 1
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- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
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- 229910052796 boron Inorganic materials 0.000 description 1
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- 238000009924 canning Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
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- 238000001415 gene therapy Methods 0.000 description 1
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- 108700008776 hepatitis C virus NS-5 Proteins 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
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- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 description 1
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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
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The application relates to a method for synthesizing a medical intermediate 2' -O-propynyl-uridine, which adopts 2,2' -dehydrated uridine as a substrate and converts the substrate into 2' -O-propynyl-uridine through the participation of other components such as propynyloxy silane and the like in a reaction. In the synthetic technical route of the application, isomers can not be generated, the purification time is shortened, the cost is reduced, and the synthesis process does not involve controlled reagents, thereby being beneficial to industrialized production.
Description
Technical Field
The invention belongs to the technical field of nucleotide synthesis, and particularly relates to a synthesis method of a medicine intermediate 2' -O-propynyl-uridine.
Background
Oligonucleotides have broad application prospects in cancer treatment and genetics, such as: an oligonucleotide is a short single stranded DNA or RNA, typically consisting of several to tens of nucleotides. They can bind to complementary DNA or RNA sequences to form stable double stranded structures, and in particular, oligonucleotides can cross-link to internal or terminal positions of DNA or RNA within a cell, which cross-link can prevent replication of the cell. Thus, the oligonucleotide can be used as a specific drug that binds to DNA or RNA of cancer cells, preventing the replication of cancer cells, and thus killing cancer cells. This method of treatment is called gene-targeted therapy because it is directed to specific gene mutations, not to all healthy or diseased cells.
In genetics, oligonucleotides are used as probes for studying the structure and function of DNA and RNA. They can also be used for gene therapy, i.e. for the treatment of genetic diseases by modification of DNA or RNA sequences. In this process, the oligonucleotides may be designed to bind to abnormal gene sequences, thereby preventing the expression of the deleterious genes.
RNAi is a common gene expression control mechanism in organisms that can inhibit the expression of a specific gene by degrading the target RNA. During RNAi, double-stranded RNA (dsRNA) is a key effector molecule that can be cleaved by the intracellular RNaseIII enzyme into small fragments, which are called siRNAs (small interfering RNAs). The siRNA can bind to the target RNA, resulting in degradation of the target RNA, thereby inhibiting expression of a particular gene.
The 2' position is an important modification site during the synthesis of siRNA. At this position, the physicochemical properties and functions of the siRNA can be altered by the addition of chemical groups (e.g., methyl, ethyl, etc.). These modifications can increase the stability and specificity of the siRNA, allowing it to bind more efficiently to the target RNA, thereby more effectively inhibiting expression of a particular gene. Wherein: sugar-modified oligonucleotides are very important substances that alter the physicochemical properties and functions of siRNA, such as: the sugar-modified oligonucleotide can activate a subsequence of the 2' -deoxy-erythro-pentofuranosyl nucleoside of RNaseH, thereby promoting degradation of the target nucleic acid.
Thus, it is important to synthesize sugar-modified oligonucleotides, 2' -O-propynyl being an organic chemical group, typically bound to the sugar moiety of the nucleotide, the presence of which can alter the chemical nature and biological activity of the nucleotide. 2 '-O-propynyl-uridine is also an intermediate for synthesizing sugar-modified oligonucleotides as a pharmaceutical intermediate containing 2' -O-propynyl, and its synthesis has received much attention.
Disclosure of Invention
In order to solve the problems, the application provides a new idea for synthesizing a medicine intermediate 2' -O-propynyl-uridine.
In order to achieve the above object, the present application is realized by the following scheme:
the application provides a method for synthesizing a medicine intermediate 2' -O-propynyl-uridine, which comprises the following steps:
Adding 2,2 '-dehydrated uridine into a reaction vessel at the temperature of minus 5 ℃ to 5 ℃, continuously introducing inert gas into the reaction vessel, continuously adding an organic solvent and propynyloxy silane into the reaction vessel under the protection of the inert gas, fully stirring for reaction, slowly dropwise adding boron trifluoride diethyl ether into the reaction vessel at the temperature of minus 5 ℃ to 5 ℃, fully stirring at the temperature of minus 5 ℃ to 5 ℃, heating the reaction vessel to 115 ℃ to 125 ℃, stirring for reaction at the temperature of 115 ℃ to 125 ℃, and sequentially carrying out reduced pressure concentration, column chromatography purification and reduced pressure concentration after the reaction is completed, thereby obtaining 2' -O-propynyl-uridine.
As a further improvement of the present application, the inert gas may be, but is not limited to, any one of nitrogen, neon, helium, argon, and the like.
As a further improvement of the present application, the propynyloxy silane is t-butyldimethyl (2-propynyloxy) silane or propynyloxy trimethylsilane.
As a further improvement of the application, the molar ratio of the 2,2' -anhydrouridine to the tert-butyldimethyl (2-propynyloxy) silane is 1:4-1:6; the molar ratio of the 2,2' -dehydrated uridine to the propynyloxy trimethylsilane is 1:4-1:6.
As a further improvement of the present application, the molar volume ratio of the 2,2' -anhydrouridine to the organic solvent ranges from 0.5mol/L to 1.5mol/L.
As a further improvement of the present application, the organic solvent is any one of N, N-dimethylacetamide and dimethylsulfoxide.
As a further improvement of the application, the molar ratio of the boron trifluoride diethyl etherate to the 2,2' -anhydrouridine is 1:2-1:3.
As a further improvement of the application, the eluent applied to the column chromatography purification is a mixed solution of dichloromethane and methanol, and the mixed solution also contains triethylamine with the volume percent of 5 percent.
As a further improvement of the application, in the mixed solution, the volume ratio of the dichloromethane to the methanol is 10:1-20:1.
As a further improvement of the application, the reaction progress is controlled by HPLC under the temperature condition of 115-125 ℃.
As a further improvement of the application, the time of the fully stirred reaction at the temperature of minus 5 ℃ to 5 ℃ is a first preset time period, and the first preset time period can be set according to the addition amount of 2,2' -anhydrouridine, propynyloxy silane and boron trifluoride diethyl ether, and can be, but not limited to, 5min to 1h, and can be, but not limited to, 10min, 20min, 30min, 50min, 1h and the like; the time for fully stirring the mixture at the temperature of 115-125 ℃ is a second preset time period, and the second preset time period can be set according to the addition amount of 2,2' -anhydrouridine, propynyloxy silane and boron trifluoride diethyl ether, and can be 1-10 h, specifically but not limited to 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h and the like.
The application has the beneficial effects that the technical route for synthesizing the 2' -O-propynyl-uridine has the following advantages:
1) Avoiding the generation of isomers and improving the purity and quality of the product.
2) The purification steps are reduced, the production cost is reduced, and the production efficiency is improved.
3) And in the synthesis process, no control reagent is used, so that the method is beneficial to industrial production and application.
4) The whole process is reasonable in design, suitable for large-scale production, and high in practicality and economy.
5) Reduces the energy consumption and the environmental pollution, and meets the requirement of sustainable development.
In conclusion, the synthetic technology route of the application has excellent economic benefit and industrial application prospect, and has positive promotion effect on the development of the related fields.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 2' -O-propynyl-uridine prepared in example 1;
FIG. 2 is an HPLC chart of 2' -O-propynyl-uridine prepared in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions of the present application will be clearly and completely described below with reference to specific embodiments of the present application and the accompanying drawings. It should be apparent that the described embodiments are only some embodiments of the present application and not all embodiments are not intended to limit the scope of the present application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
In order to solve the technical problems, the application provides a new idea for synthesizing 2' -O-propynyl-uridine, which has the following technical scheme:
The specific synthesis steps of 2' -O-propynyl-uridine are as follows:
Adding 0.442-0.446 mol (100-101 g) of 2,2' -dehydrated uridine (compound 6) into a reaction vessel at the temperature of minus 5 ℃ to 5 ℃ under the protection of nitrogen, sequentially adding 400-450 ml of N, N-Dimethylacetamide (DMAC), 2.20-2.23 mol (375-380 g) of tert-butyldimethyl (2-propynyloxy) silane (compound 7) or 2.20-2.23 mol (382-387 g) of propynyloxy trimethyl silane (compound 7) into the reaction vessel under the protection of nitrogen, fully stirring and reacting, then sucking 1.102-1.11 mol (156.5-157.5 g) of boron trifluoride diethyl ether (compound 8) by a 50ml registry at the temperature of minus 5 ℃ to 5 ℃, dropwise adding boron trifluoride diethyl ether which is a boron trifluoride diethyl ether complex into the reaction vessel, stirring the boron trifluoride diethyl ether for 2-4 h at the temperature of minus 5 ℃ to 15 ℃ to 125 ℃ for 125-115 minutes, and stirring and reacting for 16-115 h at the temperature of minus 15 ℃ to 115 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, purified by column chromatography and concentrated under reduced pressure to give 0.36mol (101.7 g) of 2 '-O-propynyl-uridine (compound 9) as a white solid product in a yield of 81.5% based on t-butyldimethyl (2-propynyloxy) silane or 0.33mol (93.8 g) of 2' -O-propynyl-uridine (compound 9) as a white solid product in a yield of 75.2% based on propynyloxy trimethylsilane. Wherein: in the process of column chromatography purification, the eluent is a mixed solution of dichloromethane and methanol, the mixed solution also contains 5% of triethylamine, the eluent can be added at one time or can be added for a plurality of times for washing in the process of elution, and the volume ratio of the dichloromethane to the methanol is reduced in gradient according to the addition sequence, for example: the volume ratio of dichloromethane to methanol can be reduced in a gradient way from 20:1 to 10:1, and the specific steps are as follows: if three eluents are adopted, the volume ratio of the methylene dichloride to the methanol is 20:1 for the first time, the volume ratio of the methylene dichloride to the methanol is 15:1 for the second time, and the volume ratio of the methylene dichloride to the methanol is 10:1 for the third time.
Wherein: the main reaction mechanism of compounds 6 to 9 is the following formula i:
Formula I.
Under the action of Lewis acid BF3, the carbon at the 2 'position is in an electron-deficient state, so that the compound 6 reacts with an oxygen atom of alkyl (2-propynyloxy) silane to generate S N2, and a steric hindrance effect is beneficial to generating a steric structure with a hydroxyl at the 3' position. The reaction was then quenched with methanol to give compound 9. In the reaction of the second step: 2,2' -anhydrouridine is used as a source for providing uridine moieties; the boron trifluoride part in the boron trifluoride diethyl etherate provides Lewis acid catalytic activity, and the diethyl etherate has the function of complexing the lone pair electron of ether linkage oxygen with electron-deficient boron of the boron trifluoride, so that the boron trifluoride is more stable and is favorable for canning and transportation as a commodity; n, N-dimethylacetamide provides a suitable solvent environment that allows the substrate and catalyst to interact effectively; the oxygen of propynyloxy has a pair of lone electrons, has higher reactivity, and reacts with SN2 of carbon atom in electron-deficient state at the 2' position in substrate molecule, thereby forming new chemical bond. The feeding process is easy to instantaneously release heat, so that the reaction system becomes mixed, and the temperature of-5 ℃ to 5 ℃ is set in the feeding and uniformly mixing process, so that the stability of the reaction system is maintained, and the occurrence of side reactions is controlled. The temperature of 115-125 ℃ is set to promote the reaction, break the initial combination of 2,2' -anhydrouridine and propynyloxy, and require a certain amount of energy which can be supplied by high temperature to further make them more susceptible to reaction with other molecules or groups. In addition, the high temperature may also help to increase the fluidity of the system, enabling better mixing and contacting of the substrate and reagents, thereby facilitating the progress of the reaction.
The technical route for synthesizing the 2' -O-propynyl-uridine is shown as the following formula II:
Formula II.
The 2,2' -anhydrouridine (compound 6) in the above technical scheme can be purchased from the market, and can also be prepared by the following steps:
410-414.1 mmol (100-101 g) of uridine (compound 11) is dissolved in 400-450 mL of N, N-dimethylformamide, after the uridine (compound 11) is fully dissolved, 447.2-451.9 mmol (96-97 g) of diphenyl carbonate (compound 12) and 7.82-8.42 mmol (0.65-0.7 g) of sodium bicarbonate are added, the mixture is heated to 115-125 ℃ for reaction for 8-10 hours, the reaction progress of the experiment is controlled by HPLC, after the reaction is completed, the temperature of the reaction is reduced to 20-30 ℃, and solids are separated out and filtered, thus obtaining a solid filter cake. 400-500 mL of methanol and the solid filter cake are mixed together at 20-30 ℃, stirred for 2-3 hours, and filtered again to sufficiently remove impurities and ions in the filter cake, thereby obtaining 88.2g of white powdery product (compound 6) with a yield of 95.2%.
The main reaction mechanism of compounds 11 to 6 is the following reaction mechanism formula iii:
Formula III.
After the basic sodium bicarbonate neutralizes the hydrogen ions on the nitrogen in compound 11, the electrons of compound 11 migrate to the carbonyl oxygen, then the oxygen with the negative nucleus attacks the carbon at the 2' position, then the electrons migrate to the hydroxyl oxygen at the 2' position, dehydroxylation becomes 2,2' -anhydrouridine (compound 6), and the dehydroxylated hydroxyl attacks the carbonyl of diphenyl carbonate (compound 12), which breaks down into phenol and monophenyl carbonate anions. In the reaction of the first step: uridine serves as a substrate for the reaction, providing the structure of the uridine moiety; sodium bicarbonate is used as an acid binding agent to help maintain a proper pH value so as to promote the reaction; diphenyl carbonate is used as a dehydrating agent and can react with the removed hydroxyl, so that the reaction is promoted; n, N-dimethylformamide is used as a solvent to help maintain the substrate and catalyst in a dissolved state to promote the reaction. The temperature of 115-125 ℃ is set to promote the reaction, break the initial bond of uridine, diphenyl carbonate and the like, and a certain amount of energy is required, and the energy can be provided at a high temperature. In addition, the high temperature may also help to increase the fluidity of the system, enabling better mixing and contacting of the substrate and reagents, thereby facilitating the progress of the reaction.
The technical route of the above compounds 11 to 6 is as follows formula IV:
formula IV.
To verify that the technical scheme of the present application has excellent effects, the following examples and comparative examples are also provided.
Example 1
The specific synthesis steps of 2' -O-propynyl-uridine are as follows:
0.442mol (100 g) of 2,2' -anhydrouridine (compound 6) was added to a reaction vessel at 0℃under nitrogen protection, 400ml of N, N-Dimethylacetamide (DMAC), 2.21mol (377 g) of t-butyldimethyl (2-propynyloxy) silane (compound 7) or 2.21mol (384 g) of propynyloxy trimethyl silane (compound 7) were sequentially added to the reaction vessel under nitrogen protection, the reaction vessel was stirred sufficiently, 1.105mol (156.9 g) of boron trifluoride diethyl ether (compound 8) was then sucked up with a 50ml register at 0℃and dropwise added thereto, the boron trifluoride diethyl ether here means boron trifluoride diethyl ether complex, the mass percentage of boron trifluoride was 47%, the time of dropwise addition was 3 hours, and after completion of dropwise addition, the reaction vessel was stirred at 0℃for 25 minutes, and then stirred at 120℃for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, purified by column chromatography and concentrated under reduced pressure to give 0.36mol (101.7 g) of 2 '-O-propynyl-uridine (compound 9) as a white solid product in a yield of 81.5% based on t-butyldimethyl (2-propynyloxy) silane or 0.33mol (93.8 g) of 2' -O-propynyl-uridine (compound 9) as a white solid product in a yield of 75.2% based on propynyloxy trimethylsilane. Wherein: in the column chromatography purification process, the eluent is a mixed solution of dichloromethane and methanol, the mixed solution also contains 5% of triethylamine, the elution process adopts a mode of three eluents, the volume ratio of the dichloromethane to the methanol is 20:1 in the first time, the volume ratio of the dichloromethane to the methanol is 15:1 in the second time, and the volume ratio of the dichloromethane to the methanol is 10:1 in the third time.
The spectrum of 1H NMR analysis for 2' -O-propynyl-uridine (Compound 9) prepared in the present example is shown in FIG. 1, and is specifically as follows:
1H NMR (400 MHz, DMSO-d6): 11.34 (s, 1H), 7.91-7.93 (d, 2H), 5.87-5.88 (m, 1H), 5.64-5.67 (m, 1H), 5.23-5.24 (d, 1H), 5.15-5.17 (t, 1H), 4.20-4.33 (m, 2H), 4.08-4.15 (m, 2H), 3.86-3.89 (q, 1H), 3.53-3.66 (m, 2H), 3.42-3.43 (t, 1H).
the HPLC purity analysis spectrum of the 2' -O-propynyl-uridine prepared in the present example is shown in FIG. 2, and the HPLC purity is more than 95%.
Example 2
This example differs from example 1 in that 2,2 '-anhydrouridine (compound 6) of example 1 is purchased commercially, and 2,2' -anhydrouridine (compound 6) is prepared by the following steps:
410mmol (100 g) of uridine (compound 11) was dissolved in 400mL of N, N-dimethylformamide, after complete dissolution, 450mmol (96.6 g) of diphenyl carbonate (compound 12) and 8.18mmol (0.68 g) of sodium hydrogencarbonate were added, heated to 120℃and reacted for 9 hours, the progress of the above-mentioned experiment was controlled by HPLC, after completion of the reaction, the temperature of the above-mentioned reaction was lowered to 25℃and solids were precipitated and filtered to obtain a solid cake. 450mL of methanol and the above solid cake were mixed together at 25℃and stirred for 2.5 hours, and filtered again to sufficiently remove impurities and ions in the cake, to give 88.2g of a white powdery product (Compound 6) in a yield of 95.2%.
The yield of 2 '-O-propynyl-uridine (compound 9) prepared using 2,2' -anhydrouridine (compound 6) of the present example was 80%.
The sources of part of the raw materials used in examples 1 and 2 above were as follows: the 2,2' -dehydrated uridine was selected from the products of Ikkan biological medicine development Co., ltd, lot number of MPC42-1569533-2, N, N-dimethylacetamide was selected from the products of Shanghai Teitatan technology Co., ltd, t-butyldimethyl (2-propynyloxy) silane was selected from the products of Ikkan biological medicine development Co., ltd, lot number of AZF23-1159477-1, propynyloxy trimethylsilane was selected from the products of Ikkan Tekkan technology Co., ltd, lot number of RDR OWEE, boron trifluoride diethyl ether was selected from the products of Ikkan technology Co., ltd, lot number of OFPQR XE, methylene chloride was selected from the products of No. 20230308, methyl chloride was selected from the products of No. lake chemical Co., ltd, white place of Ikkan chemical Co., ltd was selected from the products of AZF23-1159477-1, and sodium bicarbonate was selected from the products of Ikkan chemical Co., ltd, sodium bicarbonate was selected from the products of No. 3790, and sodium bicarbonate was selected from the products of Ukkan chemical Co., ltd, and sodium bicarbonate was selected from the products of No. 2637042.
Comparative example 1
In order to demonstrate that the technical scheme of the present application has excellent technical effects, the preparation method reported in technical scheme reference (Concise syntheses and HCV NS5B polymerase inhibition of (2'R)-3 and (2'S)-2'-ethynyluridine-10 and related nucleosides,Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5349 – 5352; or ;A Click Chemistry Approach to Pleuromutilin Conjugates with Nucleosides or Acyclic Nucleoside Derivatives and Their Binding to the Bacterial Ribosome,Journal of Medicinal Chemistry, 2008, vol. 51, # 16, p. 4957 - 4967) for preparing 2' -O-propynyl-uridine adopted in the prior art is provided as follows formula v:
Formula V.
As is clear from the technical route, the raw material adopted in the comparative example 1 is uridine, and the added auxiliary materials comprise 1, 3-dichloro-1, 3-tetraisopropyl disiloxane, bromopropyne, tetrabutylammonium fluoride and the like, and the final yield is 27.6%.
Comparative example 2
In order to prove that the technical scheme of the application has excellent technical effects, the technical scheme adopted in the prior art for preparing the 2' -O-propynyl-uridine comprises the following steps:
Step one: to 4L of methanol were added 0.409mol (100 g) of uridine (compound 1) and 0.409mol (101.93 g) of dibutyltin oxide (compound 4), heated under reflux overnight, concentrated under reduced pressure, and dried at room temperature under high vacuum overnight to give compound 5 (184.6 g, yield 95%) as a white solid.
Step two: 32.6mmol (15.5 g) of 2',3' -0- (dibutyltin base) uridine (compound 5) in the first step was added to 200mL of N, N-Dimethylformamide (DMF), and further 5.8 mL (65.2 mmol) of bromopropyne was added, and the reaction was stirred at 100℃for 6 hours, after completion of the reaction, concentrated under reduced pressure, and purified by column chromatography to give a mixed solid of 2 '-O-propynyl-uridine (compound 9) and 3' -O-propynyl-uridine (compound 10), wherein: the mass of 2' -O-propynyl-uridine was 5.7g, which was about 60% of the mixed solids, i.e., the yield was 60%. The eluent used in the column chromatography purification process is a mixed solvent of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 7:1.
The technical route for synthesizing 2' -O-propynyl-uridine of the present comparative example 2 is shown in the following formula VI:
And the formula VI.
In summary, the existing technical route for synthesizing 2' -O-propynyl-uridine comprises the following steps: 1) The synthetic technology route in comparative example 1 is long, three steps of reaction are needed, the reaction process is complex, and the yield is low; 2) The comparative example 2 contains dibutyl tin oxide (compound 4), which is a highly toxic drug, belongs to a controlled reagent, is unfavorable for industrialization, and has lower synthesis yield because 3' -O-propynyl-uridine isomer can be produced in the synthesis process. Therefore, the application provides a new idea for synthesizing 2' -O-propynyl-uridine, which adopts 2,2' -dehydrated uridine as a substrate and synthesizes 2' -O-propynyl-uridine through a series of reactions, thereby avoiding the generation of isomers, reducing the difficulty of the purification process and lowering the cost.
Although the present disclosure describes embodiments, not every embodiment is described in terms of a single embodiment, and such description is for clarity only, and one skilled in the art will recognize that the embodiments may be combined in any suitable manner to form other embodiments that will be apparent to those skilled in the art.
The above list of detailed descriptions is only specific to practical embodiments of the present invention, and they are not intended to limit the scope of the present invention, and all equivalent embodiments or modifications that do not depart from the spirit of the present invention should be included in the scope of the present invention.
Claims (4)
1. The synthesis method of the medical intermediate 2' -O-propynyl-uridine is characterized by comprising the following steps of:
Adding 2,2 '-dehydrated uridine into a reaction vessel at the temperature of minus 5 ℃ to 5 ℃, continuously introducing inert gas into the reaction vessel, continuously adding an organic solvent and propynyloxy silane into the reaction vessel under the protection of the inert gas in sequence, fully stirring for reaction, slowly dropwise adding boron trifluoride diethyl ether into the reaction vessel at the temperature of minus 5 ℃ to 5 ℃, fully stirring at the temperature of minus 5 ℃ to 5 ℃, heating the reaction vessel to 115 ℃ to 125 ℃, stirring for reaction at the temperature of 115 ℃ to 125 ℃, and sequentially carrying out reduced pressure concentration, column chromatography purification and reduced pressure concentration after the reaction is completed to obtain 2' -O-propynyl-uridine, wherein the propynyloxy silane is tert-butyldimethyl (2-propynyloxy) silane or propynyloxy trimethyl silane;
the molar ratio of the 2,2 '-dehydrated uridine to the tert-butyldimethyl (2-propynyloxy) silane is 1:4-1:6, or the molar ratio of the 2,2' -dehydrated uridine to the propynyloxy trimethyl silane is 1:4-1:6;
The molar volume ratio of the 2,2' -dehydrated uridine to the organic solvent ranges from 0.5mol/L to 1.5mol/L;
the organic solvent is any one of N, N-dimethylacetamide and dimethyl sulfoxide;
The molar ratio of the boron trifluoride diethyl etherate to the 2,2' -dehydrated uridine is 1:2-1:3.
2. The method for synthesizing 2' -O-propynyl-uridine as defined in claim 1, wherein the eluent used for the column chromatography purification is a mixed solution of dichloromethane and methanol, and the mixed solution further contains triethylamine with a volume percentage of 5%.
3. The method for synthesizing 2' -O-propynyl-uridine, which is a pharmaceutical intermediate according to claim 1, wherein the inert gas is any one of nitrogen, neon, helium and argon.
4. The method for synthesizing 2' -O-propynyl-uridine, which is a pharmaceutical intermediate according to claim 1, wherein the reaction progress is controlled by HPLC at a temperature of 115℃to 125 ℃.
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Non-Patent Citations (4)
Title |
---|
Martin Egli等.Probing the Influence of Stereoelectronic Effects on the Biophysical Properties of Oligonucleotides: Comprehensive Analysis of the RNA Affinity, Nuclease Resistance, and Crystal Structure of Ten 2’-O-Ribonucleic Acid Modifications.《Biochemistry》.2005,第44卷(第25期),全文. * |
Martin Egli等.Probing the Influence of Stereoelectronic Effects on the Biophysical Properties of Oligonucleotides: Comprehensive Analysis of the RNA Affinity, Nuclease Resistance, and Crystal Structure of Ten 2’-O-Ribonucleic Acid Modifications.《Biochemistry》.2015,第44卷全文. * |
Prediction of the stability of modified RNA duplexes based on deformability analysis: Oligoribonucleotide derivatives modified with 2 ́-O-cyanoethyl-5-propynyl-2-thiouridine as a promising component;Yoshiaki Masaki,等,;《Chemical Communication》;20120607;第48卷(第58期);全文 * |
Probing the Influence of Stereoelectronic Effects on the Biophysical Properties of Oligonucleotides: Comprehensive Analysis of the RNA Affinity, Nuclease Resistance, and Crystal Structure of Ten 2’-O-Ribonucleic Acid Modifications;Martin Egli等;《Biochemistry》;20150406;第44卷;全文 * |
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