CN114478670B - Method for synthesizing On-DNA beta substituted ketone compound - Google Patents
Method for synthesizing On-DNA beta substituted ketone compound Download PDFInfo
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- CN114478670B CN114478670B CN202011151383.4A CN202011151383A CN114478670B CN 114478670 B CN114478670 B CN 114478670B CN 202011151383 A CN202011151383 A CN 202011151383A CN 114478670 B CN114478670 B CN 114478670B
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- -1 ketone compound Chemical class 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 29
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 19
- 239000004327 boric acid Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007853 buffer solution Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 239000002773 nucleotide Substances 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 230000000379 polymerizing effect Effects 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 22
- 229910052763 palladium Inorganic materials 0.000 abstract description 10
- 125000003118 aryl group Chemical group 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 108020004414 DNA Proteins 0.000 description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 150000002611 lead compounds Chemical class 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000012917 library technology Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 125000005493 quinolyl group Chemical group 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 125000005017 substituted alkenyl group Chemical group 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 2
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940116901 diethyldithiocarbamate Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229950004394 ditiocarb Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical class C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical group [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- 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
Abstract
The invention relates to a method for synthesizing On-DNA beta substituted ketone compound, which takes On-DNA alpha, beta unsaturated carbonyl compound as raw material, reacts with aromatic boric acid or alkenyl boric acid compound in the presence of palladium catalyst and alkali to obtain On-DNA beta substituted ketone compound. The method can be carried out in a mixed water phase of an organic solvent/water phase, has simple post-treatment and mild conditions, can obtain a DNA coding compound library with high diversity in a short time and high yield, and is suitable for synthesizing the DNA coding compound by a porous plate.
Description
Technical Field
The invention belongs to the technical field of coding compound libraries, and particularly relates to a method for constructing On-DNA beta substituted ketone compounds in a DNA coding compound library.
Background
In drug development, especially new drug development, high throughput screening against biological targets is one of the main means to rapidly obtain lead compounds. However, conventional high throughput screening based on single molecules requires long time, huge equipment investment, limited numbers of library compounds (millions), and the build-up of compound libraries requires decades of accumulation, limiting the efficiency and possibilities of discovery of lead compounds. The recent advent of DNA-encoded compound library technology (WO 2005058479, WO2018166532, CN 103882532), combining combinatorial chemistry and molecular biology techniques, tagged each compound with a DNA tag at the molecular level, and capable of synthesizing up to hundred million classes of compound libraries in extremely short time, has become a trend for the next generation of compound library screening technology, and began to be widely used in the pharmaceutical industry, producing a number of positive effects (Accounts of Chemical Research,2014,47,1247-1255).
The DNA encoding compound library rapidly generates a huge compound library by combinatorial chemistry, and can screen the lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapid and efficient. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize small molecules with chemical diversity on DNA in high yields. Since DNA needs to be stable under certain conditions (solvent, pH, temperature, ion concentration), higher yields are also required for the On-DNA reaction constructed from DNA encoding compound libraries. Therefore, the kind of the reagent, the kind of the reaction and the reaction condition of the chemical reaction (called On-DNA reaction for short) performed On the DNA directly influence the richness and the selectivity of the DNA coding compound library. Thus, the development of chemical reactions compatible with DNA is also a long-term research and study direction of the current DNA coding compound library technology, and directly influences the application and commercial value of the DNA coding compound library.
Alpha, beta unsaturated carbonyl compound and boric acid compound form sp at beta position of carbonyl by conjugated addition 2 The hybridized carbon atom connecting site can enrich the topological structure of the drug compound, and introducing the beta-substituted ketone compound into the DNA coding compound library can further expand the diversity of the compound library, thereby being beneficial to improving the probability of screening effective compounds. However, no method for synthesizing On-DNA beta-substituted ketones by On-DNA alpha, beta-unsaturated carbonyl compounds has been reported. Therefore, it is hoped to develop a new synthesis method of On-DNA beta-substituted ketone compounds suitable for large-scale porous plate operation, so as to increase the diversity of DNA coding compound library and further improve the application value of DNA coding compound library technology.
Disclosure of Invention
In order to solve the problems, a synthetic method of a DNA coding compound library, which has the advantages of stable storage of raw materials, mild reaction conditions, good substrate universality, small damage to DNA and suitability for batch operation by using porous plates, is developed, and can quickly convert On-DNA alpha, beta-unsaturated carbonyl compounds into On-DNA beta substituted ketone compounds through one-step reaction.
The technical scheme adopted by the invention is as follows:
a method for synthesizing On-DNA beta substituted ketone compounds comprises the following steps: the method takes On-DNA alpha, beta unsaturated carbonyl compounds as raw materials, and reacts with boric acid compounds in the presence of palladium catalysts and alkali to obtain On-DNA beta substituted ketone compounds; wherein the structural formula of the On-DNA alpha, beta unsaturated carbonyl compound isThe structural formula of the boric acid compound is as follows: />The structural formula of the On-DNA beta substituted ketone compound is as follows: />
Wherein the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing an artificially modified and/or unmodified nucleotide monomer, and the nucleotide chain is connected with the rest of the compound through one or more chemical bonds or groups; the length of the DNA is 10-200 bp.
Wherein, the DNA in the structural formula and R 1 Or R is 3 Connected by a chemical bond or bonds. In the case of one chemical bond, it means DNA and R in the structural formula 1 Or R is 3 Directly connected; in the case of multiple chemical bonds, the terms DNA and R in the structural formula 1 Or R is 3 With multiple chemical bonds spaced apart, e.g. DNA and R 1 Or R is 3 Through a methylene group (-CH) 2 (-) are connected, namely through two chemical bonds; or DNA and R 1 Or R is 3 The amino group of DNA is connected with the carbonyl group (-CO-) through two chemical bonds; or DNA and R 1 Or R is 3 Through a methylene carbonyl (-CH) 2 CO-) is linked to the amino group of the DNA, also via three consecutive chemical bonds.
R 1 Selected from the group consisting ofA group having a molecular weight of 1000 or less directly attached to the DNA and carbonyl carbon atom or is absent;
R 2 a group selected from the group consisting of those having a molecular weight of 1000 or less and being directly attached to an alkenyl carbon atom;
R 3 selected from the group having a molecular weight of 1000 or less and being directly linked to DNA and an alkenyl carbon atom or being absent;
R 4 a group selected from the group consisting of those having a molecular weight of 1000 or less and being directly bonded to a carbonyl carbon atom;
R 5 selected from hydrogen or a group having a molecular weight of 1000 or less directly attached to an alkenyl carbon atom;
R 6 a group having a molecular weight of 1000 or less and directly bonded to a boron atom in the boric acid compound;
or R is 5 Respectively with R 1 Or R is 4 Forming a ring.
As preferable: the R is 1 、R 2 、R 3 、R 4 Respectively selected from alkyl, substituted alkyl, aryl or substituted aryl; wherein the alkyl group is C 1 ～C 20 Alkyl or C 3 ～C 8 Cycloalkyl; the number of substituents for the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more of halogen, nitro, alkoxy, halogenated phenyl, alkylphenyl and heterocyclic independently; the aryl is selected from pyridyl, quinolyl, thiazolyl, thienyl or phenyl; the number of substituents of the substituted aryl is one or more, and the substituents of the substituted aryl are independently selected from halogen, cyano, nitro, alkoxy and C 1 ～C 20 One or more of alkyl and trifluoromethyl;
the R is 5 Selected from hydrogen, C 1 ～C 20 An alkyl group;
the R is 6 Selected from alkenyl, substituted alkenyl, aryl or substituted aryl; the alkenyl group is selected from C 2 ～C 20 Alkenyl or C 3 ～C 8 A cycloalkenyl group; the number of substituents of the substituted alkenyl is one or more, and the substituents of the substituted alkenyl are independently selected from halogen, cyano, nitro and alkoxy、C 1 ～C 20 One or more of alkyl and trifluoromethyl; the aryl is selected from pyridyl, quinolyl, thiazolyl, thienyl or phenyl; the number of substituents of the substituted aryl is one or more, and the substituents of the substituted aryl are independently selected from halogen, cyano, nitro, alkoxy and C 1 ～C 20 One or more of alkyl and trifluoromethyl.
Further:
said R is 1 Selected from phenyl, thienyl; said R is 2 Selected from phenyl, C 1 ～C 6 An alkyl group; the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
said R is 3 Selected from phenyl, thienyl; said R is 4 Selected from phenyl, C 1 ～C 6 An alkyl group; the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
the R is 5 Selected from hydrogen, C 1 ～C 6 An alkyl group; or R is 5 Respectively with R 1 Or R is 4 Forming a ring; the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
said R is 6 Selected from phenyl, trifluoromethyl substituted phenyl, C 1 ～C 6 Alkoxy-substituted phenyl, C 3 ～C 8 Unsaturated cycloalkyl; the C is 1 ～C 6 The alkoxy group is specifically selected from methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy;
as preferable: the On-DNA alpha, beta-unsaturated carbonyl compound is specifically selected from the following components:
the boric acid compound is specifically selected from the following components:
a method for synthesizing On-DNA beta-substituted ketone compound, which comprises the following steps: adding 10-1000 times mole equivalent of boric acid compound and 10-1000 times mole equivalent of alkali into an On-DNA alpha, beta-unsaturated carbonyl compound solution with the molar equivalent of 1 and the molar concentration of 0.5-5mM, adding 0.1-100 times mole equivalent of palladium catalyst, and reacting for 0.1-24 hours at the temperature of 10-100 ℃.
Further, the base is selected from sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU (1, 8-diazabicycloundec-7-ene), 4-dimethylaminopyridine, 2, 6-dimethylpyridine, N-methylimidazole; preferably, the base is cesium hydroxide.
Further, the reaction is carried out in a solvent, wherein the solvent is any one or a plurality of aqueous mixed solvents of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, inorganic salt buffer solution, organic acid buffer solution and organic base buffer solution; preferably, the reaction solvent comprises water, dimethylsulfoxide.
Further, the palladium catalyst of the reaction is Pd 2 (dba) 3 Tetraphenylphosphine palladium, palladium acetate, palladium trifluoroacetate, elemental palladium (palladium black), sps pd-G2; preferably, the palladium catalyst is sSPhos-Pd-G2, palladium acetate or tetraphenylphosphine palladium.
Further, the reaction requires the addition of a ligand in an amount of 0.1 to 100 molar equivalents, the ligand being selected from triphenylphosphine, triaryl-substituted phosphine, tricyclohexylphosphine, trialkyl-substituted phosphine or monoaryl-dialkylphosphine. Preferably, the molar equivalent of the added ligand is 0.5 equivalent, 2 equivalent, 5 equivalent, 10 equivalent, 15 equivalent, 20 equivalent, 30 equivalent, 50 equivalent, 80 equivalent.
Further, the reaction temperature of the reaction is 10-100 ℃; preferably, the reaction temperature is 20 ℃,30 ℃,40 ℃,50 ℃, 60 ℃, 70 ℃,80 ℃,90 ℃,100 ℃.
Further, the reaction time of the reaction is 0.5 to 24 hours; preferably, the reaction time is 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 16 hours, 18 hours, 20 hours.
Further, in the method, the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, the molar equivalent of the boric acid compound is 10-1000, and the molar equivalent of the alkali is 10-1000; preferably, the molar equivalent of the boric acid compound is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalents of the base are 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalent of the palladium catalyst is 0.5 equivalent, 1.5 equivalent, 2.5 equivalent, 3.5 equivalent, 5 equivalent, 10 equivalent, 20 equivalent, 40 equivalent, 80 equivalent; most preferably, the molar equivalent of the boric acid compound is 100, the molar equivalent of the base is 100, and the molar equivalent of the palladium catalyst is 2.5.
Further, the method is used for batch multi-well plate operations.
Further, the method is used for the synthesis of DNA encoding compound libraries in multiwell plates.
The method can obtain On-DNA beta substituted ketone compounds from the On-DNA alpha, beta-unsaturated carbonyl compounds in a DNA coding compound library, can be widely applied to various On-DNA alpha, beta-unsaturated carbonyl substrates, and can introduce various substituted boric acid compounds On a large scale as a synthesis module. The method has single product, can be carried out in a mixed water phase of an organic solvent/water phase, is simple to operate, is environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by prefixes, for example, prefixes (Ca to C b ) Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～C 20 Alkyl refers to straight or branched chain alkyl groups containing 1 to 20 carbon atoms.
Alkyl refers to straight or branched hydrocarbon groups formed by substitution of H in the alkane molecule, e.g. methyl CH 3 -, ethyl CH 3 CH 2 -, methylene-CH 2 -。
Cycloalkyl: refers to saturated or unsaturated cycloalkyl groups formed by substitution of H;
halogen: is fluorine, chlorine, bromine or iodine.
Aromatic group: refers to a group in which part H on the aromatic ring is substituted, such as pyridyl, quinolyl, thiazolyl or phenyl.
An alkoxy group: refers to alkyl groups bound to oxygen atoms to form substituents, e.g. methoxy groups of-OCH 3 。
Halogenated phenyl: refers to a group formed by substituting H on phenyl with halogen.
Alkylphenyl: refers to a group formed by substituting H on phenyl with alkyl.
A heterocyclic group: is a saturated or unsaturated, monocyclic or polycyclic hydrocarbon group of 3 to 8 atoms which carries at least one atom selected from O, S, N.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIGS. 1 and 2 are graphs showing the conversion rate of 32 On-DNA beta-aryl substituted ketones obtained in example 2 of the present invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
In the present invention, "room temperature" means 20 to 25 ℃.
DMA: dimethylacetamide (Dimethylacetamide);
DMSO: dimethyl sulfoxide.
DNA-NH in the present invention 2 Is formed by single-stranded or double-stranded DNA and a linker group and carries-NH 2 DNA structure of linker, e.g. DNA-NH of "component 1" in WO2005058479 2 Structure is as follows. Also for example the following DNA structure:
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
EXAMPLE 1 Synthesis of On-DNA beta-aryl substituted ketones
Step 1, synthesis of On-DNA alpha, beta-unsaturated carbonyl Compound
On-DNA aryl ethanone (A) was dissolved in 250mM boric acid buffer solution (pH=9.4) to prepare a 1mM concentration solution (20. Mu.L, 20 nmol), and benzaldehyde (4000 nmol,200 eq, 200mM DMSO solution), potassium hydroxide (10000 nmol,500 eq, 1000mM H) was added sequentially to the solution 2 O solution), and the mixture was uniformly mixed and reacted at 30 ℃ for 1 hour.
Will be On-DNA aryl aldehyde compound (B) was dissolved in 250mM boric acid buffer solution (pH=9.4) to prepare 1mM concentration solution (20. Mu.L, 20 nmol), acetophenone (2000 nmol,100 eq, 200mM DMSO solution), potassium hydroxide (600 nmol,300 eq, 1000mM H) were added sequentially to the solution 2 O solution), and the mixture was uniformly mixed and reacted at 30 ℃ for 1 hour.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging at low temperature (-4 ℃) at the rotation speed of 12000rpm for half an hour, pouring out supernatant, dissolving the rest precipitate by deionized water to obtain the solution of the On-DNA alpha, beta-unsaturated carbonyl compounds (1, 2), quantifying by an enzyme-labeled instrument OD, and sending LCMS to confirm that the conversion rates of the compounds 1, 2 are 95% and 83% respectively.
Step 2, synthesis of On-DNA beta-aryl substituted ketone Compounds
The On-DNA alpha, beta-unsaturated carbonyl compound (1, 2) was prepared into a 1mM concentration solution (20. Mu.L, 20 nmol) with deionized water, and phenylboronic acid (2000 nmol,100 eq, 200mM DMA solution), cesium hydroxide (2000 nmol,100 eq, 500mM H) were added sequentially to the solution 2 O solution), pd (OAc) 2 (50 nmol,2.5 eq, 10mM DMA solution), PPh 3 (200 nmol,10 equivalents, 50mM DMA solution); uniformly mixing, and reacting for 2 hours at 90 ℃.
After the completion of the reaction, sodium diethyldithiocarbamate (DDTC) (2000 nmol,100 equivalents, 400mM H was added to the reaction system 2 O solution), and the mixture was uniformly mixed at 80 ℃ for 30 minutes. After the reaction is finished, adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, then continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, putting the reaction into dry ice, freezing for 0.5 hour, centrifuging for half an hour at a low temperature (-4 ℃) at a rotating speed of 12000rpm, and pouring out the supernatant, wherein the restDissolving the precipitate with deionized water to obtain solutions of On-DNA beta-aryl substituted ketone compounds (1 a, 2 a), quantifying by an enzyme-labeling instrument OD, and sending LCMS to confirm that the conversion rate of the compounds 1a, 2a is 84% and 81% respectively.
Example 2
According to the method of example 1,8 kinds of alpha, beta-unsaturated carbonyl compounds (1-8 shown in the figure) and 4 kinds of boric acid (a-d shown in the figure) are reacted under the same conditions to obtain 32 kinds of On-DNA beta-aryl substituted ketone compounds, and specific reaction products are shown in the figure.
In summary, the On-DNA alpha, beta-unsaturated carbonyl compounds and boric acid compounds can be reacted to obtain On-DNA beta-substituted ketone compounds by controlling the conditions of solvent, temperature, pH and the like during the reaction. The method has wide substrate application range, can be carried out in a mixed water phase of an organic solvent/water phase, is simple to operate, is environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
Claims (7)
1. A method for synthesizing On-DNA beta substituted ketone compound is characterized in that: the method takes On-DNA alpha, beta unsaturated carbonyl compounds as raw materials, and reacts with boric acid compounds in the presence of palladium acetate and cesium hydroxide to obtain On-DNA beta substituted ketone compounds; wherein the structural formula of the On-DNA alpha, beta unsaturated carbonyl compound is The structural formula of the boric acid compound is as follows: />The structural formula of the On-DNA beta substituted ketone compound is as follows:
wherein the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing an artificially modified and/or unmodified nucleotide monomer, and the nucleotide chain is connected with the rest of the compound through one or more chemical bonds or groups;
the method comprises the following steps: adding 10-1000 times of molar equivalent boric acid compound and 10-1000 times of molar equivalent cesium hydroxide into an On-DNA alpha, beta-unsaturated carbonyl compound solution with molar equivalent of 1 and molar concentration of 0.5-5mM, adding 0.1-100 times of molar equivalent palladium acetate, adding 0.1-100 times of molar equivalent triphenylphosphine, and reacting for 0.1-24 hours at 10-100 ℃;
said R is 1 Selected from phenyl, thienyl or absent;
said R is 2 Selected from phenyl, C 1 ～C 6 An alkyl group; the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
said R is 3 Selected from phenyl, thienyl;
said R is 4 Selected from phenyl, C 1 ～C 6 An alkyl group; the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
the R is 5 Selected from hydrogen, C 1 ～C 6 An alkyl group; or R is 5 Respectively with R 1 Or R is 4 Forming a ring; the C is 1 ～C 6 The alkyl is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexane;
said R is 6 Selected from phenyl, trifluoromethyl substituted phenyl, C 1 ～C 6 Alkoxy-substituted phenyl, C 3 ～C 8 Unsaturated cycloalkyl; the C is 1 ～C 6 The alkoxy group is specifically selected from methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy.
2. The method according to claim 1, characterized in that: the reaction is carried out in a solvent which is any one or a plurality of aqueous mixed solvents of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, inorganic salt buffer solution, organic acid buffer solution and organic alkali buffer solution.
3. The method according to claim 1, characterized in that: the reaction temperature of the reaction was 20 ℃,30 ℃,40 ℃,50 ℃, 60 ℃, 70 ℃,80 ℃,90 ℃,100 ℃.
4. The method according to claim 1, characterized in that: the reaction time of the reaction is 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 16 hours, 18 hours, 20 hours.
5. The method according to claim 1, characterized in that: in the method, the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, and the molar equivalent of the boric acid compound is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents; the molar equivalent of cesium hydroxide is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalent of palladium acetate is 0.5 equivalent, 1.5 equivalent, 2.5 equivalent, 3.5 equivalent, 5 equivalent, 10 equivalent, 20 equivalent, 40 equivalent, 80 equivalent.
6. The method according to any one of claims 1-5, wherein the method is used for batch multi-well plate operations.
7. The method according to any one of claims 1 to 5, wherein the method is used for the synthesis of a library of DNA-encoding compounds of a multiwell plate.
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